Dataset Information

Glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood-gas chemistry while prolonging fentanyl-induced analgesia.

ABSTRACT: There is an urgent need to develop novel compounds that prevent the deleterious effects of opioids such as fentanyl on minute ventilation while, if possible, preserving the analgesic actions of the opioids. We report that L-glutathione ethyl ester (GSHee) may be such a novel compound. In this study, we measured tail flick latency (TFL), arterial blood gas (ABG) chemistry, Alveolar-arterial gradient, and ventilatory parameters by whole body plethysmography to determine the responses elicited by bolus injections of fentanyl (75 μg/kg, IV) in male adult Sprague-Dawley rats that had received a bolus injection of GSHee (100 μmol/kg, IV) 15 min previously. GSHee given alone had minimal effects on TFL, ABG chemistry and A-a gradient whereas it elicited changes in some ventilatory parameters such as an increase in breathing frequency. In vehicle-treated rats, fentanyl elicited (1) an increase in TFL, (2) decreases in pH, pO₂ and sO₂ and increases in pCO₂ (all indicative of ventilatory depression), (3) an increase in Alveolar-arterial gradient (indicative of a mismatch in ventilation-perfusion in the lungs), and (4) changes in ventilatory parameters such as a reduction in tidal volume, that were indicative of pronounced ventilatory depression. In GSHee-pretreated rats, fentanyl elicited a more prolonged analgesia, relatively minor changes in ABG chemistry and Alveolar-arterial gradient, and a substantially milder depression of ventilation. GSHee may represent an effective member of a novel class of thiolester drugs that are able to prevent the ventilatory depressant effects elicited by powerful opioids such as fentanyl and their deleterious effects on gas-exchange in the lungs without compromising opioid analgesia.

SUBMITTER: Jenkins MW

PROVIDER: S-EPMC7997982 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Cell-penetrant thiol esters including the disulfides, D-cystine diethyl ester and D-cystine dimethyl ester, and the monosulfide, L-glutathione ethyl ester, prevent and/or reverse the deleterious effects of opioids, such as morphine and fentanyl, on breathing and gas exchange within the lungs of unanesthetized/unrestrained rats without diminishing the antinociceptive or sedative effects of opioids. We describe here the effects of the monosulfide thiol ester, D-cysteine ethyl ester (D-CYSee), on intravenous morphine-induced changes in ventilatory parameters, arterial blood-gas chemistry, alveolar-arterial (A-a) gradient (i.e., index of gas exchange in the lungs), and sedation and antinociception in freely-moving rats. The bolus injection of morphine (10 mg/kg, IV) elicited deleterious effects on breathing, including depression of tidal volume, minute ventilation, peak inspiratory flow, and inspiratory drive. Subsequent injections of D-CYSee (2 × 500 μmol/kg, IV, given 15 min apart) elicited an immediate and sustained reversal of these effects of morphine. Morphine (10 mg/kg, IV) also A-a gradient, which caused a mismatch in ventilation perfusion within the lungs, and elicited pronounced changes in arterial blood-gas chemistry, including pronounced decreases in arterial blood pH, pO2 and sO2, and equally pronounced increases in pCO2 (all responses indicative of decreased ventilatory drive). These deleterious effects of morphine were immediately reversed by the injection of a single dose of D-CYSee (500 μmol/kg, IV). Importantly, the sedation and antinociception elicited by morphine (10 mg/kg, IV) were minimally affected by D-CYSee (500 μmol/kg, IV). In contrast, none of the effects of morphine were affected by administration of the parent thiol, D-cysteine (1 or 2 doses of 500 μmol/kg, IV). Taken together, these data suggest that D-CYSee may exert its beneficial effects via entry into cells that mediate the deleterious effects of opioids on breathing and gas exchange. Whether D-CYSee acts as a respiratory stimulant or counteracts the inhibitory actions of µ-opioid receptor activation remains to be determined. In conclusion, D-CYSee and related thiol esters may have clinical potential for the reversal of the adverse effects of opioids on breathing and gas exchange, while largely sparing antinociception and sedation.

Project description:Background:The clinical efficacy of fentanyl for pain control differs greatly across individuals. The purpose of this study was to investigate the impact of CYP3A4*1G polymorphism including wild-type homozygote (CYP3A4*1/*1, GG), mutant heterozygote (CYP3A4*1/*1G, GA), and mutant homozygote (CYP3A4*1G/*1G, AA) on fentanyl analgesia in Chinese patients undergoing hysteroscopy by the assessment of analgesia nociception index (ANI). Methods:A total of 200 gynecologic patients scheduled for elective hysteroscopy under general anesthesia at Peking University People's Hospital from May to December in 2017 were enrolled in this study. Venous blood was withdrawn for genotyping of CYP3A4*1G before operation. Fentanyl 1 ?g/kg was administered preoperatively followed by target-controlled infusion of propofol for induction and maintenance. Intraoperative analgesic efficacy of fentanyl was assessed by ANI monitoring at T0 (entering room), T1 (cervical dilation), T2 (start of cervical aspiration), and T3 (end of cervical aspiration) time points. The duration of propofol infusion and total dosage of propofol were recorded as well. Results:The patients were divided into three groups according to CYP3A4*1G polymorphism, including 143 in GG group, 47 in GA group, and 10 in AA group. There was no significant difference in clinical demographics among three groups. The frequency of CYP3A4*1G variant alleles accounted for 16.8% and the distribution of variant alleles was consistent with Hardy-Weinberg equilibrium. Using a multilevel model, ANI values at T1 (63.81 ± 19.61), T2 (63.63 ± 17.82), and T3 (65.68 ± 17.79) were significantly lower than that at T0 (77.16 ± 12.93) in the study population (F = 23.50, P < 0.001), suggesting that higher levels of pain at T1, T2, and T3 than T0. Patients with GG genotype showed significantly lower ANI than those with GA or AA genotypes during hysteroscopy under the same dose of fentanyl. Conclusion:CYP3A4*1G polymorphism associated with the analgesic efficacy of intraoperative fentanyl in the patients undergoing hysteroscopy under general anesthesia.

Project description:BACKGROUND:Although routine administration of pharmacologic sedation or analgesia during mechanical ventilation in preterm neonates is not recommended, its use in clinical practice remains common. Alpha-2 agonists, mainly clonidine and dexmedetomidine, are used as adjunctive (or alternative) sedative agents alongside opioids and benzodiazepines. Clonidine has not been systematically assessed for use in neonatal sedation during ventilation. OBJECTIVES:To assess whether clonidine administered to term and preterm newborn infants receiving mechanical ventilation reduces morbidity and mortality rates. To compare the intervention versus placebo, no treatment, and dexmedetomidine; and to assess the safety of clonidine infusion for potential harms.To perform subgroup analyses according to gestational age; birth weight; administration method (infusion or bolus therapy); dose, duration, and route of clonidine administration; and pharmacologic sedation as a co-intervention. SEARCH METHODS:We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 12) in the Cochrane Library, MEDLINE via PubMed (1966 to January 10, 2017), Embase (1980 to January 10, 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to January 10, 2017). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. SELECTION CRITERIA:We searched for randomized controlled trials, quasi-randomized controlled trials, and cluster trials comparing clonidine versus placebo, no treatment, or dexmedetomidine administered to term and preterm newborns receiving mechanical ventilation via an endotracheal tube. DATA COLLECTION AND ANALYSIS:For the included trial, two review authors independently extracted data (e.g. number of participants, birth weight, gestational age, all-cause death during initial hospitalization, duration of respiratory support, sedation scale, duration of hospital stay) and assessed risk of bias (e.g. adequacy of randomization, blinding, completeness of follow-up). This review considered primary outcomes of all-cause neonatal death, all-cause death during initial hospitalization, and duration of mechanical ventilation in days. MAIN RESULTS:One trial, which included 112 infants, met the inclusion criteria for this review. Term newborn infants on mechanical ventilation with the need for continuous analgesia and sedation with fentanyl and midazolam were eligible for enrollment during the first 96 hours of ventilation. Study authors administered clonidine 1 ?g/kg/h or placebo on day 4 after intubation.We found no differences between the two groups in all-cause death during hospitalization (risk ratio [RR] 0.69, 95% confidence interval [CI] 0.12 to 3.98). The quality of the evidence supporting these findings is low owing to imprecision of the estimates (one study; few events). The median (interquartile range) duration of mechanical ventilation was 7.1 days (5.7 to 9.1 days) in the clonidine group and 5.8 days (4.9 to 7.9 days) in the placebo group, respectively (P = 0.070). Among secondary outcomes, we found no differences in terms of duration of stay in the intensive care unit. Sedation scale values (COMFORT) and analgesia scores (Hartwig) during the first 72 hours of infusion of study medication were lower in the clonidine group than in the placebo group. AUTHORS' CONCLUSIONS:At present, evidence is insufficient to show the efficacy and safety of clonidine for sedation and analgesia in term and preterm newborn infants receiving mechanical ventilation.

Dataset Information

Glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood-gas chemistry while prolonging fentanyl-induced analgesia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets