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1.
Chemosphere ; 238: 124587, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31425864

RESUMO

Pharmaceuticals are emerging as environmentally problematic compounds. As they are often not appropriately removed by sewage treatment plants, pharmaceutical compounds end up in surface water environments worldwide at concentrations in the ng to µg L-1 range. There is a need to further explore single compound and mixture effects using e.g. in vivo test model systems. We have investigated, for the first time, behavioral effects in larval zebrafish (Danio rerio) exposed to a binary mixture of an antidepressant drug (citalopram) and a synthetic opioid (tramadol). Citalopram and tramadol have a similar mode of action (serotonin reuptake inhibition) and are known to produce drug-drug interactional effects resulting in serotonin syndrome (SS) in humans. Zebrafish embryo-larvae were exposed to citalopram, tramadol and 1:1 binary mixture from fertilization until 144 h post-fertilization. No effects on heart rate, spontaneous tail coiling, or death/malformations were observed in any treatment at tested concentrations. Behavior (hypoactivity in dark periods) was on the other hand affected, with lowest observed effect concentrations (LOECs) of 373 µg L-1 for citalopram, 320 µg L-1 for tramadol, and 473 µg L-1 for the 1:1 mixture. Behavioral EC50 was calculated to be 471 µg L-1 for citalopram, 411 µg L-1 for tramadol, and 713 µg L-1 for the 1:1 mixture. The results of this study conclude that tramadol and citalopram produce hypoactivity in 144 hpf zebrafish larvae. Further, a 1:1 binary mixture of the two caused the same response, albeit at a higher concentration, possibly due to SS.


Assuntos
Analgésicos Opioides/farmacologia , Citalopram/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Tramadol/farmacologia , Poluentes Químicos da Água/farmacologia , Peixe-Zebra/embriologia , Animais , Embrião não Mamífero/efeitos dos fármacos , Larva/efeitos dos fármacos
2.
Br J Anaesth ; 123(6): 865-876, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31591020

RESUMO

BACKGROUND: There is growing interest in the effect of postoperative analgesics on oncological outcomes after cancer surgery. We investigated the impact of tramadol after breast cancer surgery on recurrence and mortality and explored the mechanism by which tramadol affects cultured breast cancer cells in vitro. METHODS: Electronic medical records of patients who underwent breast cancer surgery between November 2005 and December 2010 at Severance Hospital in Korea were reviewed. Cox regression analyses were used to identify factors related to postoperative recurrence and mortality. We performed the sensitivity test with propensity score matching to adjust for selection bias. In addition, we investigated the effects of tramadol on human breast adenocarcinoma (Michigan Cancer Foundation-7 [MCF-7]) cells via assessment of cell viability, clonogenic assay, and cell cycle analysis in vitro. RESULTS: Of 2588 breast cancer patients, 36.4% had received tramadol. Those who received tramadol had a 0.71-fold decreased risk of recurrence and a 0.56-fold decrease in mortality. The MCF-7 cell viability assays showed that tramadol had an anti-proliferative effect by cell cycle arrest, suppressing colony formation, and regulation of oestrogen and progesterone receptors. Tramadol induced apoptosis of MCF-7 cells via extracellular signal-regulated kinases by decreasing of 5-hydroxytryptamine (HT)2B receptor and transient receptor potential vanilloid-1 expression. CONCLUSIONS: After breast cancer surgery, patients who received tramadol had a decreased risk of postoperative recurrence and mortality. The anti-tumour effect of tramadol appears to involve inhibition of proliferation, induction of apoptosis, and effects on 5-HT2B receptor and TRPV-1.


Assuntos
Adenocarcinoma/cirurgia , Analgésicos Opioides/farmacologia , Neoplasias da Mama/cirurgia , Recidiva Local de Neoplasia/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Tramadol/farmacologia , Adulto , Idoso , Apoptose/efeitos dos fármacos , Mama/efeitos dos fármacos , Mama/cirurgia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Técnicas In Vitro , Células MCF-7 , Mastectomia , Pessoa de Meia-Idade , República da Coreia , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento , Células Tumorais Cultivadas
3.
Eur J Med Chem ; 183: 111701, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31550662

RESUMO

Opioid analgesics have been used for thousands of years in the treatment of pain and related disorders, and have become among the most widely prescribed medications. Among opioid analgesics, mu opioid receptor (MOR) agonists are the most commonly used and are indicated for acute and chronic pain management. However, their use results in a plethora of well-described side-effects. From selective delta opioid receptor (DOR) and kappa opioid receptor (KOR) agonists to multitarget MOR/DOR and MOR/KOR ligands, medicinal chemistry provided different approaches aimed at the development of opioid analgesics with an improved pharmacological and tolerability fingerprint. The emergent medicinal chemistry strategy to develop ameliorated opioid analgesics is based upon the concept that functional selectivity for G-protein signalling is necessary for the therapeutic effect, whether ß-arrestin recruitment is mainly responsible for the manifestation of side effects, including the development of tolerance after repeated administrations. This review summarises most relevant biased MOR, DOR, KOR and multitarget MOR/DOR ligands synthesised in the last decade and their pharmacological profile in "in vitro" and "in vivo" studies. Such biased ligands could have a significant impact on modern drug discovery and represent a new strategy for the development of better-tolerated drug candidates.


Assuntos
Analgésicos Opioides/farmacologia , Dor/tratamento farmacológico , Receptores Opioides mu/agonistas , Analgésicos Opioides/química , Animais , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Manejo da Dor , Relação Estrutura-Atividade
4.
Surgery ; 166(6): 1055-1060, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31526584

RESUMO

BACKGROUND: Opioid tolerant patients have been shown to have poor postoperative outcomes. Enhanced recovery pathways are evidence-based interventions that focus on optimizing recovery, and their effectiveness depends on the degree of compliance with the pathway. We wish to determine pathway compliance and its impact on postoperative outcomes in opioid tolerant patients undergoing abdominal surgery on an enhanced recovery pathway. METHODS: From December 2014 to June 2017, 646 patients undergoing major abdominal surgery on an enhanced recovery pathway were included. Patients <18 years and having emergency surgery were excluded. Compliance was measured to 14 perioperative pathway standards and high-compliance was defined as adhering to ≥75% standards. Opioid tolerance was defined as any patient taking a prescribed opioid medication equivalent to 60 mg of oral morphine per day for 1 week prior to surgery. The Colorectal Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity was used for risk-adjusted analyses. Outcomes of interest include length of stay, major complications (Clavien-Dindo ≥2), 30-day readmission rates, and mortality. RESULTS: Overall, 114 (18%) patients were opioid tolerant and 532 (82%) were not opioid tolerant. Opioid tolerant patients were less likely to be highly compliant with enhanced recovery pathway standards than non-tolerant patients (35% vs 54%; P < .001); particularly postoperative care standards. On adjusted analysis, opioid tolerance was associated with a 2-fold increase in readmissions following major abdominal surgery. Examining only those patients with opioid tolerance, adjusted analysis demonstrated that high compliance with the enhanced recovery pathway standards was independently associated with a 26% reduction in length of stay, over a 90% reduction in major complications, and mitigated the effect on readmissions. CONCLUSION: The authors provide evidence that opioid tolerance is associated with less favorable outcomes in patients undergoing major abdominal surgery on an enhanced recovery pathway, and this is likely due to a lack of pathway compliance. Establishing strategies to improve compliance in this challenging patient cohort may serve to mitigate the negative impact of opioid tolerance.


Assuntos
Analgésicos Opioides/farmacologia , Tolerância a Medicamentos , Cooperação do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Cavidade Abdominal/cirurgia , Idoso , Analgésicos Opioides/uso terapêutico , Estudos de Coortes , Feminino , Mortalidade Hospitalar , Humanos , Laparoscopia/efeitos adversos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias/etiologia , Período Pré-Operatório , Estudos Retrospectivos
5.
Eur J Med Chem ; 182: 111634, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472474

RESUMO

In order to discover a novel type of analgesic, we investigated dual activity ligands with TRPV1 antagonism and mu-opioid receptor affinity with the goal of eliciting synergistic analgesia while avoiding the side effects associated with single targeting. Based on a combination approach, a series of 4-benzyl-4-(dimethylamino)piperidinyl analogues were designed, synthesized and evaluated for their receptor activities. Among them, compound 49 exhibited the most promising dual-acting activity toward TRPV1 and the mu-opioid receptor in vitro. In vivo,49 displayed potent, dose-dependent antinociceptive activity in both the 1st and 2nd phases in the formalin assay. Consistent with its postulated mechanism, we confirmed that in vivo, as in vitro, compound 49 both antagonized TRPV1 and functioned as a mu-opioid agonist. This result indicates that dual-acting TRPV1 antagonist/mu-opioid ligands can be made and represent a new and promising class of analgesic.


Assuntos
Analgésicos Opioides/farmacologia , Descoberta de Drogas , Dor/tratamento farmacológico , Receptores Opioides/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Células CHO , Células Cultivadas , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Dor/metabolismo , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismo
6.
Biol Pharm Bull ; 42(10): 1637-1640, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31406051

RESUMO

Sugammadex 4 mg·kg-1 is recommended for reversal from rocuronium-induced deep neuromuscular block. However, there is limited data regarding the dose-response of sugammadex required for reversal from deep neuromuscular block in pediatric patients. The aim of this study was to determine the reversibility of rocuronium-induced deep neuromuscular block with sugammadex in infants and children. Seventy-five children (48 infants and 27 children, mean standard deviation (S.D.), age: 11.6 (6.7) months) were enrolled in this study. After induction of anesthesia and administration of 0.6 mg·kg-1 rocuronium, neuromuscular block was acceleromyographically evaluated by observing contractions of the adductor pollicis muscle to ulnar nerve train-of-four (TOF) stimulation. Subsequently, the intensity of rocuronium-induced block was determined every 6 min using post-tetanic count (PTC) stimulation during sevoflurane and remifentanil anesthesia. When the first response to the PTC stimulus was detected, either 1, 2 or 4 mg·kg-1 sugammadex was administered and the time required for facilitated recovery to a TOF ratio of 0.9 following each dose was compared. The time [mean (S.D.)] from the administration of 1 mg·kg-1 sugammadex until recovery to a TOF ratio of 0.9 was significantly longer [129.1 (83.5) s, p < 0.001] than that with 2 and 4 mg·kg-1 sugammadex [70.3 (26.7) s and 68.2 (34.5) s, respectively]. Incomplete reversal was seen in 3 patients in the 1 mg·kg-1 group. The results suggested that a 4 mg·kg-1 sugammadex dose is recommended for reversal from rocuronium-induced deep neuromuscular block even in infants and children.


Assuntos
Período de Recuperação da Anestesia , Anestesia , Contração Muscular/efeitos dos fármacos , Bloqueio Neuromuscular , Fármacos Neuromusculares não Despolarizantes/farmacologia , Rocurônio/farmacologia , Sugammadex/administração & dosagem , Analgésicos Opioides/farmacologia , Criança , Humanos , Lactente , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Pediatria , Remifentanil/farmacologia , Sevoflurano/farmacologia , Sugammadex/farmacologia , Nervo Ulnar
7.
Int J Mol Sci ; 20(17)2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31450631

RESUMO

Crosstalk between opioid and adrenergic receptors is well characterized and due to interactions between second messenger systems, formation of receptor heterodimers, and extracellular allosteric binding regions. Both classes of receptors bind both sets of ligands. We propose here that receptor crosstalk may be mirrored in ligand complementarity. We demonstrate that opioids bind to adrenergic compounds with micromolar affinities. Additionally, adrenergic compounds bind with micromolar affinities to extracellular loops of opioid receptors while opioids bind to extracellular loops of adrenergic receptors. Thus, each compound type can bind to the complementary receptor, enhancing the activity of the other compound type through an allosteric mechanism. Screening for ligand complementarity may permit the identification of other mutually-enhancing sets of compounds as well as the design of novel combination drugs or tethered compounds with improved duration and specificity of action.


Assuntos
Agonistas Adrenérgicos/química , Analgésicos Opioides/química , Desenvolvimento de Medicamentos , Receptores Adrenérgicos/química , Receptores Opioides/química , Agonistas Adrenérgicos/farmacologia , Analgésicos Opioides/farmacologia , Desenvolvimento de Medicamentos/métodos , Humanos , Cinética , Ligantes , Modelos Biológicos , Peptídeos/química , Peptídeos/metabolismo , Ligação Proteica , Receptores Opioides/agonistas , Relação Estrutura-Atividade
8.
J Pharm Pharmacol ; 71(10): 1469-1474, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31294469

RESUMO

OBJECTIVE: Osteoporosis is a skeletal disease with decreased bone mass and alteration in microarchitecture of bone tissue, and these changes put patients in risk of bone fracture. As a common symptom of osteoporosis and complication of osteoporotic fracture, chronic pain is a headache for clinicians. Nonsteroidal anti-inflammatory drugs (NSAIDs), selective COX-2 inhibitors and opioid drugs can temporarily reduce osteoporotic pain but have relevant side effects, such as addiction, tolerability and safety. The review summarized the recent advancements in the study of CB receptors in osteoporosis and osteoporotic pain and related mechanisms. KEY FINDINGS: Recent studies indicated the two nociceptive receptors, cannabinoid receptor (CB) and transient receptor potential vanilloid type 1 (TRPV1) channel, are co-expressed in bone cells and play important role in the metabolism of bone cells, suggesting that dualtargeting these 2 receptors/channel may provide a novel approach for osteoporotic pain. In addition, both CB receptor and TRPV1 channel are found to be expressed in the glial cells which play vital role in mediating inflammation, chronic pain and metabolism of bone cells, suggesting a role of glial cells inosteoporotic pain. SUMMARY: Multiple-targeting against glial cells, CB receptors and TRPV1 channel may be one effective therapeutic strategy for osteoporotic pain in the future, following the elucidation of the complicated mechanism.


Assuntos
Dor Crônica/metabolismo , Osteoporose/metabolismo , Receptores de Canabinoides/metabolismo , Analgésicos Opioides/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Canabinoides/metabolismo , Dor Crônica/tratamento farmacológico , Humanos , Canais de Cátion TRPV/metabolismo
9.
Eur J Med Chem ; 179: 527-536, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276897

RESUMO

New analogs of the endogenous opioid agonist endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH2) have been obtained by introducing modified tyrosines at the position 1 of the sequence. For all analogs, the cis/trans conformation ratio about the tyramine-Pro amide bond, lipophilicity, receptor affinities, and functional activities, have been determined. Among the novel derivatives, [Dmt(3'-Cl)]1EM-2 (4) stood out for its subnanomolar µ-opioid receptor affinity and potent agonist activity, superior to that of the parent peptide EM-2. Hybrid quantum mechanics/molecular mechanics docking computations supported the cis tyramine-Pro bioactive conformation, and allowed us to analyze the contribution of the substituents of the "message" tyramine to binding, highlighting the role of halogen-bonding in the higher receptor affinity of peptide 4.


Assuntos
Analgésicos Opioides/farmacologia , Teoria da Densidade Funcional , Oligopeptídeos/farmacologia , Receptores Opioides/agonistas , Tirosina/farmacologia , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Conformação Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Relação Estrutura-Atividade , Tirosina/química
10.
Crit Care ; 23(1): 245, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277722

RESUMO

BACKGROUND: In critically ill patients, poor patient-ventilator interaction may worsen outcomes. Although sedatives are often administered to improve comfort and facilitate ventilation, they can be deleterious. Whether opioids improve asynchronies with fewer negative effects is unknown. We hypothesized that opioids alone would improve asynchronies and result in more wakeful patients than sedatives alone or sedatives-plus-opioids. METHODS: This prospective multicenter observational trial enrolled critically ill adults mechanically ventilated (MV) > 24 h. We compared asynchronies and sedation depth in patients receiving sedatives, opioids, or both. We recorded sedation level and doses of sedatives and opioids. BetterCare™ software continuously registered ineffective inspiratory efforts during expiration (IEE), double cycling (DC), and asynchrony index (AI) as well as MV modes. All variables were averaged per day. We used linear mixed-effects models to analyze the relationships between asynchronies, sedation level, and sedative and opioid doses. RESULTS: In 79 patients, 14,166,469 breaths were recorded during 579 days of MV. Overall asynchronies were not significantly different in days classified as sedatives-only, opioids-only, and sedatives-plus-opioids and were more prevalent in days classified as no-drugs than in those classified as sedatives-plus-opioids, irrespective of the ventilatory mode. Sedative doses were associated with sedation level and with reduced DC (p < 0.0001) in sedatives-only days. However, on days classified as sedatives-plus-opioids, higher sedative doses and deeper sedation had more IEE (p < 0.0001) and higher AI (p = 0.0004). Opioid dosing was inversely associated with overall asynchronies (p < 0.001) without worsening sedation levels into morbid ranges. CONCLUSIONS: Sedatives, whether alone or combined with opioids, do not result in better patient-ventilator interaction than opioids alone, in any ventilatory mode. Higher opioid dose (alone or with sedatives) was associated with lower AI without depressing consciousness. Higher sedative doses administered alone were associated only with less DC. TRIAL REGISTRATION: ClinicalTrial.gov, NCT03451461.


Assuntos
Analgésicos Opioides/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Respiração Artificial/métodos , Mecânica Respiratória/efeitos dos fármacos , Idoso , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacologia , Estado Terminal/terapia , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/farmacologia , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Respiração Artificial/efeitos adversos , Respiração Artificial/instrumentação , Espanha
11.
J Zoo Wildl Med ; 50(2): 457-460, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31260214

RESUMO

Two anesthetic protocols in adult giraffe were compared by retrospective study. Thirteen anesthesia records for medetomidine-ketamine (MK) and seven for medetomidine-ketamine with a potent opioid (MKO) were evaluated for differences in demographic, behavioral, drug, and respiratory parameters. Giraffe stood significantly more quickly with MKO vs MK though MK animals were physically restrained to preclude premature standing as part of normal recovery practices (5.5 min vs 21.4 min, P = 0.01). Regurgitation was recorded in 5/13 and resedation in 4/13 MK animals. The range of values for blood lactate was higher in MKO (5.18-11.25 mM/L) than in MK giraffe (0.78-6.08 mM/L). Despite limitations of a retrospective study, both MK and MKO giraffe anesthesia protocols exhibit benefits and side effects. Awareness and management of these factors will improve outcomes until standardized, prospective studies of giraffe immobilization offer more comprehensive guidance on protocol selection.


Assuntos
Analgésicos Opioides/farmacologia , Anestesia/veterinária , Girafas , Ketamina/farmacologia , Medetomidina/farmacologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Anestésicos Dissociativos/administração & dosagem , Anestésicos Dissociativos/efeitos adversos , Anestésicos Dissociativos/farmacologia , Animais , Feminino , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/farmacologia , Injeções Intramusculares , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Masculino , Medetomidina/administração & dosagem , Medetomidina/efeitos adversos , Estudos Retrospectivos
12.
J Pharmacol Sci ; 140(2): 171-177, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31320243

RESUMO

Morphine, fentanyl, and oxycodone are widely used as analgesics, and recently hydromorphone has been approved in Japan. Although all of these are selective for µ-opioid receptors (MORs) and have similar structures, their analgesic potencies and adverse effects (AEs) are diverse. Recent molecular analyses of MOR signaling revealed that the G protein-mediated signaling pathway causes analgesic effects and the ß-arrestin-mediated signaling pathway is responsible for AEs. We used several cell-based analyses that selectively measure cellular responses activated by either G protein- or ß-arrestin-mediated pathways. GloSensor™ cAMP, CellKey™, and receptor internalization assays were performed with four different types of cells stably expressing differentially labelled MOR. EC50 values measured by cAMP and CellKey™ assays had potencies in the order fentanyl ≤ hydromorphone < morphine ≤ oxycodone, all also exhibiting full agonist responses. However, in the internalization assay, only fentanyl elicited a full agonist response. Hydromorphone had the strongest potency next to fentanyl; however, contribution of the ß-arrestin-mediated pathway was small, suggesting that its effect could be biased toward the G protein-mediated pathway. Based on these properties, hydromorphone could be chosen as an effective analgesic.


Assuntos
Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacologia , AMP Cíclico , Proteínas de Ligação ao GTP/metabolismo , Hidromorfona/efeitos adversos , Hidromorfona/farmacologia , Receptores Opioides mu/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , beta-Arrestinas/metabolismo , Células HEK293 , Humanos , Hidromorfona/metabolismo
13.
Can J Vet Res ; 83(3): 235-240, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31308597

RESUMO

This study evaluated the effects of 3 morphine doses combined with acepromazine, on sedation and physiological parameters in 5 clinically healthy dogs. Four treatments were administered intramuscularly in a randomized, blinded, crossover design: acepromazine, 0.05 mg/kg, alone (ACP) and acepromazine plus morphine at doses of 0.25, 0.5, and 1.0 mg/kg body weight (BW) (AM0.25, AM0.5, and AM1.0, respectively). Sedation scores and cardiorespiratory variables were evaluated for 120 min after drug administration. The sedation scores were significantly higher with the AM0.25 and AM1.0 treatments than with the ACP treatment. At 30 min the scores were 36% to 66% higher with AM1.0 than with AM0.25 and AM0.5, respectively, but these differences were not significant. The physiological variables remained acceptable for dogs. The results of this study do not support the use of AM0.5 over AM0.25 to improve sedation in dogs, but they do indicate that sedation may be greater with AM1.0 than with AM0.25 and AM0.5. Studies with a greater number of samples are warranted to confirm this statement.


Assuntos
Acepromazina/farmacologia , Analgésicos Opioides/farmacologia , Sedação Consciente/veterinária , Cães , Antagonistas de Dopamina/farmacologia , Morfina/farmacologia , Acepromazina/administração & dosagem , Analgésicos Opioides/administração & dosagem , Animais , Antagonistas de Dopamina/administração & dosagem , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Masculino , Morfina/administração & dosagem
14.
Curr Gastroenterol Rep ; 21(9): 44, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31346779

RESUMO

PURPOSE OF REVIEW: The opioid epidemic in the USA has led to a rise in opioid-related gastrointestinal (GI) side effects that are often difficult to diagnose and treat. The aim of this report is to discuss opioid pathophysiology, opioid-related GI side effects, clinical presentation, and diagnostic criteria and to review the current pharmacotherapy available. RECENT FINDINGS: Opioid-related GI disorders are increasingly recognized and include, but are not limited to, opioid-induced esophageal dysfunction (OIED), gastroparesis, opioid-induced constipation (OIC), narcotic bowel syndrome (NBS), acute post-operative ileus, and anal sphincter dysfunction. Treatment of these conditions is challenging. OIC has the most available pharmacotherapy for treatment, including classical laxatives, peripherally acting µ-receptor antagonists (PAMORAs), novel therapies (lubiprostone, prucalopride- 5-HT agonist), and preventative therapies (PR oxycodone/naloxone). The gastrointestinal effects of opioid therapy are variable and often debilitating. While medical management for some opioid-related GI side effects exists, limiting or completely avoiding opioid use for chronic non-cancer pain will mitigate these effects most effectively.


Assuntos
Analgésicos Opioides/efeitos adversos , Gastroenteropatias/terapia , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Transtornos Relacionados ao Uso de Opioides/terapia , Dor/tratamento farmacológico , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Gastroenterologia , Gastroenteropatias/etiologia , Gastroenteropatias/fisiopatologia , Humanos , Transtornos Relacionados ao Uso de Opioides/etiologia , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Padrões de Prática Médica/estatística & dados numéricos , Estados Unidos
15.
Expert Opin Pharmacother ; 20(16): 1961-1970, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31355689

RESUMO

Introduction: Given our improved understanding of the role of central sensitization (CS) in many patients with chronic pain, it seems rational to account for CS during treatment. Areas covered: First, the treatment rationale based on the complex mechanisms underlying CS in patients having chronic pain is presented. Second, emphasis is given to explaining the concept of CS when providing treatment, as well as why patients and clinicians should focus on long-term rather than short-term treatment effects. Third, possible pharmacological and non-pharmacological treatment options are discussed. Expert opinion: Centrally acting drugs such as tricyclic compounds, serotonin-norepinephrine reuptake inhibitors, and α2δ ligands each target mechanisms that are often dysfunctional in patients having chronic pain and CS, but decades of clinical practice and clinical trials have not resulted in satisfactory outcomes. This comes as no surprise; CS comprises complex psycho-neuro-immunological interactions, while each of the tested drugs targets one or two of those mechanisms from a purely biomedical viewpoint. Clinicians willing to take CS into account should design an individually tailored multimodal treatment plan comprising pain neuroscience education, cognition-targeted exercise therapy, sleep management, stress management, and/or dietary intervention.


Assuntos
Dor Crônica/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Dor Crônica/metabolismo , Dor Crônica/patologia , Humanos , Inibidores de Captação de Serotonina/farmacologia
16.
Expert Opin Pharmacother ; 20(15): 1847-1854, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31290336

RESUMO

Introduction: Pain is a common symptom in Parkinson's disease (PD), impairing quality of life. The clinical appearance and the underlying etiologies are diverse. Different subtypes of pain may occur, with musculoskeletal pain considered to be the most frequent. Often there is also a combination of different causes of pain. There is a lack of controlled studies addressing pain therapy in PD. Areas covered: In this review the authors analyzed the currently available data, taking into account the available publications in the databases, especially PubMed. The authors further provided their expert perspectives on the challenges of treating pain in PD patients. Expert opinion: There is both nociceptive and neuropathic pain and in patients with PD, some PD-related pain and some unrelated. Diagnosis requires a thorough and differentiated history and examination, and targeted diagnostics. Therapeutically, many drugs are used, but the data is unfortunately limited and not specific. Medications used include Parkinson-related, mainly dopaminergic drugs, as well as opioids and non-opioid analgetics, anticonvulsives, antidepressants, and more recently cannabinoids. Currently, therapy is performed nonspecifically, without taking into account the special requirements of PD. Unfortunately, in many cases, pain is resistant to these therapies. In the future, both diagnostic and therapeutic efforts should be made to address this issue.


Assuntos
Analgésicos Opioides/uso terapêutico , Neuralgia/tratamento farmacológico , Manejo da Dor/métodos , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Qualidade de Vida/psicologia , Analgésicos Opioides/farmacologia , Humanos , Doença de Parkinson/patologia
17.
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
18.
Eur J Med Chem ; 178: 571-588, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31220675

RESUMO

In order to obtain novel pharmacological tools and to investigate a multitargeting analgesic strategy, the CB1 and CB2 cannabinoid receptor agonist JWH-018 was conjugated with the opiate analgesic oxycodone or with an enkephalin related tetrapeptide. The opioid and cannabinoid pharmacophores were coupled via spacers of different length and chemical structure. In vitro radioligand binding experiments confirmed that the resulting bivalent compounds bound both to the opioid and to the cannabinoid receptors with moderate to high affinity. The highest affinity bivalent derivatives 11 and 19 exhibited agonist properties in [35S]GTPγS binding assays. These compounds activated MOR and CB (11 mainly CB2, whereas 19 mainly CB1) receptor-mediated signaling, as it was revealed by experiments using receptor specific antagonists. In rats both 11 and 19 exhibited antiallodynic effect similar to the parent drugs in 20 µg dose at spinal level. These results support the strategy of multitargeting G-protein coupled receptors to develop lead compounds with antinociceptive properties.


Assuntos
Analgésicos Opioides/farmacologia , Encefalinas/farmacologia , Indóis/farmacologia , Naftalenos/farmacologia , Oxicodona/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidores , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Animais , Relação Dose-Resposta a Droga , Encefalinas/química , Indóis/química , Camundongos , Estrutura Molecular , Naftalenos/química , Oxicodona/química , Ratos , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Receptores Opioides mu/metabolismo , Relação Estrutura-Atividade
19.
Vet J ; 249: 82-88, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31239171

RESUMO

There are few investigations relating anti-nociception to plasma concentrations of fentanyl in horses. The study objective was to evaluate analgesic efficacy and duration in horses and determine the minimum anti-nociceptive plasma concentrations. Eight horses were treated with saline (P) and fentanyl (F2.5=2.5µg/kg; F5=5µg/kg; F10=10µg/kg) given IV over 5min, with a wash-out period of 10 days. To evaluate thermal (°C) and mechanical (N) nociceptive threshold single stimulations were applied prior to (baseline) and 10, 30, 60, 90, 120, 180, 240, 300, 360, 420, 540min and 22.5h after treatment. Plasma fentanyl concentrations were measured at specific time points. Locomotor activity, heart rate, respiratory rate and gastrointestinal sounds were recorded. Two-way repeated measures ANOVA and pairwise comparisons were used for data analysis (P<0.05). With treatment F10, there was a significant increase in thermal threshold above baseline (47.2ö4.1°C) at t10 (53.7ö4.2°C) and t30 (52.1ö5.6°C), whereas mechanical threshold increased considerably above baseline (3.7ö1.3N) only at t10 (6.6ö3.6N). Estimated mean minimum anti-nociceptive plasma concentration determined by thermal stimulation was 6.1-6.8ng/mL. Dose-dependent increased locomotion occurred, but no significant changes in heart rate, respiratory rate and gastrointestinal sounds were observed. Fentanyl IV at 10µg/kg produced anti-nociception for 10-30min and fentanyl plasma concentrations of ≥6.1-6.8ng/mL appear necessary to induce thermal anti-nociception. Dose-dependent increased locomotion was the main side effect observed.


Assuntos
Analgésicos Opioides/farmacologia , Fentanila/farmacologia , Cavalos , Limiar da Dor/efeitos dos fármacos , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/sangue , Animais , Estudos Cross-Over , Relação Dose-Resposta a Droga , Feminino , Fentanila/efeitos adversos , Fentanila/sangue , Temperatura Alta , Masculino , Estimulação Física , Distribuição Aleatória , Receptores Opioides mu/antagonistas & inibidores , Fatores de Tempo
20.
Pain Res Manag ; 2019: 9432965, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31182985

RESUMO

Morphine has unfavorable side effects including analgesic tolerance. Morphine tolerance counteracts analgesic efficacy and drives dose escalation. The mechanisms underlying morphine tolerance remain disputed, which has prevented the development of therapies to maximize and sustain analgesic efficacy. Morphine tolerance is an adaptive process induced by chronic morphine that has been shown to result from complex alterations at the molecular level with µ opioid receptors (MORs), as well as at the synaptic, cellular, and circuit levels. MicroRNAs are noncoding RNAs that have been proposed to regulate gene expression and degradation at the posttranscriptional level, including the MOR, as well as synaptic plasticity and neuroplasticity, in both the peripheral and central nervous systems. This review covers some of the most striking microRNA functions involved in morphine tolerance and presents limitations on our knowledge of their physiological roles.


Assuntos
Analgésicos Opioides/farmacologia , Tolerância a Medicamentos/genética , MicroRNAs/genética , Morfina/farmacologia , Animais , Humanos
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