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1.
Artigo em Inglês | MEDLINE | ID: mdl-38895976

RESUMO

BACKGROUND: The use of intranasal dexmedetomidine is hampered by a limited understanding of its absorption pharmacokinetics. METHODS: We examined the pharmacokinetics and feasibility of intranasal dexmedetomidine administered in the supine position to adult patients undergoing general anaesthesia. Twenty-eight patients between 35 and 80 years of age, ASA 1-3 and weight between 50 and 100 kg, who underwent elective unilateral total hip or knee arthroplasty under general anaesthesia were recruited. All patients received 100 µg of intranasal dexmedetomidine after anaesthesia induction. Six venous blood samples (at 0, 5, 15, 45, 60, 240 min timepoints from dexmedetomidine administration) were collected from each patient and dexmedetomidine plasma concentrations were measured. Concentration-time profiles after nasal administration were pooled with earlier data from a population analysis of intravenous dexmedetomidine (n = 202) in order to estimate absorption parameters using nonlinear mixed effects. Peak concentration (CMAX) and time (TMAX) were estimated using simulation (n = 1000) with parameter estimates and their associated variability. RESULTS: There were 28 adult patients with a mean (SD) age of 66 (8) years and weight of 83 (10) kg. The mean weight-adjusted dose of dexmedetomidine was 1.22 (0.15) µg kg-1. CMAX 0.273 µg L-1 was achieved at 98 min after intranasal administration (TMAX). The relative bioavailability of dexmedetomidine was 80% (95% CI 75-91%). The absorption half-time (TABS = 120 min; 95% CI 90-147 min) was slower than that in previous pharmacokinetic studies on adult patients. Perioperative haemodynamics of all patients remained stable. CONCLUSIONS: Administration of intranasal dexmedetomidine in the supine position during general anaesthesia is feasible with good bioavailability. This administration method has slower absorption when compared to awake patients in upright position, with consequent concentrations attained after TMAX for several hours.

2.
J Arthroplasty ; 36(3): 978-985.e1, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33046329

RESUMO

BACKGROUND: Total knee arthroplasty (TKA) causes severe pain, and strong opioids are commonly used in postoperative analgesia. Dexmedetomidine is a novel alpha-2-adrenoceptor-activating drug indicated for procedural sedation, but previous studies have shown clinically relevant analgesic and antiemetic effects. We evaluated retrospectively the effect of intranasal dexmedetomidine on the postoperative opioid requirement in patients undergoing TKA. METHODS: One hundred and fifty patients with ASA status 1-2, age between 35 and 80 years, and scheduled for unilateral primary TKA under total intravenous anesthesia were included in the study. Half of the patients received 100 µg of intranasal dexmedetomidine after anesthesia induction, while the rest were treated conventionally. The postoperative opioid requirement was calculated as morphine equivalent doses for both groups. The effect of dexmedetomidine on postoperative hemodynamics, length of stay (LOS), and incidence of postoperative nausea and vomiting (PONV), was evaluated. RESULTS: The cumulative postoperative opioid consumption was significantly reduced in the dexmedetomidine group compared to the control group (-28.5 mg, 95% CI 12-47 mg P < .001). The reduction in cumulative opioid dose was significantly different between the groups already at 2, 12, 24, and 36 h postoperatively (P < .001). LOS was shorter in the dexmedetomidine group (P < .001), and the dexmedetomidine group had lower postoperative mean arterial pressure and heart rates were lower compared to the control group (P < .001). The incidence of PONV did not differ between the groups (P = .64). CONCLUSION: Intraoperatively administered intranasal dexmedetomidine reduces postoperative opioid consumption and may be associated with a shorter hospital stay in patients undergoing TKA under general anesthesia.


Assuntos
Artroplastia do Joelho , Dexmedetomidina , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgesia Controlada pelo Paciente , Analgésicos Opioides , Anestesia Geral , Artroplastia do Joelho/efeitos adversos , Método Duplo-Cego , Humanos , Pessoa de Meia-Idade , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/epidemiologia , Dor Pós-Operatória/prevenção & controle , Estudos Retrospectivos
3.
Anesth Analg ; 130(4): 949-957, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31206433

RESUMO

BACKGROUND: Our aim was to characterize the pharmacokinetics and sedative effects of intranasally (IN) administered dexmedetomidine used as an adjuvant in pediatric patients scheduled for magnetic resonance imaging (MRI) requiring sedation. METHODS: This was an open-label, single-period study without randomization. Pediatric patients from 5 months to 11 years of age scheduled for MRI and receiving IN dexmedetomidine for premedication as part of their care were included in this clinical trial. Single doses of 2-3 µg·kg of dexmedetomidine were applied IN approximately 1 hour before MRI. Five or 6 venous blood samples were collected over 4 hours for dexmedetomidine concentration analysis. Sedation was monitored with Comfort-B scores, and vital signs were recorded. Pharmacokinetic variables were calculated with noncompartmental methods and compared between 3 age groups (between 1 and 24 months, from 24 months to 6 years, and over 6-11 years). RESULTS: We evaluated 187 consecutive patients for suitability, of which 132 were excluded. Remaining 55 patients were recruited, of which 5 were excluded before the analysis. Data from 50 patients were analyzed. The average (standard deviation [SD]) dose-corrected peak plasma concentration (Cmax) was 0.011 liter (0.0051), and the median (interquartile range [IQR]) time to reach peak concentration (tmax) was 37 minutes (30-45 minutes). There was negative correlation with Cmax versus age (r = -0.58; 95% confidence interval [CI], -0.74 to -0.37; P < .001), but not with tmax (r = -0.14; 95% CI, 0.14-0.39; P = .35). Dose-corrected areas under the concentration-time curve were negatively correlated with age (r = -0.53; 95% CI, 0.70 to -0.29; P < .001). Median (IQR) maximal reduction in Comfort-B sedation scores was 8 (6-9), which was achieved 45 minutes (40-48 minutes) after dosing. Median (IQR) decrease in heart rate was 15% (9%-23%) from the baseline. CONCLUSIONS: Dexmedetomidine is relatively rapidly absorbed after IN administration and provides clinically meaningful but short-lasting sedation in pediatric patients.


Assuntos
Procedimentos Cirúrgicos Ambulatórios/métodos , Sedação Consciente/métodos , Dexmedetomidina/farmacologia , Dexmedetomidina/farmacocinética , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/farmacocinética , Administração Intranasal , Fatores Etários , Criança , Pré-Escolar , Dexmedetomidina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipnóticos e Sedativos/administração & dosagem , Lactente , Imageamento por Ressonância Magnética/métodos , Masculino , Oxigênio/sangue , Conforto do Paciente
4.
Acta Anaesthesiol Scand ; 64(9): 1278-1286, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32609878

RESUMO

BACKGROUND: Cerebral autoregulation is often impaired after aneurysmal subarachnoid haemorrhage (aSAH). Dexmedetomidine is being increasingly used, but its effects on cerebral autoregulation in patients with aSAH have not been studied before. Dexmedetomidine could be a useful sedative in patients with aSAH as it enables neurological assessment during the infusion. The aim of this preliminary study was to compare the effects of dexmedetomidine on dynamic and static cerebral autoregulation with propofol and/or midazolam in patients with aSAH. METHODS: Ten patients were recruited. Dynamic and static cerebral autoregulation were assessed using transcranial Doppler ultrasound during propofol and/or midazolam infusion and then during three increasing doses of dexmedetomidine infusion (0.7, 1.0 and 1.4 µg/kg/h). Transient hyperaemic response ratio (THRR) and strength of autoregulation (SA) were calculated to assess dynamic cerebral autoregulation. Static rate of autoregulation (sRoR)% was calculated by using noradrenaline infusion to increase the mean arterial pressure 20 mm Hg above the baseline. RESULTS: Data from nine patients were analysed. Compared to baseline, we found no statistically significant changes in THRR or sROR%. THRR was (mean ± SD) 1.20 ± 0.14, 1.17 ± 0.13 (P = .93), 1.14 ± 0.09 (P = .72) and 1.19 ± 0.18 (P = 1.0) and sROR% was 150.89 ± 84.37, 75.22 ± 27.75 (P = .08), 128.25 ± 58.35 (P = .84) and 104.82 ± 36.92 (P = .42) at baseline and during 0.7, 1.0 and 1.4 µg/kg/h dexmedetomidine infusion, respectively. Dynamic SA was significantly reduced after 1.0 µg/kg/h dexmedetomidine (P = .02). CONCLUSIONS: Compared to propofol and/or midazolam, dexmedetomidine did not alter static cerebral autoregulation in aSAH patients, whereas a significant change was observed in dynamic SA. Further and larger studies with dexmedetomidine in aSAH patients are warranted.


Assuntos
Dexmedetomidina , Propofol , Hemorragia Subaracnóidea , Circulação Cerebrovascular , Homeostase , Humanos , Midazolam
5.
BMC Anesthesiol ; 19(1): 22, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760215

RESUMO

BACKGROUND: Barbiturates are commonly used in ambulatory sedation of pediatric patients. However, use of barbiturates involve risks of respiratory complications. Dexmedetomidine, a highly selective α2-adrenoceptor agonist, is increasingly used for pediatric sedation. Premedication with intranasal (IN) dexmedetomidine offers a non-invasive and efficient possibility to sedate pediatric patients undergoing magnetic resonance imaging (MRI). Our hypothesis was that dexmedetomidine would reduce barbiturate requirements in procedural sedation. METHODS: We included 200 consecutive pediatric patients undergoing MRI, and analyzed their hospital records retrospectively. Half of the patients received 3 µg/kg of IN dexmedetomidine (DEX group) 45-60 min before MRI while the rest received only thiopental (THIO group) for procedural sedation. Sedation was maintained with further intravenous thiopental dosing as needed. Thiopental consumption, heart rate (HR) and peripheral oxygen saturation were recorded. RESULTS: The cumulative thiopental requirement during MRI was (median and interquartile range [IQR]) 4.4 (2.7-6.0) mg/kg/h in the DEX group and 12.4 (9.8-14.8) mg/kg/h in the THIO group (difference 7.9 mg/kg/h, 95% CI 6.8-8.8, P <  0.001). Lowest measured peripheral oxygen saturation remained slightly higher in the DEX group compared to the THIO group (median nadirs and IQR: 97 (95-97) % and 96 (94-97) %, P <  0.001). Supplemental oxygen was delivered to 33% of the patients in the THIO group compared to 2% in the DEX group (P <  0.001). The lowest measured HR (mean and SD) was lower (78 (16) bpm) in the DEX group compared to the THIO group (92 (12) bpm) (P <  0.001). CONCLUSION: Premedication with IN dexmedetomidine (3 µg/kg) was associated with markedly reduced thiopental dosage needed for efficient procedural sedation for pediatric MRI.


Assuntos
Dexmedetomidina/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Imageamento por Ressonância Magnética/métodos , Pré-Medicação/métodos , Tiopental/administração & dosagem , Administração Intranasal , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Humanos , Lactente , Oxigênio/administração & dosagem , Estudos Retrospectivos
6.
J Arthroplasty ; 34(4): 686-692.e2, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30733071

RESUMO

BACKGROUND: Patients undergoing total hip arthroplasty (THA) need substantial amount of opioids for postoperative pain management, which necessitates opioid-sparing modalities. Dexmedetomidine is a novel alpha-2-adrenoceptor-activating drug for procedural sedation. In addition to its sedative effect, dexmedetomidine has analgesic and antiemetic effects. We evaluated retrospectively the effect of intraoperatively administered intranasal low-dose dexmedetomidine on postoperative opioid requirement in patients undergoing THA. METHODS: We included 120 patients with American Society of Anesthesiologists status 1-2, age between 35 and 80 years, and scheduled for unilateral primary THA under general anesthesia with total intravenous anesthesia. Half of the patients received 50 µg of intranasal dexmedetomidine after anesthesia induction, while the rest were treated conventionally. Postoperative opioid requirements were calculated as morphine equivalent doses for both groups. The impact of intranasal dexmedetomidine on postoperative hemodynamics and length of stay was evaluated. RESULTS: The cumulative postoperative opioid requirement was significantly reduced in the dexmedetomidine group compared with the control group (26.3 mg, 95% confidence interval 15.6-36.4, P < .001). The cumulative dose was significantly different between the groups already at 12, 24, and 36 h postoperatively (P = .01; P = .001; P < .001, respectively). Dexmedetomidine group had lower mean arterial pressure in the postanesthesia care unit compared with the control group (P = .01). There was no difference in the postanesthesia care unit stay or postoperative length of stay between the two groups (P = .47; P = .10, respectively). CONCLUSION: Compared with the control group, intraoperative use of intranasal low-dose dexmedetomidine decreases opioid consumption and sympathetic response during acute postoperative period in patients undergoing THA.


Assuntos
Analgésicos Opioides/administração & dosagem , Artroplastia de Quadril/efeitos adversos , Dexmedetomidina/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Dor Pós-Operatória/prevenção & controle , Administração Intranasal , Idoso , Analgésicos/uso terapêutico , Anestesia Geral , Hemodinâmica , Humanos , Pessoa de Meia-Idade , Dor Pós-Operatória/etiologia , Período Pós-Operatório , Estudos Retrospectivos
7.
Eur J Clin Pharmacol ; 74(12): 1615-1622, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30167757

RESUMO

PURPOSE: Buprenorphine has low oral bioavailability. Regardless of sublingual administration, a notable part of buprenorphine is exposed to extensive first-pass metabolism by the cytochrome P450 (CYP) 3A4. As drug interaction studies with buprenorphine are limited, we wanted to investigate the effect of voriconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics and pharmacodynamics of oral buprenorphine. METHODS: Twelve healthy volunteers were given either placebo or voriconazole (orally, 400 mg twice on day 1 and 200 mg twice on days 2-5) for 5 days in a randomized, cross-over study. On day 5, they ingested 0.2 mg (3.6 mg during placebo phase) oral buprenorphine. We measured plasma and urine concentrations of buprenorphine and norbuprenorphine and monitored their pharmacological effects. Pharmacokinetic parameters were normalized for a buprenorphine dose of 1.0 mg. RESULTS: Voriconazole greatly increased the mean area under the plasma concentration-time curve (AUC0-18) of buprenorphine (4.3-fold, P < 0.001), its peak concentration (Cmax) (3.9-fold), half-life (P < 0.05), and excretion into urine (Ae; P < 0.001). Voriconazole also markedly enhanced the Cmax (P < 0.001), AUC0-18 (P < 0.001), and Ae (P < 0.05) of unconjugated norbuprenorphine but decreased its renal clearance (P < 0.001). Mild dizziness and nausea occurred during both study phases. CONCLUSIONS: Voriconazole greatly increases exposure to oral buprenorphine, mainly by inhibiting intestinal and liver CYP3A4. Effect on some transporters may explain elevated norbuprenorphine concentrations. Although oral buprenorphine is not commonly used, this interaction may become relevant in patients receiving sublingual buprenorphine together with voriconazole or other CYP3A4 or transporter inhibitors.


Assuntos
Analgésicos Opioides/farmacocinética , Antifúngicos/farmacologia , Buprenorfina/farmacocinética , Voriconazol/farmacologia , Adolescente , Adulto , Analgésicos Opioides/efeitos adversos , Antifúngicos/efeitos adversos , Área Sob a Curva , Biotransformação , Buprenorfina/efeitos adversos , Buprenorfina/análogos & derivados , Buprenorfina/metabolismo , Estudos Cross-Over , Citocromo P-450 CYP3A/metabolismo , Tontura/induzido quimicamente , Interações Medicamentosas , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Voriconazol/efeitos adversos , Adulto Jovem
8.
Anesthesiology ; 124(1): 56-68, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26556729

RESUMO

BACKGROUND: Patient-controlled analgesia (PCA) is a common method for postoperative pain therapy, but it is characterized by large variation of plasma concentrations. PCA with target-controlled infusion (TCI-PCA) may be an alternative. In a previous analysis, the authors developed a pharmacokinetic model for hydromorphone. In this secondary analysis, the authors investigated the feasibility and efficacy of TCI-PCA for postoperative pain therapy with hydromorphone. METHODS: Fifty adult patients undergoing cardiac surgery were enrolled in this study. Postoperatively, hydromorphone was applied intravenously during three sequential periods: (1) as TCI with plasma target concentrations of 1 to 2 ng/ml until extubation; (2) as TCI-PCA with plasma target concentrations between 0.8 and 10 ng/ml during the following 6 to 8 h; and (3) thereafter as PCA with a bolus dose of 0.2 mg until the next morning. During TCI-PCA, pain was regularly assessed using the 11-point numerical rating scale (NRS). A pharmacokinetic/pharmacodynamic model was developed using ordinal logistic regression based on measured plasma concentrations. RESULTS: Data of 43 patients aged 40 to 81 yr were analyzed. The hydromorphone dose during TCI-PCA was 0.26 mg/h (0.07 to 0.93 mg/h). The maximum plasma target concentration during TCI-PCA was 2.3 ng/ml (0.9 to 7.0 ng/ml). The NRS score under deep inspiration was less than 5 in 83% of the ratings. Nausea was present in 30%, vomiting in 9%, and respiratory insufficiency in 5% of the patients. The EC50 of hydromorphone for NRS of 4 or less was 4.1 ng/ml (0.6 to 12.8 ng/ml). CONCLUSION: TCI-PCA with hydromorphone offered satisfactory postoperative pain therapy with moderate side effects.


Assuntos
Analgesia Controlada pelo Paciente , Analgésicos Opioides/farmacologia , Hidromorfona/farmacologia , Dor Pós-Operatória/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/sangue , Feminino , Humanos , Hidromorfona/administração & dosagem , Hidromorfona/sangue , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
9.
Eur J Clin Pharmacol ; 72(11): 1363-1371, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27510521

RESUMO

PURPOSE: This study aimed to determine possible effects of voriconazole and posaconazole on the pharmacokinetics and pharmacological effects of sublingual buprenorphine. METHODS: We used a randomized, placebo-controlled crossover study design with 12 healthy male volunteers. Subjects were given a dose of 0.4 mg (0.6 mg during placebo phase) sublingual buprenorphine after a 5-day oral pretreatment with either (i) placebo, (ii) voriconazole 400 mg twice daily on the first day and 200 mg twice daily thereafter or (iii) posaconazole 400 mg twice daily. Plasma and urine concentrations of buprenorphine and its primary active metabolite norbuprenorphine were monitored over 18 h and pharmacological effects were measured. RESULTS: Compared to placebo, voriconazole increased the mean area under the plasma concentration-time curve (AUC0-∞) of buprenorphine 1.80-fold (90 % confidence interval 1.45-2.24; P < 0.001), its peak concentration (Cmax) 1.37-fold (P < 0.013) and half-life (t ½ ) 1.37-fold (P < 0.001). Posaconazole increased the AUC00-∞ of buprenorphine 1.25-fold (P < 0.001). Most of the plasma norbuprenorphine concentrations were below the limit of quantification (0.05 ng/ml). Voriconazole, unlike posaconazole, increased the urinary excretion of norbuprenorphine 1.58-fold (90 % confidence interval 1.18-2.12; P < 0.001) but there was no quantifiable parent buprenorphine in urine. Plasma buprenorphine concentrations correlated with the pharmacological effects, but the effects did not differ significantly between the phases. CONCLUSIONS: Voriconazole, and to a minor extent posaconazole, increase plasma exposure to sublingual buprenorphine, probably via inhibition of cytochrome P450 3 A and/or P-glycoprotein. Care should be exercised in the combined use of buprenorphine with triazole antimycotics, particularly with voriconazole, because their interaction can be of clinical importance.


Assuntos
Analgésicos Opioides/farmacocinética , Antifúngicos/farmacologia , Buprenorfina/farmacocinética , Triazóis/farmacologia , Voriconazol/farmacologia , Administração Sublingual , Adulto , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacologia , Buprenorfina/efeitos adversos , Buprenorfina/farmacologia , Estudos Cross-Over , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Masculino , Dor/tratamento farmacológico , Método Simples-Cego , Adulto Jovem
10.
Eur J Clin Pharmacol ; 71(3): 321-7, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25560051

RESUMO

BACKGROUND: Tramadol is widely used for acute, chronic, and neuropathic pain. Its primary active metabolite is O-desmethyltramadol (M1), which is mainly accountable for the µ-opioid receptor-related analgesic effect. Tramadol is metabolized to M1 mainly by cytochrome P450 (CYP)2D6 enzyme and to other metabolites by CYP3A4 and CYP2B6. We investigated the possible interaction of tramadol with the antifungal agents terbinafine (CYP2D6 inhibitor) and itraconazole (CYP3A4 inhibitor). METHODS: We used a randomized placebo-controlled crossover study design with 12 healthy subjects, of which 8 were extensive and 4 were ultrarapid CYP2D6 metabolizers. On the pretreatment day 4 with terbinafine (250 mg once daily), itraconazole (200 mg once daily) or placebo, subjects were given tramadol 50 mg orally. Plasma concentrations of tramadol and M1 were determined over 48 h and some pharmacodynamic effects over 12 h. Pharmacokinetic variables were calculated using standard non-compartmental methods. RESULTS: Terbinafine increased the area under plasma concentration-time curve (AUC0-∞) of tramadol by 115 % and decreased the AUC0-∞ of M1 by 64 % (P < 0.001). Terbinafine increased the peak concentration (C max) of tramadol by 53 % (P < 0.001) and decreased the C max of M1 by 79 % (P < 0.001). After terbinafine pretreatment the elimination half-life of tramadol and M1 were increased by 48 and 50 %, respectively (P < 0.001). Terbinafine reduced subjective drug effect of tramadol (P < 0.001). Itraconazole had minor effects on tramadol pharmacokinetics. CONCLUSIONS: Terbinafine may reduce the opioid effect of tramadol and increase the risk of its monoaminergic adverse effects. Itraconazole has no meaningful interaction with tramadol in subjects who have functional CYP2D6 enzyme.


Assuntos
Itraconazol/farmacologia , Naftalenos/farmacologia , Tramadol/administração & dosagem , Tramadol/farmacocinética , Administração Oral , Adulto , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacocinética , Antifúngicos , Estudos Cross-Over , Citocromo P-450 CYP2D6/genética , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Feminino , Genótipo , Humanos , Masculino , Testes Neuropsicológicos , Terbinafina , Tramadol/sangue , Adulto Jovem
11.
Anesthesiology ; 120(2): 378-91, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23958818

RESUMO

BACKGROUND: Hydromorphone is a µ-selective opioid agonist used in postoperative pain therapy. This study aimed to evaluate the pharmacokinetics of hydromorphone in cardiac surgery patients during postoperative analgesia with target-controlled infusion and patient-controlled analgesia. METHODS: In this study, 50 adult patients were enrolled to receive intravenous hydromorphone during postoperative pain therapy. Arterial plasma samples were collected for measurements of drug concentration. Population pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Results were validated and simulations were carried out to evaluate results. RESULTS: Data from 49 patients (age range, 40-81 yr) were analyzed. The pharmacokinetics of hydromorphone were best described by a three-compartment model. Age was incorporated as a significant covariate for elimination clearance and central volume of distribution. Scaling all parameters with body weight improved the model significantly. The final estimates of the model parameters for the typical adult patient (67 yr old, weighing 70 kg) undergoing cardiac surgery were as follows: CL1 = 1.01 l/min, V1 = 3.35 l, CL2 = 1.47 l/min, V2 = 13.9 l, CL3 = 1.41 l/min, and V3 = 145 l. The elimination clearance decreased by 43% between the age of 40 and 80 yr, and simulations demonstrated that context-sensitive half-time increased from 26 to 84 min in 40- and 80-yr-old subjects, respectively. CONCLUSIONS: The final pharmacokinetic model gave a robust representation of hydromorphone pharmacokinetics. Inclusion of age and body weight to the model demonstrated a significant influence of these covariates on hydromorphone pharmacokinetics. The application of this patient-derived population model in individualized pain therapy should improve the dosing of hydromorphone in patients undergoing cardiac surgery.


Assuntos
Analgésicos Opioides/farmacocinética , Procedimentos Cirúrgicos Cardíacos , Hidromorfona/farmacocinética , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Analgesia Controlada pelo Paciente , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Simulação por Computador , Interpretação Estatística de Dados , Interações Medicamentosas , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Hidromorfona/administração & dosagem , Hidromorfona/uso terapêutico , Infusões Intralesionais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Método Simples-Cego , Sufentanil/administração & dosagem , Sufentanil/uso terapêutico , Toracotomia
12.
Pharmacol Rev ; 63(1): 243-67, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21245208

RESUMO

GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). The type A GABA receptor (GABA(A)R) system is the primary pharmacological target for many drugs used in clinical anesthesia. The α1, ß2, and γ2 subunit-containing GABA(A)Rs located in the various parts of CNS are thought to be involved in versatile effects caused by inhaled anesthetics and classic benzodiazepines (BZD), both of which are widely used in clinical anesthesiology. During the past decade, the emergence of tonic inhibitory conductance in extrasynaptic GABA(A)Rs has coincided with evidence showing that these receptors are highly sensitive to the sedatives and hypnotics used in anesthesia. Anesthetic enhancement of tonic GABAergic inhibition seems to be preferentially increased in regions shown to be important in controlling memory, awareness, and sleep. This review focuses on the physiology of the GABA(A)Rs and the pharmacological properties of clinically used BZDs. Although classic BZDs are widely used in anesthesiological practice, there is a constant need for new drugs with more favorable pharmacokinetic and pharmacodynamic effects and fewer side effects. New hypnotics are currently developed, and promising results for one of these, the GABA(A)R agonist remimazolam, have recently been published.


Assuntos
Anestésicos Intravenosos/farmacologia , Benzodiazepinas/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Agonistas de Receptores de GABA-A/farmacologia , Neurônios/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Anestésicos Intravenosos/química , Anestésicos Intravenosos/farmacocinética , Anestésicos Intravenosos/uso terapêutico , Animais , Ansiolíticos/química , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Benzodiazepinas/química , Benzodiazepinas/farmacocinética , Benzodiazepinas/uso terapêutico , Sistema Nervoso Central/enzimologia , Sistema Nervoso Central/metabolismo , Interações Medicamentosas , Agonistas de Receptores de GABA-A/química , Agonistas de Receptores de GABA-A/farmacocinética , Agonistas de Receptores de GABA-A/uso terapêutico , Humanos , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacocinética , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Neurônios/enzimologia , Neurônios/metabolismo , Receptores de GABA-A/química , Receptores de GABA-A/genética , Ácido gama-Aminobutírico/metabolismo
13.
Clin Pharmacokinet ; 63(4): 397-422, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38485851

RESUMO

Naloxone is a World Health Organization (WHO)-listed essential medicine and is the first choice for treating the respiratory depression of opioids, also by lay-people witnessing an opioid overdose. Naloxone acts by competitive displacement of opioid agonists at the µ-opioid receptor (MOR). Its effect depends on pharmacological characteristics of the opioid agonist, such as dissociation rate from the MOR receptor and constitution of the victim. Aim of treatment is a balancing act between restoration of respiration (not consciousness) and avoidance of withdrawal, achieved by titration to response after initial doses of 0.4-2 mg. Naloxone is rapidly eliminated [half-life (t1/2) 60-120 min] due to high clearance. Metabolites are inactive. Major routes for administration are intravenous, intramuscular, and intranasal, the latter primarily for take-home naloxone. Nasal bioavailability is about 50%. Nasal uptake [mean time to maximum concentration (Tmax) 15-30 min] is likely slower than intramuscular, as reversal of respiration lag behind intramuscular naloxone in overdose victims. The intraindividual, interindividual and between-study variability in pharmacokinetics in volunteers are large. Variability in the target population is unknown. The duration of action of 1 mg intravenous (IV) is 2 h, possibly longer by intramuscular and intranasal administration. Initial parenteral doses of 0.4-0.8 mg are usually sufficient to restore breathing after heroin overdose. Fentanyl overdoses likely require higher doses of naloxone. Controlled clinical trials are feasible in opioid overdose but are absent in cohorts with synthetic opioids. Modeling studies provide valuable insight in pharmacotherapy but cannot replace clinical trials. Laypeople should always have access to at least two dose kits for their interim intervention.


Assuntos
Naloxona , Antagonistas de Entorpecentes , Humanos , Administração Intranasal , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Overdose de Drogas/tratamento farmacológico , Meia-Vida , Naloxona/farmacocinética , Naloxona/administração & dosagem , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacocinética , Antagonistas de Entorpecentes/farmacologia , Antagonistas de Entorpecentes/administração & dosagem
14.
Eur J Clin Pharmacol ; 69(4): 867-75, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23099620

RESUMO

PURPOSE: We assessed possible drug interactions of tramadol given concomitantly with the potent CYP2B6 inhibitor ticlopidine, alone or together with the potent CYP3A4 and P-glycoprotein inhibitor itraconazole. METHODS: In a randomized, placebo-controlled cross-over study, 12 healthy subjects ingested 50 mg of tramadol after 4 days of pretreatment with either placebo, ticlopidine (250 mg twice daily) or ticlopidine plus itraconazole (200 mg once daily). Plasma and urine concentrations of tramadol and its active metabolite O-desmethyltramadol (M1) were monitored over 48 h and 24 h, respectively. RESULTS: Ticlopidine increased the mean area under the plasma concentration-time curve (AUC0-∞) of tramadol by 2.0-fold (90 % confidence interval (CI) 1.6-2.4; p < 0.001) and Cmax by 1.4-fold (p < 0.001), and reduced its oral and renal clearance (p < 0.01). Ticlopidine reduced the AUC0-3 of M1 (p < 0.001) and the ratio of the AUC0-∞ of M1 to that of tramadol, but did not influence the AUC0-∞ of M1. Tramadol or M1 pharmacokinetics did not differ between the ticlopidine alone and ticlopidine plus itraconazole phases. CONCLUSIONS: Ticlopidine increased exposure to tramadol, reduced its renal clearance and inhibited the formation of M1, most likely via inhibition of CYP2B6 and/or CYP2D6. The addition of itraconazole to ticlopidine did not modify the outcome of the drug interaction. Concomitant clinical use of ticlopidine and tramadol may enhance the risk of serotonergic effects, especially when higher doses of tramadol are used.


Assuntos
Analgésicos Opioides/farmacocinética , Itraconazol/farmacologia , Rim/metabolismo , Ticlopidina/farmacologia , Tramadol/análogos & derivados , Adulto , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/sangue , Analgésicos Opioides/urina , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Biotransformação , Estudos Cross-Over , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Relação Dose-Resposta a Droga , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Itraconazol/administração & dosagem , Masculino , Taxa de Depuração Metabólica , Oxirredutases N-Desmetilantes/antagonistas & inibidores , Ticlopidina/administração & dosagem , Tramadol/administração & dosagem , Tramadol/sangue , Tramadol/farmacocinética , Tramadol/urina , Adulto Jovem
15.
Eur J Clin Pharmacol ; 69(6): 1293-301, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23242004

RESUMO

PURPOSE: Tramadol is mainly metabolized by the cytochrome P450 (CYP) 2D6, CYP2B6 and CYP3A4 enzymes. The aim of this study was to evaluate the effect of enzyme induction with rifampicin on the pharmacokinetics and pharmacodynamics of oral and intravenous tramadol. METHODS: This was a randomized placebo-controlled crossover study design with 12 healthy subjects. After pretreatment for 5 days with rifampicin (600 mg once daily) or placebo, subjects were given tramadol either 50 mg intravenously or 100 mg orally. Plasma concentrations of tramadol and its active main metabolite O-desmethyltramadol (M1) were determined over 48 h. Analgesic and behavioral effects and whole blood 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were measured. RESULTS: Rifampicin reduced the mean area under the time-concentration curve (AUC0-∞) of intravenously administered tramadol by 43 % and that of M1 by 58 % (P < 0.001); it reduced the AUC0-∞ of oral tramadol by 59 % and that of M1 by 54 % (P < 0.001). Rifampicin increased the clearance of intravenous tramadol by 67 % (P < 0.001). Bioavailability of oral tramadol was reduced by rifampicin from 66 to 49 % (P = 0.002). The pharmacological effects of tramadol or whole blood serotonin concentrations were not influenced by pretreatment with rifampicin. CONCLUSIONS: Rifampicin markedly decreased the exposure to tramadol and M1 after both oral and intravenous administration. Therefore, rifampicin and other potent enzyme inducers may have a clinically important interaction with tramadol regardless of the route of its administration.


Assuntos
Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacocinética , Sistema Enzimático do Citocromo P-450/biossíntese , Rifampina/administração & dosagem , Tramadol/administração & dosagem , Tramadol/farmacocinética , Administração Oral , Analgésicos Opioides/sangue , Área Sob a Curva , Disponibilidade Biológica , Biomarcadores/sangue , Biotransformação , Estudos Cross-Over , Citocromo P-450 CYP2D6/genética , Sistema Enzimático do Citocromo P-450/genética , Esquema de Medicação , Interações Medicamentosas , Indução Enzimática , Finlândia , Genótipo , Meia-Vida , Humanos , Ácido Hidroxi-Indolacético/sangue , Injeções Intravenosas , Taxa de Depuração Metabólica , Metilação , Testes Neuropsicológicos , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Fenótipo , Desempenho Psicomotor/efeitos dos fármacos , Serotonina/sangue , Tramadol/sangue
16.
Trials ; 24(1): 417, 2023 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-37337295

RESUMO

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a neurological emergency, affecting a younger population than individuals experiencing an ischemic stroke; aSAH is associated with a high risk of mortality and permanent disability. The noble gas xenon has been shown to possess neuroprotective properties as demonstrated in numerous preclinical animal studies. In addition, a recent study demonstrated that xenon could attenuate a white matter injury after out-of-hospital cardiac arrest. METHODS: The study is a prospective, multicenter phase II clinical drug trial. The study design is a single-blind, prospective superiority randomized two-armed parallel follow-up study. The primary objective of the study is to explore the potential neuroprotective effects of inhaled xenon, when administered within 6 h after the onset of symptoms of aSAH. The primary endpoint is the extent of the global white matter injury assessed with magnetic resonance diffusion tensor imaging of the brain. DISCUSSION: Despite improvements in medical technology and advancements in medical science, aSAH mortality and disability rates have remained nearly unchanged for the past 10 years. Therefore, new neuroprotective strategies to attenuate the early and delayed brain injuries after aSAH are needed to reduce morbidity and mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT04696523. Registered on 6 January 2021. EudraCT, EudraCT Number: 2019-001542-17. Registered on 8 July 2020.


Assuntos
Lesões Encefálicas , Hemorragia Subaracnóidea , Humanos , Hemorragia Subaracnóidea/complicações , Imagem de Tensor de Difusão , Xenônio/uso terapêutico , Estudos Prospectivos , Método Simples-Cego , Seguimentos , Lesões Encefálicas/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto
17.
Eur J Clin Pharmacol ; 68(6): 979-86, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22286159

RESUMO

PURPOSE: We examined the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral S-ketamine. METHODS: A randomized crossover open-label study design with two phases at an interval of 4 weeks was conducted in 12 healthy volunteers. Grapefruit juice or water was ingested 200 ml t.i.d. for 5 days. An oral dose of 0.2 mg/kg of S-ketamine was ingested on day 5 with 150 ml grapefruit juice or water. Plasma concentrations of ketamine and norketamine were determined for 24 h, and pharmacodynamic variables were recorded for 12 h. Noncompartmental methods were used to calculate pharmacokinetic parameters. RESULTS: Grapefruit juice increased the geometric mean value of the area under the plasma ketamine concentration-time curve(AUC0-∞) by 3.0-fold (range 2.4- to 3.6-fold; P<0.001), the peak plasma concentration (Cmax) by 2.1-fold (range 1.8- to 2.6-fold; P<0.001), and the elimination half-life by 24% (P<0.05) as compared to the water phase. The ratio of main metabolite norketamine to ketamine (AUCm/AUCp) was decreased by 57% (P<0.001) during the grapefruit phase.Self-rated relaxation was decreased (P<0.05) and the performance in the digit symbol substitution test was increased (P<0.05) after grapefruit juice, but other behavioral or analgesic effects were not affected. CONCLUSIONS: Grapefruit juice significantly increased the plasma concentrations of oral ketamine in healthy volunteers.Dose reductions of ketamine should be considered when using oral ketamine concomitantly with grapefruit juice.


Assuntos
Bebidas , Citrus paradisi , Interações Alimento-Droga , Ketamina/farmacocinética , Adulto , Idoso , Hidrocarboneto de Aril Hidroxilases/metabolismo , Estudos Cross-Over , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP3A/metabolismo , Feminino , Humanos , Ketamina/administração & dosagem , Ketamina/análogos & derivados , Ketamina/sangue , Masculino , Pessoa de Meia-Idade , Oxirredutases N-Desmetilantes/metabolismo , Adulto Jovem
18.
Antimicrob Agents Chemother ; 55(3): 1063-7, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21173180

RESUMO

Our aim was to assess the effect of miconazole oral gel on the pharmacokinetics of oral oxycodone. In an open crossover study with two phases, 12 healthy volunteers took a single oral dose of 10 mg of immediate-release oxycodone with or without thrice-daily 85-mg miconazole oral gel treatment. The plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h. Pharmacological effects of oxycodone were recorded for 12 h. Pharmacokinetic parameters were compared by use of the geometric mean ratios (GMRs) and their 90% confidence interval (CIs). Pretreatment with miconazole oral gel caused a strong inhibition of the CYP2D6-dependent metabolism and moderate inhibition of the CYP3A4-dependent metabolism of oxycodone. The mean area under the concentration-time curve (AUC) from time zero to infinity (AUC(0-∞); GMR, 1.63; 90% CI, 1.48 to 1.79) and the peak concentration of oxycodone (GMR, 1.31; 90% CI, 1.19 to 1.44) were increased. The AUC of the CYP2D6-dependent metabolite oxymorphone was greatly decreased (GMR, 0.17; 90% CI, 0.09 to 0.31) by miconazole gel, whereas that of the CYP3A4-dependent metabolite noroxycodone was increased (GMR, 1.30; 90% CI, 1.15 to 1.47) by miconazole gel. Differences in the pharmacological response to oxycodone between phases were insignificant. Miconazole oral gel increases the exposure to oral oxycodone, but the clinical relevance of the interaction is moderate. Miconazole oral gel produces a rather strong inhibitory effect on CYP2D6, which deserves further study.


Assuntos
Analgésicos Opioides/uso terapêutico , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Miconazol/uso terapêutico , Oxicodona/uso terapêutico , Administração Oral , Adulto , Analgésicos Opioides/administração & dosagem , Inibidores do Citocromo P-450 CYP2D6 , Inibidores do Citocromo P-450 CYP3A , Feminino , Humanos , Masculino , Oxicodona/administração & dosagem , Dor/tratamento farmacológico , Adulto Jovem
19.
Clin Drug Investig ; 31(3): 143-53, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21142269

RESUMO

BACKGROUND AND OBJECTIVE: Oxycodone is a µ-opioid receptor agonist that is mainly metabolized by hepatic cytochrome P450 (CYP) enzymes. Because CYP enzymes can be inhibited by other drugs, the pharmacokinetics of oxycodone are prone to drug interactions. The aim of this study was to determine whether inhibition of CYP2D6 alone by paroxetine or inhibition of both CYP2D6 and CYP3A4 by a combination of paroxetine and itraconazole alters the pharmacokinetics of and pharmacological response to intravenous oxycodone. METHODS: We used a randomized, three-phase, crossover, placebo-controlled study design in 12 healthy subjects. The subjects were given 0.1 mg/kg of intravenous oxycodone after pre-treatments with placebo, paroxetine or a combination of paroxetine and itraconazole for 4 days. Plasma concentrations of oxycodone and its oxidative metabolites were measured over 48 hours, and pharmacokinetic and pharmacodynamic parameters subsequently evaluated. RESULTS: The effect of paroxetine on the plasma concentrations of oxycodone was negligible. The combination of paroxetine and itraconazole prolonged the mean elimination half-life of oxycodone from 3.8 to 6.6 hours (p < 0.001), and increased the exposure to oxycodone 2-fold (p < 0.001). However, these changes were not reflected in pharmacological response. CONCLUSION: The results of this study indicate that there are no clinically relevant drug interactions with intravenous oxycodone and inhibitors of CYP2D6. If both oxidative metabolic pathways via CYP3A4 and 2D6 are inhibited the exposure to intravenous oxycodone increases substantially.


Assuntos
Analgésicos Opioides/classificação , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Oxicodona/farmacocinética , Adulto , Analgésicos Opioides/farmacologia , Estudos Cross-Over , Inibidores do Citocromo P-450 CYP2D6 , Inibidores do Citocromo P-450 CYP3A , Interações Medicamentosas , Inibidores Enzimáticos/farmacologia , Feminino , Meia-Vida , Humanos , Itraconazol/farmacologia , Masculino , Oxicodona/farmacologia , Paroxetina/farmacologia , Adulto Jovem
20.
J Clin Pharmacol ; 61(4): 522-530, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33027547

RESUMO

The capability of viscoelastic measurement parameters to screen anticoagulation activity of edoxaban in relation to its plasma concentrations was evaluated in 15 healthy male volunteers. Blood samples were drawn before the oral administration of edoxaban 60 mg and 2, 4, 6, 8, and 24 hours after administration. At each time, standard coagulation tests were performed, blood viscoelastic properties were measured with a thromboelastometry device ROTEM delta analyzer (Instrumentation Laboratory, Werfen, Barcelona, Spain), and edoxaban plasma concentrations were measured. Our primary interest was the possible correlation between edoxaban plasma concentrations and values for ROTEM ExTEM, and FibTEM. We also studied the correlation of edoxaban plasma concentrations with the results of standard coagulation tests. We saw the effect of a single dose of edoxaban most clearly in clotting time (CT) of ROTEM ExTEM and FibTEM. Changes in these parameters correlated significantly with edoxaban plasma concentrations up to 6 hours from the ingestion of the drug. Activated partial thromboplastin time, prothrombin time, and anti-factor Xa were also affected. Peak changes were observed 2 and 4 hours after administration of edoxaban. The changes were mostly reversed after 8 hours. In conclusion, ROTEM CT correlates significantly with edoxaban plasma concentrations and can be used to estimate the effect of edoxaban. ROTEM should be considered as part of the assessment of coagulation, with the big advantage of being readily available on site.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Viscosidade Sanguínea/efeitos dos fármacos , Piridinas/sangue , Tiazóis/sangue , Adolescente , Adulto , Testes de Coagulação Sanguínea , Voluntários Saudáveis , Humanos , Estudos Longitudinais , Masculino , Adulto Jovem
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