Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 627
Filtrar
1.
Med Hypotheses ; 146: 110468, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33385878

RESUMO

Currently, no single medication has been approved for the management of coronavirus disease-2019 (COVID-19) caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, drug repositioningby investigating the use of existing drugs for management of COVID-19 patients is considered a desperate need. Tramadol is a commonly prescribed analgesic drug for treatment of moderate to severe pain with less potential for dependence and respiratory depression. Multiple evidence support that tramadol is a promising drug for treatment of COVID-19 patients. Herein, we discuss the possible beneficial effects of using tramadol against SARS-CoV-2 infection and their underlying mechanism of action. The anti-inflammatory effect of tramadol may help to suppress the COVID-19 related cytokine storm through decreasing interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). Besides, tramadol activates natural killer (NK) and T-cells and enhances IL-2 secretion, which produce immune-enhancing effect against SARS-CoV-2. Recent studies confirmed that COVID-19 patients with acute respiratory failure showed increased fibrin formation and polymerization that may lead to thrombosis. Tramadol owing to its hypocoagulable effect may protect against venous thromboembolism in these patients. Moreover, tramadol can exert a cardioprotective effect via decreasing lactate dehydrogenase (LDH) level which is elevated in most of patients with COVID-19. Furthermore, the severity and mortality of COVID-19 have been correlated with old age patients, which may be due to the lack of antioxidant mechanisms and increased oxidative damage. Tramadol could protect COVID-19 patient from disease complications by increases the antioxidant enzymes superoxide dismutase and glutathione peroxidase while diminished malondialdehyde. More interestingly, tramadol as an effective analgesic and antitussive may have a beneficial effect on COVID-19 patients suffering from cough, headache, ache, and pain. The tramadol anti-psychotic effect may also protect against psychiatric disorders associated with SARS-CoV-2 infection. Moreover, tramadol has bactericidal activity against a wide range of pathogens including Pseudomonas aeruginosa which is common in severe COVID-19 patients leading to pneumonia with worse clinical outcomes. Therefore, we hypothesize that tramadol might be a promising adjuvant therapeutic option against SARS-CoV-2 infection. Based on that, tramadol should be considered as adjuvant therapy for COVID-19 clinical trials.


Assuntos
/tratamento farmacológico , Tramadol/farmacologia , Analgésicos Opioides/farmacologia , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Antidepressivos/farmacologia , Antioxidantes/farmacologia , /fisiopatologia , Reposicionamento de Medicamentos , Humanos , Fatores Imunológicos/farmacologia , Modelos Biológicos , Pandemias
2.
Synapse ; 74(1): e22128, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31403743

RESUMO

The auditory system has an extensive efferent innervation, which contributes to processes of control and regulation of the afferent input. The expression of receptors to various neurotransmitters and neuropeptides in the inner ear has been described, among which endogenous opioid receptors are found. The role of opioid receptors in the cochlea is not yet fully defined, it has been reported that opioid agonists and antagonists modulate the response to auditory stimuli and in clinical practice, multiple cases have been reported in which the consumption of opioid derivatives induce sensorineural hearing loss. In this work, we evaluated the effects of acute treatment with morphine, fentanyl, tramadol, and naloxone, in the auditory brain stem potentials (ABR), the compound action potential (CAP), and distortion products otacoustic emissions (DPOAE), across a wide range of stimulus frequencies and amplitudes. Adult Long-Evans rats of the strain CII/ZV weighing 180-220 g were used. For the ABR recording drugs were administered intraperitoneally or intravenously. For the CAP and DPOAE drugs were applied by direct perfusion in the middle ear. The opioid agonists produced a consistent increase in the amplitude of the PI component of the ABR and of the N1-P1 amplitude of the CAP. Naloxone produced no significant changes in the ABR and a reduction of the CAP N1-P1 amplitude. Also, opioid agonists induced a decrease in the amplitude of the DPOAE. These results show that the opioid receptor activation modulates both the afferent response at both the afferent response to acoustic stimuli, and also at the cochlear mechanics as revealed by DPOAE changes. These results present a significant step in understanding how opioid modulation of auditory responses may contribute to the auditory processing and to sensorineural hearing loss produced by opioids.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Cóclea/efeitos dos fármacos , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Antagonistas de Entorpecentes/farmacologia , Emissões Otoacústicas Espontâneas/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Cóclea/fisiologia , Fentanila/farmacologia , Morfina/farmacologia , Naloxona/farmacologia , Emissões Otoacústicas Espontâneas/fisiologia , Ratos , Ratos Long-Evans , Tramadol/farmacologia
3.
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
5.
BMJ Case Rep ; 12(12)2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31831513

RESUMO

An 18-year-old woman with a history of hollow visceral myopathy presented with a small-bowel obstruction. High-dose opioid analgesia was required subsequently during hospital admission. She suffered two episodes of documented fasting hypoglycaemia, despite adjustment of parenteral carbohydrate administration. Investigations for non-insulin-mediated hypoglycaemia revealed a low morning cortisol of 109 nmol/L and an inappropriately low Adrenocorticotropic hormone (ACTH) level of 2.2 pmol/L. A diagnosis of secondary adrenal insufficiency was confirmed on repeat cortisol and ACTH testing. The 250 µg short Synacthen test cortisol response was normal, suggestive of acute rather than chronic ACTH deficiency. This pattern was consistent after further opioid exposure. Adrenal recovery occurred shortly after opioid cessation. Opioid-induced hypoadrenalism is likely an under-recognised clinical entity with potentially serious adverse patient outcomes. There are reported cases involving commonly prescribed opioids including fentanyl and tramadol. However, we believe this is the first reported clinical case of acute transient opioid-induced secondary hypoadrenalism associated with fasting hypoglycaemia.


Assuntos
Insuficiência Adrenal/induzido quimicamente , Analgésicos Opioides/efeitos adversos , Fentanila/efeitos adversos , Hipoglicemia/etiologia , Tramadol/efeitos adversos , Adolescente , Insuficiência Adrenal/complicações , Analgésicos Opioides/farmacologia , Feminino , Fentanila/farmacologia , Humanos , Tramadol/farmacologia
6.
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
7.
Med Gas Res ; 9(3): 110-114, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31552872

RESUMO

Pain is a common complication after surgery. Insufficient control of postoperative pain has adverse effects on the physiological, metabolic and psychological state of the child. The use of local analgesics and anesthetics alone cannot produce complete anesthesia and intraoperative comfort. The addition of adjuvant drugs is commonly used to improve the quality of the block. Therefore, adding new supplements may increase the duration of analgesia. The aim of this study was to compare the addition of dexmedetomidine, tramadol and neostigmine to lidocaine 1.5% in increasing the duration of postoperative analgesia in the lower abdominal pain surgery in children aged 2-8 years. This double-blind randomized clinical trial was conducted on children candidate for lower abdominal surgery. The 96 patients were randomly divided into 3 groups including dexmedetomidine, neostigmine, and tramadol. For all children, 3 mg of midazolam was administered orally before entering the operating room. The patients underwent general anesthesia with 2 µg/kg fentanyl, 0.03 mg/kg midazolam, 0.5 mg/kg atracurium and 5-6 mg/kg thiopental. After determining the hiatus membrane, 2 mL syringes containing air and distilled water (each of which 1 mL) slowly entered the space. After eliminating caudal resistance, 1.5% lidocaine was injected at dose of 0.5 mL/kg. A total of 96 patients were enrolled in this study. The results revealed that pain scores in the dexmedetomidine group in recovery, 2, 6 and 12 hours after surgery were less than the other two groups. Furthermore, the tramadol group showed a lower score in comparison with the neostigmine group and the duration of analgesia in the dexmedetomidine group was more than the other two groups. In addition, the mean of analgesic at 24 hours after operation in the dexmedetomidine group was lower as compared to the other two groups, indicating the effect of dexmedetomidine as an adjuvant in increasing the duration of analgesia and reducing postoperative pain in patients along with lidocaine 1.5%. All three drugs (neostigmine, tramadol and dexmedetomidine drugs), along with other local anesthetic, increased the duration of analgesia and decreased postoperative pain in children. The effect of dexmedetomidine was greater than the other two drugs. The study was approved by the Ethics Committee of Arak University of Medical Sciences, Iran (approved No. IR.ARAKMU.REC.1396.112) on October 28, 2017, and registered at Iranian Registry of Clinical Trials (registration No. IRCT20141209020258N83) on August 29, 2018.


Assuntos
Dor Abdominal/cirurgia , Analgesia , Dexmedetomidina/farmacologia , Lidocaína/farmacologia , Neostigmina/farmacologia , Tramadol/farmacologia , Criança , Pré-Escolar , Método Duplo-Cego , Interações Medicamentosas , Feminino , Humanos , Masculino , Período Pós-Operatório , Fatores de Tempo
8.
Gene ; 718: 144030, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31390540

RESUMO

Opioids are widely used in the treatment of cancer related pain. They mainly exert their effects on opioid receptors. The most common opioid in the treatment of pain is morphine. Previous studies show that they may have effects on cancer cell behavior. These may include apoptosis, angiogenesis, invasion, inflammation and immune reactions. Tramadol, also an opioid is widely used in the treatment of cancer pain and is not well studied in cancer behavior. We aimed to investigate the effects of tramadol on cancer stem cells and metabolic changes in colon carcinoma cells. We used Colo320 (ATCC, CCL-220), Colo741 (ECACC, 93052621) and HCT116 (ATCC, CCL-247) colon cancer cell lines. CD133 was considered colon cancer stem cell marker and used to sort CD133+ and CD133- cells by magnetic cell sorting. MTT (mitochondria-targeted therapeutics) technique was used to detect tramadol's cytotoxic effect on cells in the study groups. Cells were treated with 1 mg/kg, 1.5 mg/kg and 2 mg/kg tramadol for 24 h at 37 °C and 5% CO2.Caspase-3, Ki-67, Bcl-2 and VGEF distributions were performed using indirect immunoperoxidase staining for immunohistochemical analysis. The study showed that tramadol has triggering effect on apoptosis in Colo320 colon cancer stem cells.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Colo , Citotoxinas/farmacologia , Células-Tronco Neoplásicas , Tramadol/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HCT116 , Humanos , Invasividade Neoplásica , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia
9.
Drugs Aging ; 36(8): 747-758, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31161580

RESUMO

BACKGROUND: Age-related changes in the concentration-effect relationship of (+)-O-desmethyl-tramadol [(+)-ODM], tramadol's active metabolite, are not documented in the elderly. OBJECTIVE: The objective of this study was to characterize, in elderly and young subjects, the (+)-ODM pharmacokinetic and pharmacodynamic relationship to examine the effect of age after single-dose administration of tramadol 200 mg extended-release tablets. METHODS: A population analysis of a double-blind, randomized, placebo-controlled, two-period cross-over study including 13 elderly (aged ≥75 years) subjects with mild renal insufficiency and 16 young (aged 18-40 years) subjects was conducted. For 48 h post-dose, blood samples were collected and pain tolerance thresholds measured using an electrically stimulated pain model. A pharmacokinetic/pharmacodynamic model incorporating a one-compartment pharmacokinetic model for (+)-ODM parameterized with first-order formation rate, clearance (CL/fm), volume of distribution (V/fm) and a sigmoid maximum effect (Emax) model incorporating baseline (E0) and placebo effect was used. RESULTS: Maximum plasma concentrations of (+)-ODM occurred later and plasma concentrations declined more slowly in the elderly than in young subjects. In the elderly, V/fm was 76% larger and CL/fm 16% slower. Baseline (E0) and sensitivity (C50) for pain tolerance were similar between young and elderly subjects. However, the Emax parameter was 2.5 times higher in the elderly and maximum possible treatment-related effect was 169 (135-221) in the young and 194 (149-252) in the elderly; that is, 15% higher in the elderly. CONCLUSIONS: This exploratory analysis suggests that age-related differences exist in the distribution and elimination of (+)-ODM, including a 76% larger distribution outside the central compartment and 16% slower clearance of (+)-ODM. These pharmacokinetic changes are associated with a 15% higher maximum possible treatment-related effect and carry the potential for greater efficacy but also the potential for increased side effects at the same dose in elderly subjects. Clinicaltrials.gov identifier: NCT02329561.


Assuntos
Envelhecimento/sangue , Analgésicos Opioides/sangue , Analgésicos Opioides/farmacologia , Modelos Biológicos , Dor/tratamento farmacológico , Tramadol/análogos & derivados , Adolescente , Adulto , Idoso , Analgésicos Opioides/administração & dosagem , Estudos Cross-Over , Método Duplo-Cego , Estimulação Elétrica , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Dor/sangue , Tramadol/administração & dosagem , Tramadol/sangue , Tramadol/farmacologia , Adulto Jovem
10.
Biomed Pharmacother ; 117: 109123, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31234026

RESUMO

Chrysanthemum trifurcatum is common to Mediterranean countries and widely-used in traditional medicine. Due to the scarcity of data about the pharmacological properties of C. trifurcatum, this present study was designed to determine the effects of C. trifurcatumethanolic extract (CEE) for its anti-nociceptive, anti-epileptic, anti-inflammatory, and hepatoprotective activities in mice and rat models. We demonstrate that CEE contains alkaloids, carbohydrates, and flavonoids, and in a dose-dependent (300 and 500 mg/kg) manner exhibited significant reductions in paracetamol (PCM; 500 mg/kg)-induced increased serum AST, ALT and ALP levels, similar to as seen by silymarin (25 mg/kg). Additionally, CEE (300 mg/kg) elicited inhibition in acetic acid-induced abdominal writhes, delayed latency time to paw's licking in hot plate tests, exerted an anti-convulsant effect by prolonging the onset of clonic and tonic convulsions, and reduced pentylenetetrazole (PTZ; 80 mg/kg)-induced mortality. Moreover, CEE (500 mg/kg) exhibited a prominent reduction in carrageenan-induced paw edema. These studies indicate that CEE possesses profound central and peripheral analgesic, anti-convulsant, anti-inflammatory, and hepatoprotective activities.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Anticonvulsivantes/farmacologia , Asteraceae/química , Fígado/patologia , Substâncias Protetoras/farmacologia , Animais , Carragenina , Feminino , Fígado/efeitos dos fármacos , Camundongos , Nociceptividade/efeitos dos fármacos , Compostos Fitoquímicos/análise , Ratos Wistar , Tramadol/farmacologia , Ácido Valproico/farmacologia
11.
JAMA Netw Open ; 2(6): e195345, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31173123

RESUMO

Importance: Implementation of pharmacogenetic testing to guide drug prescribing has potential to improve drug response and prevent adverse events. Robust data exist for more than 30 gene-drug pairs linking genotype to drug response phenotypes; however, it is unclear which pharmacogenetic tests, if implemented, would provide the greatest utility for a given patient population. Objectives: To project the proportion of veterans in the US Veterans Health Administration (VHA) with actionable pharmacogenetic variants and evaluate how testing might be associated with prescribing decisions. Design, Setting, and Participants: This cross-sectional study included veterans who used national VHA pharmacy services from October 1, 2011, to September 30, 2017. Data analyses began April 26, 2018, and were completed February 6, 2019. Exposures: Receipt of level A drugs based on VHA pharmacy dispensing records. Main Outcomes and Measures: Projected prevalence of actionable pharmacogenetic variants among VHA pharmacy users based on variant frequencies from the 1000 Genomes Project and veteran demographic characteristics; incident number of level A prescriptions, and proportion of new level A drug recipients projected to carry an actionable pharmacogenetic variant. Results: During the study, 7 769 359 veterans (mean [SD] age, 58.1 [17.8] years; 7 021 504 [90.4%] men) used VHA pharmacy services. It was projected that 99% of VHA pharmacy users would carry at least 1 actionable pharmacogenetic variant. Among VHA pharmacy users, 4 259 153 (54.8%) received at least 1 level A drug with 1 188 124 (15.3%) receiving 2 drugs, and 912 189 (11.7%) receiving 3 or more drugs. The most common incident prescriptions during the study were tramadol (923 671 new recipients), simvastatin (533 928 new recipients), citalopram (266 952 new recipients), and warfarin (205 177 new recipients). Gene-drug interactions projected to have substantial clinical impacts in the VHA population include the interaction of SLCO1B1 with simvastatin (1 988 956 veterans [25.6%]), CYP2D6 with tramadol (318 544 veterans [4.1%]), and CYP2C9 or VKORC1 with warfarin (7 163 349 veterans [92.2%]). Conclusions and Relevance: Clinically important pharmacogenetic variants are highly prevalent in the VHA population. Almost all veterans would carry an actionable variant, and more than half of the population had been exposed to a drug affected by these variants. These results suggest that pharmacogenetic testing has the potential to affect pharmacotherapy decisions for commonly prescribed outpatient medications for many veterans.


Assuntos
Frequência do Gene/genética , Variantes Farmacogenômicos/genética , Medicamentos sob Prescrição/uso terapêutico , Saúde dos Veteranos , Estudos Transversais , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2D6/genética , Interações Medicamentosas/genética , Utilização de Instalações e Serviços , Feminino , Genótipo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Masculino , Pessoa de Meia-Idade , Assistência Farmacêutica/estatística & dados numéricos , Polimorfismo Genético/genética , Prevalência , Sinvastatina/farmacologia , Tramadol/farmacologia , Estados Unidos , United States Department of Veterans Affairs/estatística & dados numéricos , Vitamina K Epóxido Redutases/genética , Varfarina/farmacologia
12.
Neurosci Lett ; 705: 177-182, 2019 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-31051223

RESUMO

In the present study, the effect of tramadol - an opioid painkiller drug with abuse potential- on amnesia and state-dependent memory and its interaction with the opioidergic system was investigated in male Wistar rats. Intra CA-1 administration of tramadol (0.5, 1, and 2 µg/rat) before training, dose-dependently decreased the learning ability in passive avoidance task. Amnesia induced by pre-train tramadol administration was significantly reversed by pre-test administration of tramadol (1 µg/rat). Pre-test administration of naltrexone (a µ-opioid receptor (MOR) antagonist) inhibited the effect of tramadol on memory retrieval. In addition, the pre-test administration of morphine (1 µg/rat, intra-CA1) also reversed memory impairment induced by pre-train tramadol administration. Although, pre-train morphine administration (1 µg/rat, intra-CA1), induced memory impairment reversed by pre-test tramadol administration (1 µg/rat, intra-CA1). In addition, the level of MOR in the hippocampus decreased in animals with memory impairment due to using tramadol in the training day. However, state-dependent retrieval using tramadol or cross state-dependent retrieval using morphine enhanced the MOR level in the hippocampus. The results of the study suggested that intra-CA1 tramadol administration induced memory impairment, improved by pre-test administration of either tramadol or morphine (MOR agonist). It could be concluded that tramadol is capable to induced state-dependent memory and also, it has a cross state-dependent memory with morphine in the hippocampus, done possibly through MOR.


Assuntos
Amnésia/induzido quimicamente , Região CA1 Hipocampal/efeitos dos fármacos , Memória/efeitos dos fármacos , Morfina/farmacologia , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores , Tramadol/farmacologia , Amnésia/prevenção & controle , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Masculino , Rememoração Mental/efeitos dos fármacos , Microinjeções , Morfina/farmacocinética , Naltrexona/farmacologia , Ratos , Tramadol/antagonistas & inibidores
13.
CNS Drugs ; 33(5): 481-501, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31004280

RESUMO

Tramadol-an atypical opioid analgesic-has a unique pharmacokinetic and pharmacodynamic profile, with opioidergic, noradrenergic, and serotonergic actions. Tramadol has long been used as a well-tolerated alternative to other drugs in moderate pain because of its opioidergic and monoaminergic activities. However, cumulative evidence has been gathered over the last few years that supports other likely mechanisms and uses of tramadol in pain management. Tramadol has modulatory effects on several mediators involved in pain signaling, such as voltage-gated sodium ion channels, transient receptor potential V1 channels, glutamate receptors, α2-adrenoceptors, adenosine receptors, and mechanisms involving substance P, calcitonin gene-related peptide, prostaglandin E2, and proinflammatory cytokines. Tramadol also modifies the crosstalk between neuronal and non-neuronal cells in peripheral and central sites. Through these molecular effects, tramadol could modulate peripheral and central neuronal hyperexcitability. Given the broad spectrum of molecular targets, tramadol as a unimodal analgesic relieves a broad range of pain types, such as postoperative, low back, and neuropathic pain and that associated with labor, osteoarthritis, fibromyalgia, and cancer. Moreover, tramadol has anxiolytic, antidepressant, and anti-shivering activities that could improve pain management outcomes. The aim of this review was to address these issues in the context of maladaptive physiological and psychological processes that are associated with different pain types.


Assuntos
Analgésicos Opioides/farmacologia , Manejo da Dor/métodos , Dor/tratamento farmacológico , Tramadol/farmacologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/uso terapêutico , Humanos , Tramadol/administração & dosagem , Tramadol/efeitos adversos , Tramadol/uso terapêutico
14.
J Pain ; 20(10): 1218-1235, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31005596

RESUMO

Desmetramadol is an investigational analgesic consisting of (+) and (-) enantiomers of the tramadol metabolite O-desmethyltramadol (M1). Tramadol is racemic and exerts analgesia by monoaminergic effects of (-)-tramadol and (-)-M1, and by the opioid (+)-M1. Tramadol labeling indicates cytochrome P450 (CYP) isozyme 2D6 ultrarapid metabolizer can produce dangerous (+)-M1 levels, and CYP2D6 poor metabolizers insufficient (+)-M1 for analgesia. We hypothesized that desmetramadol could provide the safety and analgesia of tramadol without its metabolic liabilities. We conducted consecutive double-blind, randomized, placebo-controlled, 3 segment cross-over trials A and B to investigate the steady-state pharmacokinetics and analgesia of 20 mg desmetramadol and 50 mg tramadol in 103 healthy participants without (n = 43) and with (n = 60) cotreatment with the CYP inhibitor paroxetine. In the absence of CYP inhibition (trial A), 20 mg desmetramadol and 50 mg tramadol dosed every 6 hours gave equivalent steady-state (+)-M1, similar adverse events, and analgesia significantly greater than placebo, but equal to each other. In trial B, CYP inhibition significantly depressed tramadol steady-state (+)-M1, reduced its adverse events, and led to insignificant analgesia comparable with placebo. In contrast, CYP inhibition in trial B had no deleterious effect on desmetramadol (+)-M1 or (-)-M1, which gave significant analgesia as in trial A and superior to tramadol (P = .003). Desmetramadol has the safety and efficacy of tramadol without its metabolic liabilities. CLINICALTRIALS.GOV REGISTRATIONS: NCT02205554, NCT03312777 PERSPECTIVE: To our knowledge, this is the first study of desmetramadol in humans and the first to show it provides the same safety and analgesia as tramadol, but without tramadol's metabolic liabilities and related drug-drug interactions. Desmetramadol could potentially offer expanded safety and usefulness to clinicians seeking an alternative to schedule II opioids.


Assuntos
Analgésicos Opioides/farmacologia , Citocromo P-450 CYP2D6/metabolismo , Percepção da Dor/efeitos dos fármacos , Tramadol/análogos & derivados , Tramadol/farmacologia , Adulto , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/metabolismo , Citocromo P-450 CYP2D6/genética , Método Duplo-Cego , Feminino , Humanos , Masculino , Tramadol/efeitos adversos , Tramadol/metabolismo , Adulto Jovem
15.
Mater Sci Eng C Mater Biol Appl ; 99: 1493-1501, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30889684

RESUMO

Tramadol is an analgesic usually prescribed for the management of pain, with a certain risk of addiction in chronic patients. The incorporation of tramadol in sustained-release systems results particularly attractive for the administration of accurate doses. In this work, emulsion electrospinning was used for the preparation of tramadol-loaded nanofibrous membranes based on poly(ε-caprolactone). Compositional and processing parameters were screened and evaluated in terms of the morphology of the resulting nanofibers, encapsulation efficiency and drug release in time. The polymer concentration, surfactant type and amount, and the homogenization rate used for the emulsions preparation were found to greatly affect the fluid stability and the resulting materials structure and functionality. The intrinsic features of the starting fluid studied in this work played a significant role for the modulation of tramadol release from nanofibrous matrices. The use of sodium dodecyl sulfate as surfactant with an optimal homogenization rate allowed the preparation of electrospun fibrous membranes with good encapsulation efficiency, a minimal burst release and a sustained delivery of tramadol in time.


Assuntos
Emulsões/química , Engenharia Tecidual/métodos , Tramadol/farmacologia , Preparações de Ação Retardada/farmacologia , Liberação Controlada de Fármacos , Membranas Artificiais , Tamanho da Partícula , Tensoativos/química , Termogravimetria , Difração de Raios X
16.
Neuropharmacology ; 149: 204-211, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30817933

RESUMO

The antineoplastic agent oxaliplatin is a first-line treatment for colorectal cancer. However, neuropathic pain, characterized by hypersensitivity to cold, emerges soon after treatment. In severe instances, dose reduction or curtailing treatment may be necessary. While a number of potential treatments for oxaliplatin-induced neuropathic pain have been proposed based on preclinical findings, few have demonstrated efficacy in randomized, placebo-controlled clinical studies. This failure could be related, in part, to the use of rodents as the primary preclinical species, as there are a number of distinctions in pain-related mechanisms between rodents and humans. Also, an indicator of preclinical pharmacological efficacy less subjective than behavioral endpoints that is translatable to clinical usage is lacking. Three days after oxaliplatin treatment in Macaca fascicularis, a significantly reduced response latency to cold (10 °C) water was observed, indicating cold hypersensitivity. Cold-evoked bilateral activation of the secondary somatosensory (SII) and insular (Ins) cortex was observed with functional magnetic resonance imaging. Duloxetine alleviated cold hypersensitivity and significantly attenuated activation in both SII and Ins. By contrast, neither clinically used analgesics pregabalin nor tramadol affected cold hypersensitivity and cold-evoked activation of SII and Ins. The current findings suggest that suppressing SII and Ins activation leads to antinociception, and, therefore, could be used as a non-behavioral indicator of analgesic efficacy in patients with oxaliplatin-induced neuropathic pain.


Assuntos
Analgésicos/uso terapêutico , Antineoplásicos/efeitos adversos , Encéfalo/efeitos dos fármacos , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Neuralgia/tratamento farmacológico , Oxaliplatina/efeitos adversos , Animais , Encéfalo/diagnóstico por imagem , Córtex Cerebral/efeitos dos fármacos , Síndromes Periódicas Associadas à Criopirina/induzido quimicamente , Modelos Animais de Doenças , Cloridrato de Duloxetina/farmacologia , Macaca fascicularis , Imagem por Ressonância Magnética , Masculino , Neuralgia/induzido quimicamente , Pregabalina/farmacologia , Córtex Somatossensorial/efeitos dos fármacos , Tramadol/farmacologia
17.
Rev Assoc Med Bras (1992) ; 65(2): 262-269, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30892453

RESUMO

INTRODUCTION: Opioids interact with both innate and adaptive immune systems and have direct effects on opioid receptors located on immune cells. Research on this topic has provided evidence of the opioid influence on the immune response associated with surgical stress. The immunological effects of opioids are currently being investigated, particularly whether they influence the outcome of surgery or the underlying disease regarding important aspects like infection or cancer progression. This review addresses background research related to the influence of the opioid receptor on the immune system, the immunosuppressive effect associated with major opioids during the perioperative period, and their clinical relevance. The objective of the study was to review the effects of opioids on the immune system.


Assuntos
Analgésicos Opioides/farmacologia , Sistema Imunitário/efeitos dos fármacos , Imunidade Adaptativa/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Fentanila/administração & dosagem , Fentanila/farmacologia , Humanos , Morfina/administração & dosagem , Morfina/farmacologia , Período Perioperatório , Remifentanil/administração & dosagem , Remifentanil/farmacologia , Tramadol/administração & dosagem , Tramadol/farmacologia
18.
Lab Anim ; 53(6): 610-618, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30907232

RESUMO

Postoperative ileus (POI) is a common complication after abdominal surgery characterized by motility disturbances leading to increased morbidity and mortality in surgical patients. Intestinal manipulation of the murine small bowel is an established animal model resulting in an increased postsurgical inflammation within the intestinal muscular externa and a delayed gastrointestinal transit. Some analgesics have been shown to affect inflammation. In this study, we compared the immunomodulatory effects of two different analgesics. Mice were treated with tramadol, metamizole or saline as a control in our established POI model. The postoperative inflammatory response was assessed by gene expression of pro-inflammatory cytokines at different time points and immunocytes extravasation into the muscularis externa. Functional motility analyses were performed by a gastrointestinal transit measurement. Metamizole application reduced the pro-inflammatory response after surgery and improved gastrointestinal motility, while tramadol showed no alteration in cytokine gene expression, influx of immunocytes and gastrointestinal transit compared with the controls. In conclusion. we suggest tramadol as analgesia in immunological studies on POI in mice as it does not affect the underlying inflammation of POI.


Assuntos
Dipirona/farmacologia , Íleus/cirurgia , Fatores Imunológicos/farmacologia , Complicações Pós-Operatórias/tratamento farmacológico , Tramadol/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL
19.
Mol Pain ; 15: 1744806918824243, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799694

RESUMO

To reveal cellular mechanisms for antinociception produced by clinically used tramadol, we investigated the effect of its metabolite O-desmethyltramadol (M1) on glutamatergic excitatory transmission in spinal dorsal horn lamina II (substantia gelatinosa; SG) neurons. The whole-cell patch-clamp technique was applied at a holding potential of -70 mV to SG neurons of an adult rat spinal cord slice with an attached dorsal root. Under the condition where a postsynaptic action of M1 was inhibited, M1 superfused for 2 min reduced the frequency of spontaneous excitatory postsynaptic current in a manner sensitive to a µ-opioid receptor antagonist CTAP; its amplitude and also a response of SG neurons to bath-applied AMPA were hardly affected. The presynaptic effect of M1 was different from that of noradrenaline or serotonin which was examined in the same neuron. M1 also reduced by almost the same extent the peak amplitudes of monosynaptic primary-afferent Aδ-fiber and C-fiber excitatory postsynaptic currents evoked by stimulating the dorsal root. These actions of M1 persisted for >10 min after its washout. These results indicate that M1 inhibits the quantal release of L-glutamate from nerve terminals by activating µ-opioid but not noradrenaline and serotonin receptors; this inhibition is comparable in extent between monosynaptic primary-afferent Aδ-fiber and C-fiber transmissions. Considering that the SG plays a pivotal role in regulating nociceptive transmission, the present findings could contribute to at least a part of the inhibitory action of tramadol on nociceptive transmission together with its hyperpolarizing effect as reported previously.


Assuntos
Analgésicos Opioides/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Neurônios/efeitos dos fármacos , Substância Gelatinosa/citologia , Tramadol/análogos & derivados , Animais , Interações Medicamentosas , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Técnicas In Vitro , Masculino , Antagonistas de Entorpecentes/farmacologia , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/fisiologia , Neurônios/fisiologia , Norepinefrina/farmacologia , Técnicas de Patch-Clamp , Peptídeos/farmacologia , Ratos , Serotonina/farmacologia , Tramadol/farmacologia
20.
Am J Physiol Renal Physiol ; 316(4): F703-F711, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30672315

RESUMO

This study in α-chloralose-anesthetized cats revealed a role of hypogastric nerve afferent axons in nociceptive bladder activity induced by bladder irritation using 0.25% acetic acid (AA). In cats with intact hypogastric and pelvic nerves, AA irritation significantly ( P < 0.05) reduced bladder capacity to 45.0 ± 5.7% of the control capacity measured during a saline cystometrogram (CMG). In cats with the hypogastric nerves transected bilaterally, AA irritation also significantly ( P < 0.05) reduced bladder capacity, but the change was significantly smaller (capacity reduced to 71.5 ± 10.6% of saline control, P < 0.05) than that in cats with an intact hypogastric nerve. However, application of hypogastric nerve stimulation (HGNS: 20 Hz, 0.2 ms pulse width) to the central end of the transected nerves at an intensity (16 V) strong enough to activate C-fiber afferent axons facilitated the effect of AA irritation and further ( P < 0.05) reduced bladder capacity to 48.4 ± 7.4% of the saline control. This facilitation by HGNS was effective only at selected frequencies (1, 20, and 30 Hz) when the stimulation intensity was above the threshold for activating C-fibers. Tramadol (an analgesic agent) at 3 mg/kg iv completely blocked the nociceptive bladder activity and eliminated the facilitation by HGNS. HGNS did not alter non-nociceptive bladder activity induced by saline distention of the bladder. These results indicate that sympathetic afferents in the hypogastric nerve play an important role in the facilitation of the nociceptive bladder activity induced by bladder irritation that activates the silent C-fibers in the pelvic nerve.


Assuntos
Neurônios Aferentes/fisiologia , Nociceptividade/fisiologia , Sistema Nervoso Simpático/fisiologia , Bexiga Urinária/fisiologia , Ácido Acético , Analgésicos Opioides/farmacologia , Animais , Axônios/fisiologia , Gatos , Estimulação Elétrica , Feminino , Masculino , Fibras Nervosas Amielínicas/fisiologia , Neurônios Aferentes/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Tramadol/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...