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2.
N Engl J Med ; 384(9): 818-828, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33657294

RESUMO

BACKGROUND: The vasoconstrictor terlipressin is used for type 1 hepatorenal syndrome (HRS-1) in many parts of the world and is part of the clinical practice guidelines in Europe. METHODS: We conducted a phase 3 trial to confirm the efficacy and safety of terlipressin plus albumin in adults with HRS-1. The patients were randomly assigned in a 2:1 ratio to receive terlipressin or placebo for up to 14 days; in both groups, concomitant use of albumin was strongly recommended. The primary end point was verified reversal of HRS, defined as two consecutive serum creatinine measurements of 1.5 mg per deciliter or less at least 2 hours apart and survival without renal-replacement therapy for at least 10 days after the completion of treatment. Four prespecified secondary end points were analyzed with the Hochberg procedure to account for multiple comparisons. RESULTS: A total of 300 patients underwent randomization - 199 were assigned to the terlipressin group and 101 to the placebo group. Verified reversal of HRS was reported in 63 patients (32%) in the terlipressin group and 17 patients (17%) in the placebo group (P = 0.006). With respect to the prespecified secondary end points, HRS reversal, defined as any serum creatinine level of 1.5 mg per deciliter or less during the first 14 days, was reported in 78 patients (39%) in the terlipressin group and 18 (18%) in the placebo group (P<0.001); HRS reversal without renal-replacement therapy by day 30, in 68 (34%) and 17 (17%), respectively (P = 0.001); HRS reversal among patients with systemic inflammatory response syndrome (84 patients in the terlipressin group and 48 patients in the placebo group), in 31 (37%) and 3 (6%), respectively (P<0.001); and verified reversal of HRS without recurrence by day 30, in 52 (26%) and 17 (17%), respectively (P = 0.08). At day 90, liver transplantations had been performed in 46 patients (23%) in the terlipressin group and 29 patients (29%) in the placebo group, and death occurred in 101 (51%) and 45 (45%), respectively. More adverse events, including abdominal pain, nausea, diarrhea, and respiratory failure, occurred with terlipressin than with placebo. Death within 90 days due to respiratory disorders occurred in 22 patients (11%) in the terlipressin group and 2 patients (2%) in the placebo group. CONCLUSIONS: In this trial involving adults with cirrhosis and HRS-1, terlipressin was more effective than placebo in improving renal function but was associated with serious adverse events, including respiratory failure. (Funded by Mallinckrodt Pharmaceuticals; CONFIRM ClinicalTrials.gov number, NCT02770716.).


Assuntos
Síndrome Hepatorrenal/tratamento farmacológico , Terlipressina/uso terapêutico , Vasoconstritores/uso terapêutico , Albuminas/uso terapêutico , Terapia Combinada , Método Duplo-Cego , Feminino , Síndrome Hepatorrenal/etiologia , Síndrome Hepatorrenal/mortalidade , Humanos , Infusões Intravenosas , Cirrose Hepática/complicações , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Terapia de Substituição Renal , Insuficiência Respiratória/induzido quimicamente , Terlipressina/efeitos adversos , Resultado do Tratamento , Vasoconstritores/efeitos adversos
3.
Rinsho Ketsueki ; 62(1): 30-34, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33551422

RESUMO

From December 2019, a 71-year-old male underwent three cycles of a combination therapy of pomalidomide, bortezomib, and dexamethasone for relapsed multiple myeloma and a very good partial response was achieved. In March 2020, he developed a fever of 38.9°C and computed tomography revealed bilateral ground-glass opacities. Antibiotic therapy was ineffective. Bronchoscopy was performed and bortezomib-induced lung injury was initially suspected. Due to respiratory exacerbation, high-dose steroid therapy was administered, which resulted in a dramatic improvement of the patient's respiratory failure. Thereafter, reverse transcription polymerase chain reaction performed on a preserved bronchial lavage sample tested positive, and thus his diagnosis was corrected to COVID-19 pneumonia. It is difficult to discriminate COVID-19 pneumonia from drug-induced lung disease, as both disorders can present similar ground-glass opacities on computed tomography. Therefore, with this presented case, we summarize our experience with steroid therapy for COVID-19 associated respiratory distress at our institution.


Assuntos
Bortezomib/efeitos adversos , Lesão Pulmonar , Insuficiência Respiratória , Idoso , Humanos , Lesão Pulmonar/induzido quimicamente , Masculino , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/diagnóstico , Esteroides
5.
Br J Cancer ; 124(7): 1183, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33398065

RESUMO

The use of granulocyte colony-stimulating factor (G-CSF) in patients with haematological malignancies is associated with less febrile neutropenia episodes. But in the presence of COVID-19 infection, the administration of G-CSF is challenging as it may trigger a robust inflammatory reaction resulting in cytokine storm, respiratory failure and severe outcomes.


Assuntos
/epidemiologia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , /complicações , Síndrome da Liberação de Citocina/induzido quimicamente , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Neoplasias Hematológicas/complicações , Humanos , Prognóstico , Insuficiência Respiratória/induzido quimicamente , /isolamento & purificação
7.
Emerg Med Clin North Am ; 38(4): 841-856, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32981621
9.
Anesth Analg ; 131(4): 1012-1024, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32925318

RESUMO

BACKGROUND: Opioid-related adverse events are a serious problem in hospitalized patients. Little is known about patients who are likely to experience opioid-induced respiratory depression events on the general care floor and may benefit from improved monitoring and early intervention. The trial objective was to derive and validate a risk prediction tool for respiratory depression in patients receiving opioids, as detected by continuous pulse oximetry and capnography monitoring. METHODS: PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) was a prospective, observational trial of blinded continuous capnography and oximetry conducted at 16 sites in the United States, Europe, and Asia. Vital signs were intermittently monitored per standard of care. A total of 1335 patients receiving parenteral opioids and continuously monitored on the general care floor were included in the analysis. A respiratory depression episode was defined as respiratory rate ≤5 breaths/min (bpm), oxygen saturation ≤85%, or end-tidal carbon dioxide ≤15 or ≥60 mm Hg for ≥3 minutes; apnea episode lasting >30 seconds; or any respiratory opioid-related adverse event. A risk prediction tool was derived using a multivariable logistic regression model of 46 a priori defined risk factors with stepwise selection and was internally validated by bootstrapping. RESULTS: One or more respiratory depression episodes were detected in 614 (46%) of 1335 general care floor patients (43% male; mean age, 58 ± 14 years) continuously monitored for a median of 24 hours (interquartile range [IQR], 17-26). A multivariable respiratory depression prediction model with area under the curve of 0.740 was developed using 5 independent variables: age ≥60 (in decades), sex, opioid naivety, sleep disorders, and chronic heart failure. The PRODIGY risk prediction tool showed significant separation between patients with and without respiratory depression (P < .001) and an odds ratio of 6.07 (95% confidence interval [CI], 4.44-8.30; P < .001) between the high- and low-risk groups. Compared to patients without respiratory depression episodes, mean hospital length of stay was 3 days longer in patients with ≥1 respiratory depression episode (10.5 ± 10.8 vs 7.7 ± 7.8 days; P < .0001) identified using continuous oximetry and capnography monitoring. CONCLUSIONS: A PRODIGY risk prediction model, derived from continuous oximetry and capnography, accurately predicts respiratory depression episodes in patients receiving opioids on the general care floor. Implementation of the PRODIGY score to determine the need for continuous monitoring may be a first step to reduce the incidence and consequences of respiratory compromise in patients receiving opioids on the general care floor.


Assuntos
Analgésicos Opioides/efeitos adversos , Capnografia/métodos , Oximetria/métodos , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Feminino , Humanos , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Monitorização Fisiológica , Valor Preditivo dos Testes , Estudos Prospectivos , Taxa Respiratória , Fatores de Risco
10.
Anesthesiology ; 133(3): 559-568, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32788558

RESUMO

BACKGROUND: To improve understanding of the respiratory behavior of oliceridine, a µ-opioid receptor agonist that selectively engages the G-protein-coupled signaling pathway with reduced activation of the ß-arrestin pathway, the authors compared its utility function with that of morphine. It was hypothesized that at equianalgesia, oliceridine will produce less respiratory depression than morphine and that this is reflected in a superior utility. METHODS: Data from a previous trial that compared the respiratory and analgesic effects of oliceridine and morphine in healthy male volunteers (n = 30) were reanalyzed. A population pharmacokinetic-pharmacodynamic analysis was performed and served as basis for construction of utility functions, which are objective functions of probability of analgesia, P(analgesia), and probability of respiratory depression, P(respiratory depression). The utility function = P(analgesia ≥ 0.5) - P(respiratory depression ≥ 0.25), where analgesia ≥ 0.5 is the increase in hand withdrawal latency in the cold pressor test by at least 50%, and respiratory depression ≥ 0.25 is the decrease of the hypercapnic ventilatory response by at least 25%. Values are median ± standard error of the estimate. RESULTS: The two drugs were equianalgesic with similar potency values (oliceridine: 27.9 ± 4.9 ng/ml; morphine 34.3 ± 9.7 ng/ml; potency ratio, 0.81; 95% CI, 0.39 to 1.56). A 50% reduction of the hypercapnic ventilatory response by morphine occurred at an effect-site concentration of 33.7 ± 4.8 ng/ml, while a 25% reduction by oliceridine occurred at 27.4 ± 3.5 ng/ml (potency ratio, 2.48; 95% CI, 1.65 to 3.72; P < 0.01). Over the clinically relevant concentration range of 0 to 35 ng/ml, the oliceridine utility function was positive, indicating that the probability of analgesia exceeds the probability of respiratory depression. In contrast, the morphine function was negative, indicative of a greater probability of respiratory depression than analgesia. CONCLUSIONS: These data indicate a favorable oliceridine safety profile over morphine when considering analgesia and respiratory depression over the clinical concentration range.


Assuntos
Analgésicos Opioides/farmacologia , Morfina/farmacologia , Insuficiência Respiratória/induzido quimicamente , Compostos de Espiro/farmacologia , Tiofenos/farmacologia , Adulto , Analgésicos Opioides/efeitos adversos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/efeitos adversos , Valores de Referência , Medição de Risco , Compostos de Espiro/efeitos adversos , Tiofenos/efeitos adversos , Adulto Jovem
13.
Subst Use Misuse ; 55(11): 1900-1901, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32657207

RESUMO

BACKGROUND: Alarms have been raised that COVID-19 may disproportionately affect certain populations with substance use disorders, particularly Opioid Use Disorder (OUD), however warnings have largely focused on social risks such as reduced availability of services. Objectives: This commentary highlights three plausible biological mechanisms for potentially worsened outcomes in patients with OUD who contract COVID-19. Results: Opioid-related respiratory depression may amplify risks of hypoxemia from COVID-19 viral pneumonia. Complex opioid immune modulation may impact host response to COVID-19, though the effect direction and clinical significance are unclear. Drug-drug interactions may affect individuals with OUD who are co-administered medications for OUD and medications for COVID-19, particularly due to cardiac adverse effects. Conclusions/Importance: There are plausible biological mechanisms for potentially worsened outcomes in patients with OUD who contract COVID-19; these mechanisms require further study, and should be considered in individuals with OUD.


Assuntos
Analgésicos Opioides/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Infecções por Coronavirus/complicações , Hospedeiro Imunocomprometido/imunologia , Transtornos Relacionados ao Uso de Opioides/complicações , Pneumonia Viral/complicações , Insuficiência Respiratória/induzido quimicamente , Imunidade Adaptativa/imunologia , Analgésicos Opioides/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Interações Medicamentosas , Humanos , Imunidade Inata/imunologia , Metadona/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/imunologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Prognóstico , Insuficiência Respiratória/fisiopatologia
14.
Br J Anaesth ; 125(3): 358-372, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32660719

RESUMO

BACKGROUND: Intrathecal hydrophilic opioids decrease systemic opioid consumption after abdominal surgery and potentially facilitate enhanced recovery. A meta-analysis is needed to quantify associated risks and benefits. METHODS: A systematic search was performed to find RCTs investigating intrathecal hydrophilic opioids in abdominal surgery. Caesarean section and continuous regional or neuraxial techniques were excluded. Several subgroup analyses were prespecified. A conventional meta-analysis, meta-regression, trial sequential analysis, and provision of GRADE scores were planned. RESULTS: The search yielded 40 trials consisting of 2500 patients. A difference was detected in 'i.v. morphine consumption' at Day 1 {mean difference [MD] -18.4 mg, (95% confidence interval [CI]: -22.3 to -14.4)} and Day 2 (MD -25.5 mg [95% CI: -30.2 to -20.8]), pain scores at Day 1 in rest (MD -0.9 [95% CI: -1.1 to -0.7]) and during movement (MD -1.2 [95% CI: -1.6 to -0.8]), length of stay (MD -0.2 days [95% CI: -0.4 to -0.1]) and pruritus (relative risk 4.3 [95% CI: 2.5-7.5]) but not in nausea or sedation. A difference was detected for respiratory depression (odds ratio 5.5 [95% CI: 2.1-14.2]) but not when two small outlying studies were excluded (odds ratio 1.4 [95% CI: 0.4-5.2]). The level of evidence was graded as high for morphine consumption, in part because the required information size was reached. CONCLUSIONS: This study showed important opioid-sparing effects of intrathecal hydrophilic opioids. Our data suggest a dose-dependent relationship between the risk of respiratory depression and the dose of intrathecal opioids. Excluding two high-dose studies, intrathecal opioids have a comparable incidence of respiratory depression as the control group. CLINICAL TRIAL REGISTRATION: PROSPERO-registry: CRD42018090682.


Assuntos
Abdome/cirurgia , Analgesia Epidural/métodos , Analgésicos Opioides/uso terapêutico , Analgésicos Opioides/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Gravidez , Insuficiência Respiratória/induzido quimicamente
15.
Clin Drug Investig ; 40(8): 755-764, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32583295

RESUMO

BACKGROUND AND OBJECTIVE: Opioid-induced respiratory depression (OIRD) is a potentially fatal complication associated with conventional opioids. Currently, there is a paucity of validated endpoints available to measure respiratory safety. Oliceridine, an investigational intravenous (IV) opioid, is a G-protein selective µ-agonist with limited activity on ß-arrestin2, a signaling pathway associated with adverse events including OIRD. In controlled phase III trials, oliceridine 0.35 mg and 0.5 mg demand doses demonstrated comparable analgesia to morphine 1 mg with favorable improvements in respiratory safety. In this exploratory analysis, we report dosing interruption (DI) and average cumulative duration of DI (CDDI) for both oliceridine and morphine. METHODS: Patients requiring analgesia after bunionectomy or abdominoplasty were randomized to IV demand doses of placebo, oliceridine (0.1 mg, 0.35 mg, or 0.5 mg), or morphine (1 mg), administered via patient-controlled analgesia (PCA), following a loading dose (oliceridine 1.5 mg, morphine 4 mg, volume-matched placebo) with a 6-min lockout interval. Certified nurse anesthetists monitored each patient and withheld study medication according to the patient's respiratory status. For each patient, the duration of all DIs was summed and reported as CDDI. A zero-inflated gamma mixture model was used to compute the mean CDDI for each treatment. RESULTS: Proportion of patients with DI was lower with oliceridine (0.1 mg: 3.2%, 0.35 mg: 13.9%, 0.5 mg: 15.1%) versus morphine (22%). The CDDI was also lower across all demand doses of oliceridine versus morphine. CONCLUSION: Using DI as a surrogate for OIRD indicates improved respiratory safety with oliceridine versus morphine that merits further investigation.


Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos Opioides/efeitos adversos , Morfina/efeitos adversos , Dor Pós-Operatória/tratamento farmacológico , Insuficiência Respiratória/induzido quimicamente , Compostos de Espiro/efeitos adversos , Tiofenos/efeitos adversos , Adulto , Analgesia Controlada pelo Paciente , Analgésicos Opioides/administração & dosagem , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Manejo da Dor , Medição da Dor , Insuficiência Respiratória/tratamento farmacológico , Compostos de Espiro/administração & dosagem , Tiofenos/administração & dosagem
17.
Anesthesiology ; 132(5): 1197-1211, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32294065

RESUMO

BACKGROUND: Opioids can induce significant respiratory depression when administered as analgesics for the treatment of acute, postoperative, and chronic pain. There are currently no pharmacologic means of reversing opioid-induced respiratory depression without interfering with analgesia. Further, there is a growing epidemic of opioid overdose that could benefit from therapeutic advancements. The aim of this study was to test the ability of two partial agonists of α4ß2 nicotinic acetylcholine receptors, varenicline (used clinically for smoking cessation) and ABT 594 (tebanicline, developed as an analgesic), to reduce respiratory depression induced by fentanyl, remifentanil, morphine, and a combination of fentanyl and diazepam. METHODS: Whole body plethysmographic recordings, nociception testing, and righting reflex testing were used to examine ventilation, analgesia, and sedation in adult male Sprague-Dawley rats. RESULTS: Pre-, co-, or postadministration of varenicline or ABT 594 did not alter baseline breathing but markedly reduced opioid-induced respiratory depression. Varenicline had no effect on fentanyl-induced analgesia and ABT 594 potentiated fentanyl-induced analgesia. Specifically, 10-min administration of fentanyl induced a decrease in respiratory rate to 43 ± 32% of control in vehicle group, which was alleviated by preadministration of varenicline (85 ± 14% of control, n = 8, P < 0.001) or ABT 594 (81 ± 36% of control, n = 8, P = 0.001). ABT 594 or varenicline with a low dose of naloxone (1 µg/kg), but not varenicline alone, partially reversed fentanyl-induced lethal apnea, but neither compound provided the very rapid and complete reversal of apnea achieved with high doses of naloxone (0.03 to 1 mg/kg). Administration of varenicline (n = 4, P = 0.034) or ABT 594 (n = 4, P = 0.034) prevented lethal apneas induced by the combination of fentanyl and diazepam. CONCLUSIONS: Activation of α4ß2 nicotinic acetylcholine receptors by varenicline and ABT 594 counters opioid-induced respiratory depression without interfering with analgesia.


Assuntos
Analgésicos Opioides/toxicidade , Azetidinas/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Piridinas/administração & dosagem , Receptores Nicotínicos/fisiologia , Insuficiência Respiratória/prevenção & controle , Vareniclina/administração & dosagem , Animais , Agonismo Parcial de Drogas , Masculino , Ratos , Ratos Sprague-Dawley , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/fisiopatologia
18.
Anesth Analg ; 130(5): 1147-1156, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32287122

RESUMO

BACKGROUND: Opioid-induced respiratory depression (OIRD) is traditionally recognized by assessment of respiratory rate, arterial oxygen saturation, end-tidal CO2, and mental status. Although an irregular or ataxic breathing pattern is widely recognized as a manifestation of opioid effects, there is no standardized method for assessing ataxic breathing severity. The purpose of this study was to explore using a machine-learning algorithm for quantifying the severity of opioid-induced ataxic breathing. We hypothesized that domain experts would have high interrater agreement with each other and that a machine-learning algorithm would have high interrater agreement with the domain experts for ataxic breathing severity assessment. METHODS: We administered target-controlled infusions of propofol and remifentanil to 26 healthy volunteers to simulate light sleep and OIRD. Respiration data were collected from respiratory inductance plethysmography (RIP) bands and an intranasal pressure transducer. Three domain experts quantified the severity of ataxic breathing in accordance with a visual scoring template. The Krippendorff alpha, which reports the extent of interrater agreement among N raters, was used to assess agreement among the 3 domain experts. A multiclass support vector machine (SVM) was trained on a subset of the domain expert-labeled data and then used to quantify ataxic breathing severity on the remaining data. The Vanbelle kappa was used to assess the interrater agreement of the machine-learning algorithm with the grouped domain experts. The Vanbelle kappa expands on the Krippendorff alpha by isolating a single rater-in this case, the machine-learning algorithm-and comparing it to a group of raters. Acceptance criteria for both statistical measures were set at >0.8. The SVM was trained and tested using 2 sensor inputs for the breath marks: RIP and intranasal pressure. RESULTS: Krippendorff alpha was 0.93 (95% confidence interval [CI], 0.91-0.95) for the 3 domain experts. Vanbelle kappa was 0.98 (95% CI, 0.96-0.99) for the RIP SVM and 0.96 (0.92-0.98) for the intranasal pressure SVM compared to the domain experts. CONCLUSIONS: We concluded it may be feasible for a machine-learning algorithm to quantify ataxic breathing severity in a manner consistent with a panel of domain experts. This methodology may be helpful in conjunction with traditional measures to identify patients experiencing OIRD.


Assuntos
Algoritmos , Analgésicos Opioides/efeitos adversos , Aprendizado de Máquina , Insuficiência Respiratória/induzido quimicamente , Taxa Respiratória/efeitos dos fármacos , Índice de Gravidade de Doença , Adulto , Analgésicos Opioides/administração & dosagem , Feminino , Humanos , Masculino , Insuficiência Respiratória/fisiopatologia , Taxa Respiratória/fisiologia
19.
Br J Anaesth ; 125(1): e140-e147, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32241547

RESUMO

BACKGROUND: We hypothesised that Calabadion 1, an acyclic cucurbit[n]uril molecular container, reverses fentanyl-induced respiratory depression and dysfunction of the CNS. METHODS: Experiments were conducted in male Sprague-Dawley rats. A constant-rate i.v. infusion of fentanyl (12.5 or 25 µg kg-1 over 15 min) was administered followed by an i.v. bolus of Calabadion 1 (0.5-200 mg kg-1) or placebo. The primary outcome was reversal of ventilatory and respiratory depression, assessed by pneumotachography and arterial blood gas analysis, respectively. Key secondary outcomes were effects on fentanyl-induced central nervous dysfunction quantified by righting reflex, balance beam test, and electromyography (EMG). RESULTS: Calabadion 1 reversed fentanyl-induced respiratory depression across the endpoints minute ventilation, pH, and Paco2 (P=0.001). Compared with placebo, Calabadion 1 dose dependently (P for trend <0.001) reversed fentanyl-induced hypoventilation {81.9 [5.1] (mean [standard error of the mean]) vs 45.5 [12.4] ml min-1; P<0.001}, acidosis (pH 7.43 [0.01] vs 7.28 [0.04]; P=0.005), and hypercarbia (Paco2 43.4 [1.6] vs 63.4 [8.1] mm Hg; P=0.018). The effective Calabadion 1 doses required to reverse respiratory depression by 50% and 90% (ED50Res and ED90Res) were 1.7 and 15.6 mg kg-1, respectively. Higher effective doses were needed for recovery of righting reflex (ED50CNS: 9.6 mg kg-1; ED90CNS: 86.1 mg kg-1), which was accelerated by Calabadion 1 (4.6 [0.3] vs 9.0 [0.7] min; P<0.001). Calabadion 1 also significantly accelerated recovery of full functional mobility and reversal of muscle rigidity. CONCLUSIONS: Calabadion 1 selectively and dose dependently reversed the respiratory system and CNS side-effects of fentanyl.


Assuntos
Analgésicos Opioides/efeitos adversos , Fentanila/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/prevenção & controle , Ácidos Sulfônicos/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley
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