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1.
Eur J Pharm Sci ; 141: 105093, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31648049

RESUMO

Reaction phenotyping is a method commonly used for characterizing drug metabolism. It determines the drug metabolic pathways and ratios by measuring the metabolized fractions of individual enzymes. However, currently published results have focused on cytochrome P450s (CYPs), while not considering phase II metabolism. Therefore, the morphinan analgesic, nalbuphine, primarily metabolized in the liver via CYPs and UDP-glucuronosyltransferases (UGTs), was selected as a model drug to establish a dual-phase platform to elucidate its comprehensive metabolic pathway. Enzyme kinetics was studied using 8 common recombinant (r)CYPs, 10 rUGTs, and pooled human liver microsomes. The overall fraction of nalbuphine metabolized by each isozyme was evaluated by determining parent drug depletion. Finally, in vitro-in vivo correlation was validated in animal studies. Fluconazole, a specific UGT2B7 inhibitor, was administered orally to rats to determine the pharmacokinetic effects on nalbuphine and nalbuphine metabolites. Seventy-five percent and 25% of nalbuphine was metabolized by UGTs and CYPs, respectively. UGT2B7, UGT1A3, and UGT1A9 were primarily responsible for nalbuphine glucuronidation; only UGT2B7 produced nalbuphine-6-glucuronide. CYP2C9 and CYP2C19 were the two CYP isozymes that produced 3'-hydroxylnalbuphine and 4'-hydroxylnalbuphine. In vivo, the maximum serum concentration (Cmax) and area under the curve (AUC) of nalbuphine increased 12.4-fold and 13.2-fold, respectively, with fluconazole co-administration. A dual system platform for drug metabolism was successfully established in this study and was used to generate a complete metabolic scheme for nalbuphine. This platform has been verified by in vivo evaluations and can be utilized to study drugs that undergo multisystem metabolism.


Assuntos
Analgésicos Opioides/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Glucuronosiltransferase/metabolismo , Nalbufina/farmacocinética , Analgésicos Opioides/sangue , Analgésicos Opioides/farmacologia , Animais , Humanos , Isoenzimas/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Nalbufina/sangue , Nalbufina/farmacologia , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo
2.
Forensic Sci Int ; 305: 109999, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31671355

RESUMO

In the US, the use of synthetic opioids (e.g. fentanyl and derivatives) has become an increasing health issue with thousands of overdose deaths being observed since 2013. With the high mortality rate associated with these substances, postmortem analyses and interpretation of synthetic opioids has become extremely important. However, due to the novelty of these compounds, the available data are limited and provides challenges to toxicologists. The objectives of this study were (1) to develop and validate analytical methods for the determination of synthetic opioids in vitreous humor and brain, and (2) to investigate the postmortem distribution of new synthetic opioids in blood, vitreous humor, and brain tissue. Vitreous humor (0.5mL) and brain tissue (5g) homogenized in water (diluted 1:3, w/w) were extracted by mixed mode cation exchange-reversed phase solid phase extraction. Extracts were analyzed by liquid chromatography tandem mass spectrometry (LC-MSMS). The chromatographic separation was performed by reversed-phase with 0.1% formic acid in water and in acetonitrile as mobile phases in gradient mode, with a total run time of 21min. Data were acquired with ESI+ in dynamic multiple reaction mode (dMRM), monitoring 2 transitions per compound. The methods were succesfully validated following SWGTOX guidelines, with limits of quantification of 0.1ng/mL in vitreous humor and 0.1ng/g in brain. Fifty-eight authentic case samples from the New York City Office of the Chief Medical Examiner (NYC-OCME) were analyzed to assess the distribution and detectability of synthetic opioids in these postmortem samples. Of the fifteen synthetic opioids included in the method, six synthetic opioids and metabolites (4-ANPP, acetylfentanyl, fentanyl, furanylfentanyl, norfentanyl, U-47700) were detected in the authentic cases. Concentrations for most analytes were within the 0.1 to 100ng/mL or ng/g calibration range across all three matrices, with only concentrations from acetylfentanyl and U-47700 exceeding 100ng/mL or ng/g. The highest concentrations were observed in brain (except norfentanyl), followed by blood and vitreous humor. Most analytes were detected in all three matrices in a given case. This was followed by detection of an analyte in combinations of brain and another matrix or brain only. Through the case analyses, vitreous humor and brain demonstrated to be viable alternatives to blood when performing postmortem analyses of synthetic opioids. Brain exhibited a higher detectability for most analytes when compared to blood and vitreous humor.


Assuntos
Analgésicos Opioides/análise , Química Encefálica , Medicamentos Sintéticos/análise , Corpo Vítreo/química , Analgésicos Opioides/farmacocinética , Cromatografia Líquida , Toxicologia Forense , Humanos , Psicotrópicos/análise , Psicotrópicos/farmacocinética , Extração em Fase Sólida , Medicamentos Sintéticos/farmacocinética , Espectrometria de Massas em Tandem
3.
Pharm Res ; 36(12): 171, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654287

RESUMO

PURPOSE: Physiologically-based pharmacokinetic (PBPK) modeling offers a unique modality to predict age-specific pharmacokinetics. The objective of this study was to assess the ability of PBPK model to predict plasma exposure of oxycodone, a widely used opioid for pain management, in adults and children. METHODS: A full PBPK model of oxycodone following intravenous and oral administration was developed using a 'bottom-up' and 'top-down' combined strategy. The model was then extrapolated to pediatrics through a reasonable scaling method. The adult and pediatric model was evaluated using data from 17 clinical PK studies by testing predicted/observed goodness of fit. The mean fold error for PK parameters was calculated. Finally, we used the validated PBPK model to visualize adult-children dose conversion for oxycodone. RESULTS: The developed PBPK model successfully predicted the oxycodone disposition in adults, wherein the predicted versus observed AUC, Cmax, and tmax were within 0.90 to 1.20-fold difference. After scaling anatomy/physiology, protein binding, and clearance, the model showed satisfactory prediction performance for pediatric populations as predicted AUC were within the 1.50-fold range of the observed values. According to the application of PBPK model, we found that different intravenous doses should be given in children of different ages compared to a standard 0.1 mg/kg in adults, while a progressive increasing dose with age growth following oral administration is recommended for children. CONCLUSIONS: The current example provides the opportunity for using the PBPK model to guide dose adjustment of oxycodone in the design of future pediatric clinical studies.


Assuntos
Analgésicos Opioides/farmacocinética , Oxicodona/farmacocinética , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Analgésicos Opioides/administração & dosagem , Criança , Pré-Escolar , Simulação por Computador , Relação Dose-Resposta a Droga , Humanos , Lactente , Recém-Nascido , Taxa de Depuração Metabólica , Modelos Biológicos , Oxicodona/administração & dosagem , Pediatria
4.
Vet Surg ; 48(8): 1473-1482, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31513300

RESUMO

OBJECTIVE: To determine synovial butorphanol concentrations and mechanical nociceptive threshold (MNT) changes after butorphanol intravenous regional limb perfusion (IVRLP). STUDY DESIGN: Experimental ANIMALS: Six adult horses. METHODS: Cephalic IVRLP was performed with 10 mg butorphanol in sedated horses with a wide rubber tourniquet and a total volume of 30 mL. Radiocarpal synovial fluid and serum concentrations along with MNT were evaluated prior to and 0.5, 1, 2, 4, and 6 hours after IVRLP. Butorphanol concentrations were determined with liquid chromatography coupled to tandem mass spectrometry positive electrospray ionization. RESULTS: Butorphanol concentrations reached mean (SD) peak concentrations of 9.47 ng/mL (±12.00) in synovial fluid and 3.89 ng/mL (3.29) in serum 30 minutes after IVRLP. Concentrations remained above baseline for 4 hours in synovial fluid (P ≤ .017) and for 2 hours in serum (P ≤ .016). The only difference in MNT was detected 1 hour after IVRLP, when MNT were higher in controls than in treated horses (P = .047). CONCLUSION: Butorphanol IVRLP seemed well tolerated and resulted in measurable levels of butorphanol in the radiocarpal synovial fluid of five of six horses. CLINICAL SIGNIFICANCE: Intravenous regional limb perfusion appears to be a viable alternative to administer butorphanol, but additional investigation is required to evaluate the dose and local concentrations required for analgesia.


Assuntos
Analgésicos Opioides/farmacocinética , Butorfanol/farmacocinética , Cavalos/metabolismo , Administração Intravenosa , Amicacina/administração & dosagem , Analgésicos Opioides/administração & dosagem , Animais , Antibacterianos/administração & dosagem , Butorfanol/administração & dosagem , Membro Anterior , Dor/veterinária , Perfusão/veterinária , Postura , Fluxo Sanguíneo Regional , Líquido Sinovial/química , Procedimentos Cirúrgicos Vasculares
5.
Toxicol Lett ; 316: 127-135, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31539569

RESUMO

Carfentanil (CRF) is an extremely potent opioid capable of inducing fatal respiratory depression. Naloxone (NX) and naltrexone (NTX) are opioid antagonists for which the efficacy against CRF remains largely unexplored. In this study, the effects of aerosolized CRF on respiratory function were investigated using adult male CD-1 mice. Mice were exposed to 0.4 mg/m3 of CRF for 15 min using custom whole-body plethysmograph units. Minute volume (MV), respiratory frequency (f), duty cycle (DC), and tidal volume (TV) were monitored and compared to control animals exposed to aerosolized H2O. CRF exposure induced respiratory depression, characterized by a marked decrease in MV, which was sustained throughout 24 h post-exposure. Prophylactic and therapeutic treatment with intramuscular (i.m.) NX marginally improved MV, with slight dose-dependent effects. Analogous treatment with i.m. NTX returned MV to baseline levels, with all doses and intervention times performing similarly. Despite improvements in MV, treatment administration did not reverse changes in DC, a measure of respiratory timing. Overall, NX and NTX administration alleviated volumetric aspects of opioid-induced respiratory toxicity, while changes in respiratory timing remained unresolved throughout post-exposure observation. These sustained changes and differences in recovery between two aspects of respiratory dynamics may provide insights for further exploration into the underlying mechanism of action of opioids and opioid antagonists.


Assuntos
Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/toxicidade , Fentanila/análogos & derivados , Pulmão/efeitos dos fármacos , Naloxona/administração & dosagem , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Respiração/efeitos dos fármacos , Insuficiência Respiratória/prevenção & controle , Administração por Inalação , Aerossóis , Analgésicos Opioides/farmacocinética , Animais , Simulação por Computador , Relação Dose-Resposta a Droga , Fentanila/administração & dosagem , Fentanila/farmacocinética , Fentanila/toxicidade , Humanos , Pulmão/fisiopatologia , Masculino , Camundongos , Modelos Biológicos , Pletismografia Total , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/fisiopatologia , Medição de Risco
6.
J Formos Med Assoc ; 118(10): 1450-1457, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31471221

RESUMO

BACKGROUND/PURPOSE: Enhanced recovery after surgery (ERAS) is a growing tendency in modern perioperative period management, but no protocol has been established for a strategy that optimally facilitates rapid recovery from anesthesia. We hypothesized that applying a total intravenous anesthesia (TIVA) method to the response surface model (RSM) would allow prediction of the emergence and endotracheal tube extubation in cases undergoing video-assisted thoracotomy surgery (VATS). METHODS: Thirty patients who were scheduled to undergo VATs under TIVA were enrolled. Pharmacokinetic profiles were calculated using a Tivatrainer. Emergence from anesthesia was observed and the exact time point of the regained response (RR) was recorded. The effect of concentration was analyzed and applied to a response surface model. RESULTS: The cumulative prediction curve of the RR was closer to the 50% probability as set by the OAA/S ≥ 4 than by the OAA/S ≥ 2 model. The median, averages, and standard deviations of the time differences were 14.5, 22.05 ± 19.23 min for the OAA/S ≥2 model and 10.4, 14.26 ± 10.40 min for the OAA/S ≥ 4 model. CONCLUSION: The OAA/S ≥ 4 model could identify the target concentration in propofol-remifentanil pairs that predicted the time of emergence from VATS in 10 min. Our results indicate that RSM can be used to derive an ERAS protocol for VATS under TIVA. Further studies should investigate application of RSM to predict ERAS for various types of procedures.


Assuntos
Extubação , Anestesia Geral , Modelos Teóricos , Adulto , Idoso , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacocinética , Período de Recuperação da Anestesia , Anestésicos Intravenosos/administração & dosagem , Anestésicos Intravenosos/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Probabilidade , Propofol/administração & dosagem , Propofol/farmacocinética , Remifentanil/administração & dosagem , Remifentanil/farmacocinética , Cirurgia Torácica Vídeoassistida , Fatores de Tempo
7.
Drugs R D ; 19(3): 297-305, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31482303

RESUMO

BACKGROUND: Researchers have long been interested in the potential drug-drug interactions (DDIs) between opioids and benzodiazepines. However, much remains unknown concerning the interactions between these two drug classes. The objective of this work is to study the mechanism underlying the DDIs between opioids and benzodiazepines from the perspective of their pharmacokinetic (PK) interactions. A PK interaction occurs when two drugs are metabolized by the same cytochrome P450 enzymes and is one of the most common reasons for DDIs. METHODS: We quantitatively predicted the DDIs between three opioids (fentanyl, oxycodone and buprenorphine) and four benzodiazepines (alprazolam, diazepam, midazolam and triazolam) using a physiologically based pharmacokinetic (PBPK) modeling approach. A set of PBPK models was first constructed for these common opioids and benzodiazepines using SimCYP software, and the DDIs between them were then explored at various dosages. RESULTS: Our simulation results suggested there were no PK interactions between normal doses of opioids and benzodiazepines; but weak interactions can be expected with the combination of opioids and overdosed benzodiazepines. Particular attention should be given to the combination of fentanyl and overdosed alprazolam since a PK interaction can be observed between them. CONCLUSION: Our results appear to indicate that pharmacodynamics may play a more important role than PKs in causing DDIs between opioids and benzodiazepines. This study also demonstrated that molecular modeling can be a very useful tool to mitigate the problem of "missing metabolic reaction parameters" in PK modeling and simulation.


Assuntos
Analgésicos Opioides/farmacocinética , Benzodiazepinas/farmacocinética , Interações Medicamentosas/fisiologia , Simulação por Computador , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Modelos Biológicos
9.
Forensic Sci Int ; 304: 109915, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31416646

RESUMO

Fatal intoxications due to accidental or voluntary intake of synthetic opioids represent an actual emerging issue. We report a case where we have analyzed furanyl fentanyl and its metabolite 4-anilino-N-phenetyl-piperidine (4-ANPP) in blood, urine, gastric content, bile and cerebrospinal fluid. In this case, a 53-year-old man was found dead at home with a needle still inserted in a vein; a plastic bag containing a white powder (later identified as a furanyl fentanyl-based product) was discovered in the room. Biological samples were collected during autopsy and extracted/purified onto a SPE cartridge before instrumental analysis. Qualitative and quantitative analyses were performed by LC-MS/MS on peripheral and cardiac blood, urine, cerebrospinal fluid (CSF), bile and gastric content. Furanyl fentanyl was identified and quantified in all the biological fluids collected. Interestingly, gastric content revealed an unexpected high amount of furanyl fentanyl; yet, cardiac blood and femoral blood provided significantly different concentrations (11.8 and 2.7 ng/g respectively). The concentration of furanyl fentanyl in CSF was similar to that measured in femoral blood (2.6 ng/mL), thus confirming that CSF could be a good alternative biological fluid whenever a postmortem redistribution is suspected. Concentrations of 93.5, 50.4, 171.7, 41.9, 10.2 ng/mL(g) were measured for 4-ANPP in cardiac blood, femoral blood, urine, bile and cerebrospinal fluid, respectively. The outcomes from the presented case report suggest that the two substances have been not only injected intravenously, but probably also ingested by the man. Fentanyl derivative and its precursor seemed to undergo an extensive postmortem redistribution.


Assuntos
Analgésicos Opioides/análise , Analgésicos Opioides/farmacocinética , Fentanila/análogos & derivados , Furanos/análise , Furanos/farmacocinética , Mudanças Depois da Morte , Bile/química , Cromatografia Líquida , Fentanila/análise , Fentanila/farmacocinética , Toxicologia Forense/métodos , Conteúdo Gastrointestinal/química , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Opioides/complicações , Medicamentos Sintéticos/análise , Medicamentos Sintéticos/farmacocinética
11.
J Clin Psychopharmacol ; 39(5): 489-493, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31305338

RESUMO

PURPOSE: We aimed to study the pharmacokinetics of methadone and buprenorphine in blood and oral fluid after single-dose administration and investigate correlations between concentrations in blood and neurocognitive functions. METHODS: A 5-way, double-blind, randomized, placebo-controlled, double-dummy, crossover study was performed to study the pharmacokinetics and neurocognitive effects of methadone (5 and 10 mg per oral) and buprenorphine (0.2 and 0.4 mg sublingual) in 22 healthy volunteers. Blood and oral fluid were collected throughout the test days, and drug concentrations in both matrices were analyzed using ultrahigh-performance liquid chromatography-tandem mass spectrometry. On-road driving testing, neurocognitive computerized tests, and subjective questionnaires were performed. RESULTS: Large individual variations in concentrations of methadone and buprenorphine in blood and oral fluid, and accordingly oral fluid/blood drug concentration ratios, were observed. The mean ratio 6.5 hours after drug administration was 2.0 (range, 0.49-7.39) for methadone after both doses. Buprenorphine was not detected above the limit of quantification in blood after 6.5 hours. No significant correlation between methadone concentration in blood and effect was found. Significant correlations were found between buprenorphine concentration in blood and standard deviation of lateral position in the driving test and some measures of reaction time, divided attention, balance, alertness, contentedness. and sleepiness. CONCLUSIONS: Concentrations of methadone and buprenorphine in blood and oral fluid showed large interindividual variations. No concentration-effect correlations were found for methadone, whereas low to moderate correlations were observed between buprenorphine concentration and driving, psychomotor function, and subjective rating of sleep and alertness.


Assuntos
Analgésicos Opioides/administração & dosagem , Buprenorfina/administração & dosagem , Cognição/efeitos dos fármacos , Metadona/administração & dosagem , Desempenho Psicomotor/efeitos dos fármacos , Administração Oral , Administração Sublingual , Adulto , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/farmacologia , Condução de Veículo , Buprenorfina/farmacocinética , Buprenorfina/farmacologia , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Metadona/farmacocinética , Metadona/farmacologia , Pessoa de Meia-Idade , Tempo de Reação/efeitos dos fármacos , Espectrometria de Massas em Tandem , Adulto Jovem
12.
Drugs R D ; 19(3): 255-265, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31197606

RESUMO

BACKGROUND: Two phase I studies assessed the pharmacokinetics of buprenorphine, its metabolite norbuprenorphine, and naloxone following administration of buprenorphine/naloxone sublingual tablets in Chinese participants. METHODS: In the first phase I, open-label, single ascending-dose (SAD) study, 82 opioid-naïve volunteers received a single buprenorphine/naloxone dose ranging from 2 mg/0.5 mg to 24 mg/6 mg while under naltrexone block. In a second phase I, open-label, multiple ascending-dose (MAD) study, 27 patients with opioid dependence in withdrawal received buprenorphine/naloxone doses of either 16 mg/4 mg or 24 mg/6 mg for 9 consecutive days. Serial blood samples were collected after a single dose (SAD study) and at steady-state (MAD study). Pharmacokinetic parameters were calculated using non-compartmental analysis. Safety assessments included adverse events monitoring and laboratory tests. RESULTS: The pharmacokinetic profiles of buprenorphine and naloxone were consistent between single- and multiple-dose studies. Peak plasma concentrations (Cmax) were reached early for buprenorphine (0.75-1.0 h) and naloxone (0.5 h), supporting rapid absorption. In the SAD study, increases in plasma exposures to buprenorphine and naloxone were less than dose proportional, in line with previous observations in Western populations. Buprenorphine-to-naloxone ratios for Cmax and area under the curve (AUC) were constant over the dose range investigated and also consistent with Western populations data. Steady state was reached within 7 days of daily dosing, with slight accumulation over repeated doses. No serious adverse events were observed. CONCLUSIONS: The present data suggest that buprenorphine/naloxone pharmacokinetic profiles in Chinese participants are consistent, overall, with those in Western populations, supporting no differences in dosing. CLINICAL TRIAL REGISTRATION: The protocols were registered on the official website of the China Food and Drug Administration (CFDA): http://www.chinadrugtrials.org.cn/ ; Registration numbers CTR20132963 (RB-CN-10-0012), CTR20140153 (RB-CN-10-0015).


Assuntos
Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacocinética , Buprenorfina/administração & dosagem , Buprenorfina/farmacocinética , Comprimidos/administração & dosagem , Comprimidos/farmacocinética , Administração Sublingual , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Disponibilidade Biológica , Buprenorfina/análogos & derivados , Feminino , Humanos , Masculino , Naloxona/administração & dosagem , Naloxona/farmacocinética , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/metabolismo
13.
J Vet Pharmacol Ther ; 42(4): 392-400, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31197847

RESUMO

This study aimed to define the pharmacokinetic profiles of dexmedetomidine and methadone administered simultaneously in dogs by either an oral transmucosal route or intramuscular route and to determine the bioavailability of the oral transmucosal administration relative to the intramuscular one of both drugs, so as the applicability of this administration route in dogs. Twelve client-owned dogs, scheduled for diagnostic procedures, were treated with a combination of dexmedetomidine hydrochloride (10 µg/kg) and methadone hydrochloride (0.4 mg/kg) through an oral transmucosal route or intramuscularly. Oral transmucosal administration caused ptyalism in most subjects, and intramuscular administration caused transient peripheral vasoconstriction. The results showed reduced and delayed absorption of both dexmedetomidine and methadone when administered through an oral transmucosal route, with median (range) Cmax values of 0.82 (0.42-1.49) ng/ml and 13.22 (2.80-52.30) ng/ml, respectively. The relative bioavailability was low: 16.34% (dexmedetomidine) and 15.5% (methadone). Intramuscular administration resulted in a more efficient absorption profile, with AUC and Cmax values for both drugs approximately 10 times higher. Dexmedetomidine and methadone administered simultaneously by an oral transmucosal route using injectable formulations were not well absorbed through the oral mucosa. Nevertheless, additional studies on these drugs combination using alternative administration routes are recommended.


Assuntos
Anestesia/veterinária , Dexmedetomidina/farmacocinética , Cães , Metadona/farmacocinética , Administração Bucal , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacocinética , Animais , Área Sob a Curva , Dexmedetomidina/administração & dosagem , Combinação de Medicamentos , Feminino , Meia-Vida , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacocinética , Injeções Intramusculares , Masculino , Metadona/administração & dosagem
14.
PLoS One ; 14(6): e0217371, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31170174

RESUMO

Most clinically used opioids are thought to induce analgesia through activation of the mu opioid receptor (MOR). However, disparities have been observed between the efficacy of opioids in activating the MOR in vitro and in inducing analgesia in vivo. In addition, some clinically used opioids do not produce cross-tolerance with each other, and desensitization produced in vitro does not match tolerance produced in vivo. These disparities suggest that some opioids could be acting through other targets in vivo, but this has not been comprehensively tested. We thus screened 9 clinically relevant opioids (buprenorphine, hydrocodone, hydromorphone, morphine, O-desmethyl-tramadol, oxycodone, oxymorphone, tapentadol, tramadol) against 9 pain-related receptor targets (MOR, delta opioid receptor [DOR], kappa opioid receptor [KOR], nociceptin receptor [NOP], cannabinoid receptor type 1 [CB1], sigma-1 receptor [σ1R], and the monoamine transporters [NET/SERT/DAT]) expressed in cells using radioligand binding and functional activity assays. We found several novel interactions, including monoamine transporter activation by buprenorphine and σ1R binding by hydrocodone and tapentadol. Tail flick anti-nociception experiments with CD-1 mice demonstrated that the monoamine transporter inhibitor duloxetine selectively promoted buprenorphine anti-nociception while producing no effects by itself or in combination with the most MOR-selective drug oxymorphone, providing evidence that these novel interactions could be relevant in vivo. Our findings provide a comprehensive picture of the receptor interaction profiles of clinically relevant opioids, which has not previously been performed. Our findings also suggest novel receptor interactions for future investigation that could explain some of the disparities observed between opioid performance in vitro and in vivo.


Assuntos
Analgésicos Opioides , Receptores Opioides , Analgésicos Opioides/química , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/farmacologia , Animais , Células CHO , Cricetulus , Células HEK293 , Humanos , Camundongos , Receptores Opioides/química , Receptores Opioides/genética , Receptores Opioides/metabolismo
15.
Drug Alcohol Depend ; 200: 168-180, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31122724

RESUMO

BACKGROUND: The use of oral methadone in opioid substitution treatment (OST) for the management of opioid use disorder is established clinical practice. Confounding treatment is the increased risks of contracting Mycobacterium tuberculosis, the mainstay treatment of which incorporates the potent CYP 2B6 inducer rifampicin. METHODS: This study applied pharmacokinetic modelling using virtual clinical trials, to pharmacokinetically quantify the extent and impact of rifampicin-mediated drug-drug interactions (DDI) on methadone plasma concentrations. An R-methadone model was developed and validated against 11 retrospective clinical studies prior to use in all subsequent studies. The aims were to investigate: (i) the impact of the DDI on daily methadone doses of 60 mg, 90 mg and 120 mg; (ii) dose escalation during rifampicin and (iii) dose reduction following rifampicin cessation. RESULTS: A dose increase to 160 mg daily during rifampicin treatment phases was required to maintain peak methadone plasma concentrations within a derived therapeutic window of 80-700 ng/mL. Dose escalation prior to rifampicin initiation was not required and resulted in an increase in subjects with supra-therapeutic concentrations. However, during rifampicin cessation, a dose reduction of 10 mg every 2 days commencing prior to rifampicin cessation, ensured that most patients possessed a peak methadone plasma concentration within an optimal therapeutic window. IMPLICATIONS: Rifampicin significantly alters methadone plasma concentrations and necessitates dose adjustments. Daily doses of almost double those used perhaps more commonly in clinical practice are required for optimal plasma concentration and careful consideration of dose reduction strategies would be required during the deinduction phase.


Assuntos
Analgésicos Opioides/farmacocinética , Metadona/farmacocinética , Modelos Biológicos , Rifampina/farmacocinética , Adulto , Analgésicos Opioides/administração & dosagem , Relação Dose-Resposta a Droga , Interações Medicamentosas/fisiologia , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metadona/administração & dosagem , Pessoa de Meia-Idade , Inibidores da Síntese de Ácido Nucleico/administração & dosagem , Inibidores da Síntese de Ácido Nucleico/farmacocinética , Tratamento de Substituição de Opiáceos/métodos , Tratamento de Substituição de Opiáceos/normas , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/metabolismo , Estudos Retrospectivos , Rifampina/administração & dosagem
16.
Anesth Analg ; 128(6): 1234-1241, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31094793

RESUMO

BACKGROUND: The transversus abdominis plane (TAP) block has become a common regional anesthesia technique for pain management in a wide variety of abdominal procedures. Evidence to support any particular local anesthetic regimen as well as pharmacokinetic and systemic toxicity risks of TAP block remain insufficiently studied in children. The aim of this study was to compare the analgesic effects and investigate pharmacokinetic profile of levobupivacaine after ultrasound-guided TAP block using a low volume/high concentration (LVHC) or a high volume/low concentration (HVLC) solution in children. METHODS: This prospective randomized study included children scheduled for day-case inguinal surgery. Children were randomized to receive TAP block using 0.4 mg·kg levobupivacaine as either HVLC (0.2 mL·kg of 0.2% levobupivacaine) or LVHC (0.1 mL·kg of 0.4% levobupivacaine). The primary outcome was the number of children who required opioid rescue analgesia postoperatively. Pharmacokinetic profile study of levobupivacaine was also performed. RESULTS: Seventy patients were equally randomized, and 65 were included in the final analysis. Seventy-one percent of patients did not require any postoperative opioid analgesia. The number of patients who received rescue analgesia was 12 (35%) in the LVHC group and 7 (23%) in the HVLC group (relative risk, 0.64; 95% confidence interval [CI], 0.29-1.42; P = .26). Mean pain scores (FLACC [faces, legs, activity, cry, and consolability]) at postanesthesia care unit discharge did not differ between LVHC and HVLC groups, respectively, 0.39 ± 0.86 and 1 ± 1.71 with mean group difference -0.60 (95% CI, -1.27 to 0.06; P = .08). The pharmacokinetic profile of levobupivacaine was comparable in the 2 groups: the mean total and free levobupivacaine peak concentrations were 379 ± 248 and 3.95 ± 3.16 ng·mL, respectively, occurring 22.5 ± 11 minutes after injection. The highest total and free levobupivacaine concentrations collected, respectively, 1360 and 15.1 ng·mL, remained far below theoretical toxic thresholds. CONCLUSIONS: In children, quality of postoperative pain control provided by TAP block using levobupivacaine 0.4 mg·kg administered as either HVLC or LVHC did not differ and was associated with a very low risk of local anesthetic systemic toxicity.


Assuntos
Músculos Abdominais/efeitos dos fármacos , Anestesia Local/métodos , Levobupivacaína/farmacocinética , Bloqueio Nervoso/métodos , Analgesia/métodos , Analgésicos Opioides/farmacocinética , Anestésicos Locais/farmacocinética , Bupivacaína/farmacocinética , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Lactente , Masculino , Manejo da Dor/métodos , Dor Pós-Operatória/tratamento farmacológico , Estudos Prospectivos , Ultrassonografia
17.
Vet Anaesth Analg ; 46(4): 501-509, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30982709

RESUMO

OBJECTIVE: To determine the effects of fluconazole on oral methadone pharmacokinetics and central effects mediated by opioid receptors in dogs. STUDY DESIGN: Prospective, incomplete block. ANIMALS: A total of 12 healthy Beagle dogs. METHODS: Dogs were randomly allocated into two groups of six dogs. In total, four treatments (two treatments/group) were administered including: oral methadone (1 mg kg-1); oral fluconazole (5 mg kg-1) every 12 hours starting 24 hours prior to oral methadone (1 mg kg-1); oral fluconazole (2.5 mg kg-1) every 12 hours starting 24 hours prior to oral methadone (1 mg kg-1); and oral fluconazole (5 mg kg-1) every 24 hours starting 12 hours prior to oral methadone (1 mg kg-1). At least 28 days were implemented as a washout period between fluconazole treatments. Rectal temperature (RT), heart rate (HR), respiratory rate (fR), sedation scores and blood samples were obtained for 24 hours after methadone administration. Plasma drug concentrations were measured with liquid chromatography/mass spectrometry. RESULTS: Significantly higher maximum plasma methadone concentration (mean, 25-46 ng mL-1) occurred in all fluconazole-administered treatments than in methadone alone (1.5 ng mL-1). The mean 12 hour methadone plasma concentration in fluconazole treatments was 11-20 ng mL-1. Significantly decreased RT and variable sedation occurred in all fluconazole treatments, but no changes occurred with methadone alone. There were no differences in HR or fR among treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Fluconazole significantly increases the extent and duration of oral methadone exposure in dogs resulting in significant central opioid effects.


Assuntos
Analgésicos Opioides/farmacocinética , Antifúngicos/farmacocinética , Fluconazol/farmacocinética , Metadona/farmacocinética , Administração Oral , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Antifúngicos/administração & dosagem , Estudos Cross-Over , Cães , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Fluconazol/administração & dosagem , Fluconazol/farmacologia , Masculino , Metadona/administração & dosagem , Metadona/sangue , Metadona/farmacologia
18.
Expert Opin Investig Drugs ; 28(5): 399-409, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31023091

RESUMO

INTRODUCTION: Pain management is a major unmet need due to the suboptimal efficacy and undesirable side effects of current analgesics. Multimodal therapies recruiting complementary mechanisms of action may help address this. Co-crystals incorporating two active pharmaceutical ingredients (APIs) constitute an innovative approach to multimodal therapy, particularly if modification of the physicochemical properties of constituent APIs can be translated into clinical benefits. AREAS COVERED: The preclinical and clinical profiles of Co-Crystal of Tramadol-Celecoxib (CTC), a novel API-API co-crystal (1:1 molecular ratio of rac-tramadol.hydrochloride and celecoxib) are described. EXPERT OPINION: CTC may provide a relevant addition to pain therapy due to its: i) unique co-crystal structure conferring differentiated intrinsic dissolution profiles on constituent APIs, ii) modified clinical pharmacokinetics (slower absorption of tramadol and faster absorption of celecoxib) compared with commercially available single-entity reference products (in agreement with modified dissolution rates), iii) superior benefit-risk ratio compared with reference products (suggested by preclinical synergistic antinociceptive effects, without potentiation of adverse effects), and iv) efficacy in a phase 2 trial of moderate to severe pain following extraction of ≥2 impacted third molars requiring bone removal, where CTC doses containing low doses of APIs exerted a significant effect. Phase 3 studies are currently ongoing.


Assuntos
Celecoxib/administração & dosagem , Dor/tratamento farmacológico , Tramadol/administração & dosagem , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/química , Analgésicos Opioides/farmacocinética , Animais , Celecoxib/química , Celecoxib/farmacocinética , Cristalização , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Combinação de Medicamentos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Humanos , Tramadol/química , Tramadol/farmacocinética
19.
Eur J Drug Metab Pharmacokinet ; 44(5): 591-609, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31006834

RESUMO

Pain management in the pediatric population is complex for many reasons. Mild pain is usually managed quite well with oral acetaminophen or ibuprofen. Situations involving more severe pain often require the use of an opioid, which may be administered by many different routes, depending on clinical necessity. Acute and chronic disease states, as well as the constantly changing maturational process, produce unique challenges at every level of pediatrics in dosing and management of all medications, especially with regard to high-risk opioids. Although there has been significant progress in the understanding of opioid pharmacokinetics and pharmacodynamics in neonates, infants, children, and adolescents, somewhat limited data exist from which necessary information, concerning the safe and effective use of these agents, may be drawn. The evidence here provided is intended to be helpful in directing the practitioner to patient-specific reasons for preferring one opioid over another. As our knowledge of opioids and their effects has grown, it has become clear that older medications like codeine and meperidine (pethidine) have very limited use in pediatrics. This review provides pharmacokinetic and pharmacodynamic evidence on the currently available opioids: morphine, fentanyl (and derivatives), codeine, meperidine, oxycodone, hydrocodone, hydromorphone, methadone, buprenorphine, butorphanol, nalbuphine, pentazocin, ketobemidone, tramadol, piritramide, naloxone and naltrexone. Morphine, being the most studied opioid analgesic, is the standard against which all others are compared. Pharmacokinetic parameters of morphine that have been found in neonates, i.e., higher volume of distribution, immature metabolic processes that develop at various rates, elimination that is variable based on age and weight, as well as treated and untreated disease processes, are an example of all opioids in the population discussed in this review. Outside the premature and neonatal population, the use of opioids in infants, children, and adolescents quickly begins to resemble the established values found in adults. As such, the concerns (risks) of these medications become comparable to those seen in adults.


Assuntos
Analgésicos Opioides/farmacologia , Analgésicos Opioides/farmacocinética , Animais , Criança , Humanos , Lactente , Recém-Nascido , Dor/tratamento farmacológico , Dor/metabolismo , Manejo da Dor/métodos
20.
J Vet Pharmacol Ther ; 42(4): 401-410, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30919469

RESUMO

The objective of the current study was to describe and characterize the pharmacokinetics and selected pharmacodynamic effects of morphine and its two major metabolites in horses following several doses of morphine. A total of ten horses were administered a single intravenous dose of morphine: 0.05, 0.1, 0.2, or 0.5 mg/kg, or saline control. Blood samples were collected up to 72 hr, analyzed for morphine, and metabolites by LC/MS/MS, and pharmacokinetic parameters were determined. Step count, heart rate and rhythm, gastrointestinal borborygmi, fecal output, packed cell volume, and total protein were also assessed. Morphine-3 glucuronide (M3G) was the predominant metabolite detected, with concentrations exceeding those of morphine-6 glucuronide (M6G) at all time points. Maximal concentrations of M3G and M6G ranged from 55.1 to 504 and 6.2 to 28.4 ng/ml, respectively, across dose groups. The initial assessment of morphine pharmacokinetics was done using noncompartmental analysis (NCA). The volume of distribution at steady-state and systemic clearance ranged from 9.40 to 16.9 L/kg and 23.3 to 32.4 ml min-1  kg-1 , respectively. Adverse effects included signs of decreased gastrointestinal motility and increased central nervous excitation. There was a correlation between increasing doses of morphine, increases in M3G concentrations, and adverse effects. Findings from this study support direct administration of purified M3G and M6G to horses to better characterize the pharmacokinetics of morphine and its metabolites and to assess pharmacodynamic activity of these metabolites.


Assuntos
Analgésicos Opioides/farmacocinética , Cavalos/sangue , Derivados da Morfina/urina , Morfina/farmacocinética , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/urina , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Injeções Intravenosas , Masculino , Morfina/administração & dosagem , Morfina/urina
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