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1.
Toxicol Appl Pharmacol ; 419: 115483, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33722667

RESUMO

The number of new psychoactive substances (NPS) on the illicit drug market increases fast, posing a need to urgently understand their toxicity and behavioural effects. However, with currently available rodent models, NPS assessment is limited to a few substances per year. Therefore, zebrafish (Danio rerio) embryos and larvae have been suggested as an alternative model that would require less time and resources to perform an initial assessment and could help to prioritize substances for subsequent evaluation in rodents. To validate this model, more information on the concordance of zebrafish larvae and mammalian responses to specific classes of NPS is needed. Here, we studied toxicity and behavioural effects of opioids in zebrafish early life stages. Synthetic opioids are a class of NPS that are often used in pain medication but also frequently abused, having caused multiple intoxications and fatalities recently. Our data shows that fentanyl derivatives were the most toxic among the tested opioids, with toxicity in the zebrafish embryo toxicity test decreasing in the following order: butyrfentanyl>3-methylfentanyl>fentanyl>tramadol> O-desmethyltramadol>morphine. Similar to rodents, tramadol as well as fentanyl and its derivatives led to hypoactive behaviour in zebrafish larvae, with 3-methylfentanyl being the most potent. Physico-chemical properties-based predictions of chemicals' uptake into zebrafish embryos and larvae correlated well with the effects observed. Further, the biotransformation pattern of butyrfentanyl in zebrafish larvae was reminiscent of that in humans. Comparison of toxicity and behavioural responses to opioids in zebrafish and rodents supports zebrafish as a suitable alternative model for rapidly testing synthetic opioids.


Assuntos
Analgésicos Opioides/toxicidade , Fentanila/toxicidade , Peixe-Zebra/embriologia , Analgésicos Opioides/farmacocinética , Animais , Comportamento Animal/efeitos dos fármacos , Biotransformação , Carga Corporal (Radioterapia) , Relação Dose-Resposta a Droga , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Fentanila/análogos & derivados , Fentanila/farmacocinética , Larva/efeitos dos fármacos , Larva/metabolismo , Locomoção/efeitos dos fármacos , Modelos Animais , Reprodutibilidade dos Testes , Especificidade da Espécie , Toxicocinética , Peixe-Zebra/metabolismo
2.
Molecules ; 26(2)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33467733

RESUMO

The precise and reliable determination of buprenorphine concentration is fundamental in certain medical or research applications, particularly in pharmacokinetic studies of this opioid. The main challenge is, however, the development of an analytical method that is sensitive enough, as the detected in vivo concentrations often fall in very low ranges. Thus, in this study we aimed at developing a sensitive, repeatable, cost-efficient, and easy HPLC analytical protocol for buprenorphine in rabbit plasma. In order to obtain this, the HPLC-MS2 system was used to elaborate and validate the method for samples purified with liquid-liquid extraction. Fragment ions 468.6→396.2 and 468.6→414.2 were monitored, and the method resulted in a high repeatability and reproducibility and a limit of quantification of 0.25 µg/L with a recovery of 98.7-109.0%. The method was linear in a range of 0.25-2000 µg/L. The suitability of the analytical procedure was tested in rabbits in a pilot pharmacokinetic study, and it was revealed that the method was suitable for comprehensively describing the pharmacokinetic profile after buprenorphine intravenous administration at a dose of 300 µg/kg. Thus, the method suitability for pharmacokinetic application was confirmed by both the good validation results of the method and successful in vivo tests in rabbits.


Assuntos
Analgésicos Opioides/sangue , Analgésicos Opioides/farmacocinética , Buprenorfina/sangue , Buprenorfina/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Administração Intravenosa , Analgésicos Opioides/administração & dosagem , Animais , Buprenorfina/administração & dosagem , Masculino , Coelhos , Distribuição Tecidual
3.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33374986

RESUMO

In previous work we evaluated an opioid glycopeptide with mixed µ/δ-opioid receptor agonism that was a congener of leu-enkephalin, MMP-2200. The glycopeptide analogue showed penetration of the blood-brain barrier (BBB) after systemic administration to rats, as well as profound central effects in models of Parkinson's disease (PD) and levodopa (L-DOPA)-induced dyskinesia (LID). In the present study, we tested the glycopeptide BBI-11008 with selective δ-opioid receptor agonism, an analogue of deltorphin, a peptide secreted from the skin of frogs (genus Phyllomedusa). We tested BBI-11008 for BBB-penetration after intraperitoneal (i.p.) injection and evaluated effects in LID rats. BBI-11008 (10 mg/kg) demonstrated good CNS-penetrance as shown by microdialysis and mass spectrometric analysis, with peak concentration levels of 150 pM in the striatum. While BBI-11008 at both 10 and 20 mg/kg produced no effect on levodopa-induced limb, axial and oral (LAO) abnormal involuntary movements (AIMs), it reduced the levodopa-induced locomotor AIMs by 50% after systemic injection. The N-methyl-D-aspartate receptor antagonist MK-801 reduced levodopa-induced LAO AIMs, but worsened PD symptoms in this model. Co-administration of MMP-2200 had been shown prior to block the MK-801-induced pro-Parkinsonian activity. Interestingly, BBI-11008 was not able to block the pro-Parkinsonian effect of MK-801 in the LID model, further indicating that a balance of mu- and delta-opioid agonism is required for this modulation. In summary, this study illustrates another example of meaningful BBB-penetration of a glycopeptide analogue of a peptide to achieve a central behavioral effect, providing additional evidence for the glycosylation technique as a method to harness therapeutic potential of peptides.


Assuntos
Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/fisiopatologia , Glicopeptídeos/farmacologia , Atividade Motora/efeitos dos fármacos , Doença de Parkinson Secundária/fisiopatologia , Receptores Opioides delta/agonistas , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/farmacologia , Animais , Corpo Estriado/metabolismo , Maleato de Dizocilpina/farmacologia , Discinesia Induzida por Medicamentos/metabolismo , Glicopeptídeos/administração & dosagem , Glicopeptídeos/farmacocinética , Levodopa , Masculino , Atividade Motora/fisiologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/metabolismo , Ratos Sprague-Dawley , Receptores Opioides delta/metabolismo
4.
Obstet Gynecol ; 136(5): 905-907, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33030873

RESUMO

BACKGROUND: We report a case of delayed norfentanyl clearance in a 33-year-old pregnant woman. Norfentanyl is the major metabolite of fentanyl. CASE: A multigravid woman with opioid use disorder presented at 7 weeks of gestation for treatment. Despite opioid abstinence, her urine was positive for norfentanyl on 10 distinct gas chromatography-mass spectrometry urine screens. The results demonstrated a steady decrease of norfentanyl over the course of 70 days after her last fentanyl usage, far exceeding expected rates of fentanyl clearance. CONCLUSION: This case highlights the importance of acknowledging pregnancy, genetic, or medication-induced changes to fentanyl pharmacokinetics when interpreting urine tests, especially given the potential sequelae of a false-positive urine test result.


Assuntos
Analgésicos Opioides/farmacocinética , Fentanila/análogos & derivados , Fentanila/farmacocinética , Transtornos Relacionados ao Uso de Opioides/urina , Complicações na Gravidez/urina , Adulto , Feminino , Fentanila/urina , Humanos , Taxa de Depuração Metabólica , Gravidez
5.
J Opioid Manag ; 16(4): 297-306, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32885838

RESUMO

Tramadol is a centrally acting dual-mechanism (opioid and monoamine reuptake inhibition) analgesic that has been noted to have a lower risk of abuse compared to conventional opioids such as morphine. Oral tramadol has been ap-proved in the United States since 1995 and intravenous (IV) tramadol has been widely prescribed outside the United States (OUS); nevertheless, IV tramadol has not yet been approved for use in the United States. This paper provides a review of the pharmacokinetics (PK) of the IV tramadol dosing regimen being developed in the United States, its abuse potential as documented in the literature, and its safety record in clinical practice, and discusses how IV tramadol may become a useful option for patients in the United States with acute pain.


Assuntos
Dor Aguda , Analgésicos Opioides , Transtornos Relacionados ao Uso de Opioides , Tramadol , Dor Aguda/tratamento farmacológico , Administração Intravenosa , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacocinética , Humanos , Morfina , Tramadol/efeitos adversos , Tramadol/farmacocinética
6.
AAPS PharmSciTech ; 21(7): 244, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32856114

RESUMO

Ethylmorphine hydrochloride (EtM) is a derivative of morphine used as analgesic to treat severe pain in case of cancer and bone injury. This study aimed to formulate and evaluate core in cup tablets containing 2 doses of EtM, the cup was formulated as lyophilized oro-dispersible tablet (ODT) for immediate release (IR), and the core was formulated as directly compressed tablet for sustained release (SR). Factorial design was adopted for the optimization of tablets prepared via lyophilized form and direct compression techniques: a 41.22 design was used for the former, while a 32 one was used for the latter. All prepared tablets showed acceptable physical properties which were in accordance with pharmacopeial standards. Two lyophilized ODTs (F9 and F10) formulae were selected as the cup for instant release. While one directly compressed tablet formula (S6) was selected based on the in vitro release profile to represent the sustained core, the outcome was 2 core in cup tablets, namely B1 and B2 which were evaluated for their in vivo absorption and showed a maximum plasma concentration (Cpmax) of 354.12 ± 17.55 ng/mL and 350.82 ± 12.15 ng/mL respectively attained after 3.0 h which were twofolds significantly higher in comparison to the market tablet with Cpmax of only 172.05 ± 12.53 ng/mL attained after 2.20 ± 0.24 h.


Assuntos
Analgésicos Opioides/química , Analgésicos Opioides/farmacocinética , Etilmorfina/química , Etilmorfina/farmacocinética , Dor/tratamento farmacológico , Analgésicos Opioides/uso terapêutico , Animais , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Composição de Medicamentos , Etilmorfina/uso terapêutico , Liofilização , Masculino , Ratos , Comprimidos
7.
Br J Anaesth ; 125(6): 976-985, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32861508

RESUMO

BACKGROUND: We aimed to characterise the population pharmacokinetics of fentanyl in adults and to determine the minimum effective concentration (MEC) and minimum effective analgesic concentration (MEAC) of i.v. fentanyl in patients after major abdominal open surgery. METHODS: In the pharmacokinetic study, subjects received an intravenous bolus of fentanyl 100 µg during operation, and arterial blood was sampled at pre-set intervals. In addition, data from previously published fentanyl pharmacokinetic studies were incorporated to build a pharmacokinetic model. In the MEAC study, subjects were asked to rate their pain every 10 min using a VAS (0=no pain, 10=most severe pain) in the PACU. The first blood sample was obtained when wound pain was rated as ≥3 at rest or ≥5 during compression. Then, fentanyl 50 µg was administered every 10 min until the pain intensity had decreased to <3 at rest and <5 during compression, at which point the second blood was sampled and the first MEAC of fentanyl was measured. The same procedure was repeated to obtain a third sample (MEC) and a fourth sample (second MEAC). RESULTS: In the population pharmacokinetic study (n=95), the plasma concentration of fentanyl over time was well-described by the three-compartment mammillary model using an allometric expression. The V1, V2, V3, Cl, Q1, and Q2 of a 70 kg subject were 10.1, 26.5, 206 L, 0.704, 2.38, and 1.49 L min-1, respectively. In the MEAC study (n=30), the median (inter-quartile range) MEC and MEAC were 0.72 (0.58-1.05) ng ml-1, and 0.99 (0.76-1.28) ng ml-1, respectively. CONCLUSION: These results provide a scientific basis for the use of fentanyl for acute postoperative pain management in surgical patients. CLINICAL TRIAL REGISTRATION: KCT0003273 (http://cris.nih.go.kr).


Assuntos
Abdome/cirurgia , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/uso terapêutico , Fentanila/farmacocinética , Fentanila/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Conjuntos de Dados como Assunto , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Curr Opin Anaesthesiol ; 33(4): 483-489, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32530894

RESUMO

PURPOSE OF REVIEW: Growing concerns about the environmental effects of volatile anaesthetics are likely to lead to increased use of intravenous anaesthetic drugs. Pharmacokinetic/pharmacodynamic (PKPD) models can increase the accuracy of intravenous drug titration, especially in populations that differ from the 'average.' However, with a growing number of PKPD models, and other technology available to date, it can be hard to see the wood for the trees. This review attempts to guide the reader through the PKPD jungle. RECENT FINDINGS: General purpose PKPD models for propofol and remifentanil designed to apply to a broader population, including children, the elderly and the obese, reduce the need for population-specific models. PKPD models for drugs such as dexmedetomidine and antimicrobial agents may be useful for procedural sedation or in the ICU. Technological advances such as Bayesian model adjustment based on point-of-care plasma concentration measurements, closed-loop drug delivery and artificial intelligence may improve the ease of use of the anaesthetic drugs and increase the accuracy of titration. SUMMARY: Newer and more complex modelling techniques and technological advancements can help to deliver anaesthetic drugs, sedatives and other drugs in a more stable and thereby safer way.


Assuntos
Analgésicos Opioides/farmacologia , Analgésicos Opioides/farmacocinética , Anestésicos/farmacologia , Anestésicos/farmacocinética , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/farmacocinética , Propofol/farmacologia , Propofol/farmacocinética , Remifentanil/farmacologia , Remifentanil/farmacocinética , Idoso , Anestesia , Anestésicos Intravenosos , Inteligência Artificial , Teorema de Bayes , Criança , Relação Dose-Resposta a Droga , Humanos , Modelos Biológicos
10.
J Opioid Manag ; 16(3): 209-214, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32421841

RESUMO

Naloxone is an opioid antagonist used for the acute treatment of opioid overdoses. There has been a dramatic increase of deaths due to synthetic opioids such as fentanyl, some requiring multiple doses of naloxone for reversal of opioid tox-icity. Fentanyl appears to differ from other opiates as having a very rapid onset and transport in and out of the central nervous system (CNS). Fentanyl is therefore widely distributed in the CNS. Furthermore, a high range of systemic levels of fentanyl have been observed in overdose victims. Taken together, we believe it is very likely that higher doses of naloxone are needed to combat this new era of overdoses. We examined the bioavailability of an investigational 5 mg intramuscular naloxone in a prefilled syringe (PFS) compared to 2 mg intramuscular naloxone in an autoinjector (AI) at the current approved dose in a crossover design which included 14 healthy subjects. Overall, both doses were well tol-erated with no adverse events noted during the trial. The pharmacokinetic results showed that a higher dose of intra-muscular naloxone hydrochloride increases Cmax, AUC, and t1/2; however, Tmax was similar for both treatments. Statistical analysis indicated that there were statistical differences between the test and reference treatments for Cmax, AUCs, and t1/2 with ratios of test to reference for Cmax of 337.1 percent (CI: 263.3 percent, 431.5 percent), AUC0-t of 277.5 percent (CI: 260.4 percent, 295.7 percent), AUC0-inf of 273.4 percent (CI: 255.6 percent, 292.4 percent), and t1/2 of 110.5 percent (CI: 95.5, 127.9). These results are consistent with the study rationale that indicated higher doses of intramuscular naloxone hy-drochloride would result in higher Cmax and AUCs. These PK characteristics may be desirable for reversing opioid toxicity caused by the higher, more potent synthetic opioids.


Assuntos
Analgésicos Opioides , Naloxona , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacocinética , Disponibilidade Biológica , Estudos Cross-Over , Voluntários Saudáveis , Humanos , Naloxona/administração & dosagem , Naloxona/farmacocinética
11.
J Opioid Manag ; 16(2): 127-139, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32329888

RESUMO

Opioids can be an effective treatment option for appropriate patients with chronic pain for whom nonpharmacological or nonopioid treatment does not provide adequate pain relief. However, extended-release (ER) opioid formulations, because of their high drug content, are attractive options for nonmedical use and abuse. Xtampza® ER (oxycodone DETERx®) capsules, an ER abuse-deterrent formulation (ADF), contain microspheres that combine oxycodone with inactive ingredients to increase the difficulty of tampering with the ER mechanism. The aim of this article is to review five previously published studies highlighting the impact of physical manipula-tion (ie, crushing and chewing) on the pharmacokinetic (PK) properties of orally administered Xtampza ER compared with immedi-ate-release (IR) oxycodone and/or reformulated OxyContin® (the first approved oxycodone ER ADF). Across five studies, manipulated (crushed or chewed) Xtampza ER retained an ER PK profile similar to that of intact Xtampza ER, with respect to maximum plasma con-centration (Cmax) and time to Cmax. Additionally, bioequivalence was established between manipulated and intact Xtampza ER, based on Cmax and area under the concentration-time curve values in healthy volunteers and nondependent recreational opioid users. In contrast, crushed OxyContin failed to retain the ER PK profile of intact OxyContin and was bioequivalent to IR oxycodone, based on Cmax in healthy volunteers. The retention of ER PK properties when capsule contents are physically manipulated before oral administra-tion suggests Xtampza ER has lower potential to be manipulated for oral abuse when compared with IR oxycodone or OxyContin.


Assuntos
Analgésicos Opioides , Dor Crônica , Transtornos Relacionados ao Uso de Opioides , Oxicodona , Analgésicos Opioides/química , Analgésicos Opioides/farmacocinética , Preparações de Ação Retardada , Humanos , Oxicodona/química , Oxicodona/farmacocinética
12.
Clin Pharmacol Ther ; 107(4): 934-943, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31957870

RESUMO

Postmarketing population pharmacokinetic (PK) and pharmacodynamic (PD) studies can be useful to capture patient characteristics affecting PK or PD in real-world settings. These studies require longitudinally measured dose, outcomes, and covariates in large numbers of patients; however, prospective data collection is cost-prohibitive. Electronic health records (EHRs) can be an excellent source for such data, but there are challenges, including accurate ascertainment of drug dose. We developed a standardized system to prepare datasets from EHRs for population PK/PD studies. Our system handles a variety of tasks involving data extraction from clinical text using a natural language processing algorithm, data processing, and data building. Applying this system, we performed a fentanyl population PK analysis, resulting in comparable parameter estimates to a prior study. This new system makes the EHR data extraction and preparation process more efficient and accurate and provides a powerful tool to facilitate postmarketing population PK/PD studies using information available in EHRs.


Assuntos
Interpretação Estatística de Dados , Registros Eletrônicos de Saúde/estatística & dados numéricos , Fentanila/farmacocinética , Lamotrigina/farmacocinética , Vigilância de Produtos Comercializados/estatística & dados numéricos , Tacrolimo/farmacocinética , Adolescente , Adulto , Idoso , Analgésicos Opioides/farmacocinética , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vigilância de Produtos Comercializados/métodos , Adulto Jovem
13.
J Med Case Rep ; 14(1): 1, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900197

RESUMO

BACKGROUND: Sufentanil is a potent opioid uncommonly used to manage pain and is rarely administered via an intrathecal pain pump system. CASE PRESENTATION: This case illustrates the use of intrathecal sufentanil in a 50-year-old Caucasian man for the management of chronic pain; however, the intrathecal drug delivery system experienced a malfunction which led to 1/100th output of the correct dosage. Interesting aspects of this case report include the uncommon choice of sufentanil use for an intrathecal drug delivery system, as well as the unusual pharmacokinetics of this drug. Specifically, this patient did not experience the major withdrawal that would be expected given significant under dosing of opioid, and this may be explained by the lipophilicity and context-sensitive half-times of sufentanil. CONCLUSIONS: Because of the absence of a clinically significant withdrawal in this case report, clinicians must be aware of relevant pharmacokinetic properties and unusual intrathecal drug delivery system technologies that influence a patient's response when device malfunction occurs.


Assuntos
Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacocinética , Falha de Equipamento , Sufentanil/administração & dosagem , Sufentanil/farmacocinética , Sistemas de Liberação de Medicamentos/instrumentação , Humanos , Injeções Espinhais/instrumentação , Masculino , Pessoa de Meia-Idade , Medição da Dor
14.
J Med Chem ; 63(5): 2673-2687, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31834798

RESUMO

Four novel fluorinated cyclic analogues of biphalin with excellent to modest binding affinity for µ-, δ-, and κ-receptors were synthesized. The cyclic peptides have a combination of piperazine or hydrazine linker with or without a xylene bridge. Among the ligands, MACE3 demonstrated a better activity than biphalin after intravenous administration, and its corresponding analogue incorporating the hydrazine linker (MACE2) was able to induce longer lasting analgesia following subcutaneous administration. An analogue of MACE2 containing 2,6-dimethyl-l-tyrosine (MACE4) showed the best potency and in vivo antinociceptive activity of this series.


Assuntos
Analgésicos Opioides/uso terapêutico , Peptídeos Opioides/uso terapêutico , Dor/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Administração Intravenosa , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/farmacologia , Animais , Células CHO , Cricetulus , Feminino , Humanos , Infusões Subcutâneas , Masculino , Camundongos , Modelos Moleculares , Peptídeos Opioides/administração & dosagem , Peptídeos Opioides/farmacocinética , Peptídeos Opioides/farmacologia , Dor/metabolismo , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/farmacocinética , Peptídeos Cíclicos/farmacologia , Receptores Opioides/metabolismo
15.
Vet Anaesth Analg ; 47(1): 119-128, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31806432

RESUMO

OBJECTIVE: To compare the perioperative effects and pharmacoeconomics of peripheral nerve blocks (PNBs) versus fentanyl target-controlled infusion (fTCI) in dogs undergoing tibial plateau levelling osteotomy (TPLO). STUDY DESIGN: Randomized clinical study. ANIMALS: A total of 39 dogs undergoing unilateral TPLO. METHODS: After acepromazine and methadone, anaesthesia was induced with propofol and maintained with isoflurane. Dogs were allocated to group fTCI [target plasma concentration (TPC) 1 ng mL-1] or group PNB (nerve stimulator-guided femoral-sciatic block using 0.2 and 0.1 mL kg-1 of levobupivacaine 0.5%, respectively). If nociceptive response occurred, isoflurane was increased by 0.1%, and TPC was increased by 0.5 ng mL-1 in group fTCI; a fentanyl bolus (1 µg kg-1) was administered in group PNB. During the first 24 postoperative hours, methadone (0.2 mg kg-1) was administered intramuscularly according to the Short Form Glasgow Composite Pain Scale, or if pain was equal to 5/24 or 4/20 for two consecutive assessments, or if the dog was non-weight bearing. The area under the curve (AUC) of pain scores, cumulative postoperative methadone requirement, food intake and pharmacoeconomic implications were calculated. RESULTS: Incidence of bradycardia (p = 0.025), nociceptive response to surgery (p = 0.041) and AUC of pain scores (p < 0.0001) were greater in group fTCI. Postoperatively, 16/19 (84.2%) and eight/20 (40%) dogs in groups fTCI and PNB, respectively, were given at least one dose of methadone (p = 0.0079). Food intake was greater in group PNB (p = 0.049). Although total cost was not different (p = 0.083), PNB was more cost-effective in dogs weighing >15 kg. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with group fTCI, incidence of bradycardia, nociceptive response to surgery, postoperative pain scores, cumulative methadone requirement were lower, and food intake was greater in group PNB, with an economic advantage in dogs weighing >15 kg.


Assuntos
Analgésicos Opioides/administração & dosagem , Anestésicos Locais/administração & dosagem , Cães/cirurgia , Fentanila/administração & dosagem , Levobupivacaína/administração & dosagem , Bloqueio Nervoso/veterinária , Osteotomia/veterinária , Dor Pós-Operatória/veterinária , Tíbia/cirurgia , Analgésicos Opioides/farmacocinética , Anestésicos Locais/farmacocinética , Animais , Feminino , Fentanila/farmacocinética , Infusões Intravenosas/veterinária , Levobupivacaína/farmacocinética , Masculino , Bloqueio Nervoso/economia , Medição da Dor/veterinária , Dor Pós-Operatória/prevenção & controle , Nervo Isquiático
16.
Anesthesiology ; 132(3): 491-503, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31794512

RESUMO

BACKGROUND: Patients often use complementary and alternative herbal medicines, hence, potential exists for adverse herb-drug interactions. Fentanyl is metabolized by hepatic CYP3A4 and considered transported by blood-brain barrier P-glycoprotein. Both disposition processes could be upregulated by the herbal St. John's wort. This investigation evaluated effects of St. John's wort on fixed-dose and apparent steady-state IV fentanyl pharmacokinetics, pharmacodynamics, and clinical effects. METHODS: Healthy volunteers received a fentanyl fixed-dose infusion and an individually tailored target controlled infusion on separate days, before and after 30-day St. John's wort (300 mg thrice daily; n = 8) or placebo control (n = 8) in a randomized parallel-group design. Fentanyl plasma concentrations, pupil diameter, analgesic response to experimental pain (cold pressor), subjective side effects, and cognitive effects were measured. Plasma fentanyl concentrations and changes in pupil diameter were subjected to pharmacokinetic-pharmacodynamic modeling. RESULTS: St. John's wort did not alter fentanyl pharmacokinetics. Clearance (l/min) before and after St. John's wort (1.13 ± 0.29 and 1.24 ± 0.26, respectively) or placebo (0.96 ± 0.28 and 1.12 ± 0.27, respectively) were not different. St. John's wort also did not affect fentanyl pharmacodynamics as measured by pupil constriction after fixed-dose and tailored fentanyl infusions. EC50 (ng/ml) was 1.1 ± 0.7 and 1.4 ± 0.9 before and after St. John's wort versus 1.2 ± 0.8 and 1.4 ± 1.7 before and after placebo. Effect site equilibration time, T½,ke0 (min), was 12.8 ± 5.3 and 11.3 ± 6.4 before and after St. John's wort versus 11.4 ± 6.4 and 11.1 ± 5.6 before and after placebo. St. John's wort had no influence on analgesia, cognitive performance, or somatic cognitive-affective effects of fentanyl. CONCLUSIONS: St. John's wort did not alter fentanyl pharmacokinetics, pharmacodynamics or clinical effects, suggesting no effect on hepatic clearance or blood-brain barrier efflux. Patients taking St. John's wort will likely not respond differently to IV fentanyl for anesthesia or analgesia.


Assuntos
Analgésicos Opioides/farmacologia , Analgésicos Opioides/farmacocinética , Fentanila/farmacologia , Fentanila/farmacocinética , Interações Ervas-Drogas , Hypericum/efeitos adversos , Adulto , Analgésicos Opioides/administração & dosagem , Feminino , Fentanila/administração & dosagem , Humanos , Infusões Intravenosas , Masculino , Pupila/efeitos dos fármacos , Adulto Jovem
17.
Basic Clin Pharmacol Toxicol ; 126(3): 263-276, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31597014

RESUMO

Oral controlled-release formulations are playing an ever-increasing role in opioid therapy; however, little is known about their influence on the relationship between pharmacokinetics and pharmacodynamics. The study aim was to characterize the pharmacokinetic-pharmacodynamics of two controlled-release tablet formulations and a liquid formulation of oxycodone in healthy, opioid-naïve volunteers, which can serve as a reference for future patient studies. A semi-double-blinded, three-way crossover study was conducted, with fifteen healthy volunteers receiving two differently designed 20 mg monophasic controlled-release oxycodone tablets and 10 mg oral solution oxycodone in a randomized order. Venous plasma concentrations and pupil diameter were determined pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.33, 2.66, 3, 3.33, 3.66, 4, 5, 6, 8, 12 and 24 hour post-dose. Oxycodone pharmacokinetics was best described by a two-compartment model with first-order absorption. The controlled-release formulations had an absorption lag of 0.23 hour and a slower absorption rate constant (kaCR  = 0.19 hour-1 ) compared to the oral solution (kaSOL  = 0.94 hour-1 ). Effects on pupil diameter were delayed relative to plasma (14 minutes half-life) for all formulations and were best described by a proportional Emax model. The plasma concentration of oxycodone at half-maximum effect was lower in males (31.1 µg/L) compared to females (52.8 µg/L; P < .001). The absorption profile of controlled-release oxycodone formulations provided a prolonged onset and offset of action compared to oral solution oxycodone. The controlled-release formulations showed no differences in pharmacokinetic and pharmacodynamic parameters suggesting that both may be used interchangeably in human beings with normal gastrointestinal function.


Assuntos
Analgésicos Opioides/administração & dosagem , Modelos Biológicos , Oxicodona/administração & dosagem , Administração Oral , Adulto , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/farmacologia , Estudos Cross-Over , Preparações de Ação Retardada , Método Duplo-Cego , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Oxicodona/farmacocinética , Oxicodona/farmacologia
18.
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
19.
Toxicol In Vitro ; 62: 104696, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31669393

RESUMO

There is growing concern regarding potential occupational exposures to the ultra-potent synthetic opioid carfentanil. However, little data are available on the toxicity of carfentanil in humans, particularly for dermal exposures. To begin to address this, permeation of carfentanil formulated in three vehicles, water, ethanol, and hand sanitizer was measured under infinite-dose conditions in an in vitro static diffusion cell system using the EpiDerm™ (EPI-606-X) RhE model. The permeation rate was fastest for carfentanil in water (3.9 × 10-3 cm/h), followed by hand sanitizer (1.2 × 10-3 cm/h), and slowest for carfentanil in ethanol (0.2 × 10-3 cm/h). In both ethanol and hand sanitizer, a lag-time between exposure and permeation of approximately 1.5 h was observed, while lag-time in water was approximately half an hour. Flux at steady-state was greater at 50.6 µg/ml than at 5.3 µg/ml for both water and ethanol; however, the percent of dose absorbed did not differ between doses for either vehicle. Slight differences in percutaneous permeation of carfentanil were observed between two brands of hand sanitizer, likely due to differences in relative proportion of alcohol and skin penetration enhancers. These data indicate that small skin exposures may not result in rapid, significant toxicity as previously reported.


Assuntos
Analgésicos Opioides/farmacocinética , Fentanila/análogos & derivados , Administração Cutânea , Cultura em Câmaras de Difusão , Etanol , Fentanila/farmacocinética , Humanos , Técnicas In Vitro , Veículos Farmacêuticos , Absorção Cutânea , Solventes , Água
20.
Clin Drug Investig ; 40(2): 139-148, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31679120

RESUMO

BACKGROUND AND OBJECTIVES: Oxycodone tamper resistant (OTR) is a new extended-release abuse-deterrent formulation providing improvements in the tamper resistant characteristics. This study aimed to investigate the pharmacokinetic properties of the new OTR tablets and evaluate the bioequivalence of oxycodone from OTR and the original extended release (ER) formulation tablets administered with an opioid antagonist in patients with chronic pain. METHODS: In this open-label, randomized, cross-over study, the enrolled patients were randomised to receive a single dose of 40 mg OTR or 40 mg OXYCONTIN® (OXY) tablet administered with naltrexone blockade under fasting conditions. Serial blood samples for pharmacokinetic analysis were collected. Plasma oxycodone was quantified by a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. Tolerability was evaluated by monitoring adverse events, physical examinations, 12-lead ECG and laboratory tests. RESULTS: A total of 38 patients were enrolled and 33 subjects completed the study. After a single dose of 40 mg tablets, pharmacokinetic results of the new OTR tablet were found to be similar to those of original extended-release oxycodone tablet. OTR 40 mg was bioequivalent to OXY 40 mg and was well tolerated in patients with chronic pain. CONCLUSIONS: The new OTR formulation could provide a new choice in the treatment of chronic pain and reduce the potential for oxycodone abuse. Chictr.org identifier: ChiCTR1800017253.


Assuntos
Analgésicos Opioides/farmacocinética , Dor Crônica/tratamento farmacológico , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Oxicodona/farmacocinética , Adulto , Estudos Cross-Over , Preparações de Ação Retardada , Jejum , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxicodona/administração & dosagem , Comprimidos , Equivalência Terapêutica
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