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1.
Pain Manag ; 12(1): 13-16, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34284647

RESUMO

The objective of this clinical case report is to highlight unusual adverse effects brought on by naloxegol therapy in a patient with underlying psychiatric illness. The patient is a 68-year-old female, with a psychiatric history of bipolar disorder, who presented for chronic pain management and opioid-induced constipation. After failing other therapies, she was trialed on naloxegol on three separate occasions. She experienced mood lability with symptoms including agitation, confusion, irritability, hysteria and unprompted crying spells on each occasion. Notably, the drug manufacturer does not describe mood lability, nor the profound psychiatric manifestations outlined in our case report, as side effects of Naloxegol. Clinicians may consider judicious prescription of naloxegol when treating opioid-induced constipation in patients with pre-existing psychiatric co-morbidities.


Assuntos
Analgésicos Opioides , Constipação Induzida por Opioides , Idoso , Analgésicos Opioides/efeitos adversos , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/complicações , Constipação Intestinal/tratamento farmacológico , Feminino , Humanos , Morfinanos , Antagonistas de Entorpecentes/efeitos adversos , Polietilenoglicóis
2.
Handb Exp Pharmacol ; 271: 137-162, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33834276

RESUMO

Nalfurafine has been used clinically in Japan for treatment of itch in kidney dialysis patients and in patients with chronic liver diseases. A one-year post-marketing study showed nalfurafine to be safe and efficacious without producing side effects of typical KOR agonists such as anhedonia and psychotomimesis. In this chapter, we summarize in vitro characterization and in vivo preclinical studies on nalfurafine. In vitro, nalfurafine is a highly potent and moderately selective KOR full agonist; however, whether it is a biased KOR agonist is a matter of debate. In animals, nalfurafine produced anti-pruritic effects in a dose range lower than that caused side effects, including conditioned place aversion (CPA), hypolocomotion, motor incoordination, consistent with the human data. In addition, nalfurafine showed antinociceptive effects in several pain models at doses that did not cause the side effects mentioned above. It appears to be effective against inflammatory pain and mechanical pain, but less so against thermal pain, particularly high-intensity thermal pain. U50,488H and nalfurafine differentially modulated several signaling pathways in a brain region-specific manners. Notably, U50,488H, but not nalfurafine, activated the mTOR pathway, which contributed to U50,488H-induced CPA. Because of its lack of side effects associated with typical KOR agonists, nalfurafine has been investigated as a combination therapy with an MOR ligand for pain treatment and for its effects on opioid use disorder and alcohol use disorder, and results indicate potential usefulness for these indications. Thus, although in vitro data regarding uniqueness of nalfurafine in terms of signaling at the KOR are somewhat equivocal, in vivo results support the assertion that nalfurafine is an atypical KOR agonist with a significantly improved side-effect profile relative to typical KOR agonists.


Assuntos
Morfinanos , Compostos de Espiro , Animais , Humanos , Morfinanos/farmacologia , Morfinanos/uso terapêutico , Dor , Receptores Opioides kappa , Compostos de Espiro/farmacologia
3.
Nat Commun ; 12(1): 6030, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34654815

RESUMO

For millions of years, plants evolve plenty of structurally diverse secondary metabolites (SM) to support their sessile lifestyles through continuous biochemical pathway innovation. While new genes commonly drive the evolution of plant SM pathway, how a full biosynthetic pathway evolves remains poorly understood. The evolution of pathway involves recruiting new genes along the reaction cascade forwardly, backwardly, or in a patchwork manner. With three chromosome-scale Papaver genome assemblies, we here reveal whole-genome duplications (WGDs) apparently accelerate chromosomal rearrangements with a nonrandom distribution towards SM optimization. A burst of structural variants involving fusions, translocations and duplications within 7.7 million years have assembled nine genes into the benzylisoquinoline alkaloids gene cluster, following a punctuated patchwork model. Biosynthetic gene copies and their total expression matter to morphinan production. Our results demonstrate how new genes have been recruited from a WGD-induced repertoire of unregulated enzymes with promiscuous reactivities to innovate efficient metabolic pathways with spatiotemporal constraint.


Assuntos
Vias Biossintéticas , Cromossomos/metabolismo , Morfinanos/metabolismo , Noscapina/metabolismo , Papaver/genética , Papaver/metabolismo , Alcaloides/química , Alcaloides/metabolismo , Benzilisoquinolinas/metabolismo , Vias Biossintéticas/genética , Evolução Molecular , Genoma , Genômica , Família Multigênica , Proteínas de Plantas/genética
4.
Molecules ; 26(18)2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34577147

RESUMO

Adequate pain management, particularly chronic pain, remains a major challenge associated with modern-day medicine. Current pharmacotherapy offers unsatisfactory long-term solutions due to serious side effects related to the chronic administration of analgesic drugs. Morphine and structurally related derivatives (e.g., oxycodone, oxymorphone, buprenorphine) are highly effective opioid analgesics, mediating their effects via the activation of opioid receptors, with the mu-opioid receptor subtype as the primary molecular target. However, they also cause addiction and overdose deaths, which has led to a global opioid crisis in the last decades. Therefore, research efforts are needed to overcome the limitations of present pain therapies with the aim to improve treatment efficacy and to reduce complications. This review presents recent chemical and pharmacological advances on 14-oxygenated-N-methylmorphinan-6-ones, in the search of safer pain therapeutics. We focus on drug design strategies and structure-activity relationships on specific modifications in positions 5, 6, 14 and 17 on the morphinan skeleton, with the goal of aiding the discovery of opioid analgesics with more favorable pharmacological properties, potent analgesia and fewer undesirable effects. Targeted molecular modifications on the morphinan scaffold can afford novel opioids as bi- or multifunctional ligands targeting multiple opioid receptors, as attractive alternatives to mu-opioid receptor selective analgesics.


Assuntos
Morfinanos , Receptores Opioides mu , Analgésicos/farmacologia , Analgésicos Opioides , Animais , Transdução de Sinais/efeitos dos fármacos
5.
Molecules ; 26(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200341

RESUMO

Sinomenine is a morphinan alkaloid with a variety of biological activities. Its derivatives have shown significant cytotoxic activity against different cancer cell lines in many studies. In this study, two series of sinomenine derivatives were designed and synthesized by modifying the active positions C1 and C4 on the A ring of sinomenine. Twenty-three compounds were synthesized and characterized by spectroscopy (IR, 1H-NMR, 13C-NMR, and HRMS). They were further evaluated for their cytotoxic activity against five cancer cell lines, MCF-7, Hela, HepG2, SW480 and A549, and a normal cell line, Hek293, using MTT and CCK8 methods. The chlorine-containing compounds exhibited significant cytotoxic activity compared to the nucleus structure of sinomenine. Furthermore, we searched for cancer-related core targets and verified their interaction with derivatives through molecular docking. The chlorine-containing compounds 5g, 5i, 5j, 6a, 6d, 6e, and 6g exhibited the best against four core targets AKT1, EGFR, HARS and KARS. The molecular docking results were consistent with the cytotoxic results. Overall, results indicate that chlorine-containing derivatives might be a promising lead for the development of new anticancer agents.


Assuntos
Morfinanos/química , Morfinanos/farmacologia , Células A549 , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular/métodos
6.
Int J Pharm ; 606: 120894, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34280485

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune joint disorder that affects about 1% of the world population and may lead to severe disability and comorbidity. Despite breakthroughs in past decades to understand its pathogenesis and the development of transforming disease-modifying antirheumatic drugs, the symptoms of many patients are not substantially improved. Sinomenine (SIN), a natural alkaloid with poor solubility, has been used to treat RA in China for years because of its unique immunoregulative activity. However, its commercial hydrochloride form has a short half-time, which may cause huge fluctuations of blood drug concentration leading to severe adverse reactions. In this study, co-amorphous systems of SIN with three nonsteroidal anti-inflammatory drugs (NSAIDs), including indomethacin, naproxen, and sulindac, were prepared for the combination therapy, as well as the improvement of its aqueous solubility and controlled release. Each co-amorphous sample was characterized by powder X-ray diffraction (PXRD), temperature-modulated differential scanning calorimetry (mDSC), and Fourier transform infrared spectroscopy (FTIR). The CO2- and N+H stretching vibration in the three co-amorphous samples appears in FTIR spectra, suggesting the formation of salts between SIN and NSAIDs. SIN also exhibits sustained release rates in all three co-amorphous samples. These co-amorphous systems show excellent physicochemical stability because no recrystallization was observed at 25 °C and 75% relative humidity (RH) after four months. Our study suggests that SIN-NSAIDs co-amorphous systems represent an affordable and promising treatment against RA.


Assuntos
Anti-Inflamatórios não Esteroides , Artrite Reumatoide , Artrite Reumatoide/tratamento farmacológico , Varredura Diferencial de Calorimetria , Preparações de Ação Retardada , Combinação de Medicamentos , Estabilidade de Medicamentos , Humanos , Morfinanos , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
7.
Bull Cancer ; 108(9): 837-842, 2021 Sep.
Artigo em Francês | MEDLINE | ID: mdl-34246457

RESUMO

The new paradigm of precision medicine in oncology questions today the respective place of evidence-based medicine and doctor-patient relationship. Based on the results of a randomized study comparing the efficacy of a homeopathic molecule in the prevention of nausea and vomiting induced by chemotherapy in non-metastatic breast cancer, this article extends and develops the discussion of maintaining an unresolved tension between medical art and medical science, between care and cure. This tension sets a base for the authors of the therapeutic alliance in medicine, defined as a dialectic constantly adjourned between the alliance of the doctor with the patient and his therapy, and the therapeutic effect of this alliance. Because if a policy or a public opinion were to promote an exclusively rational medicine deprived of the field of relation to care, or on the contrary a medicine based only on clinical sense and intuition, then respectively the ethics of care and the progress of therapy would be threatened. It is advisable to be aware of erring from the truth, amplified today by social networks, as much due to a tide of scientific positivism, as an excess of the "good caring soul". Taking into account the therapeutic alliance makes it possible to no longer oppose scientific medicine and care relationship.


Assuntos
Medicina Baseada em Evidências , Relações Médico-Paciente , Medicina de Precisão , Ciência , Aliança Terapêutica , Neoplasias da Mama/tratamento farmacológico , Atenção à Saúde/ética , Feminino , Humanos , Materia Medica/uso terapêutico , Medicina , Metáfora , Morfinanos/uso terapêutico , Náusea/induzido quimicamente , Náusea/terapia , Redes Sociais Online , Estudo de Prova de Conceito , Ensaios Clínicos Controlados Aleatórios como Assunto , Vômito/induzido quimicamente , Vômito/terapia
8.
Int J Nanomedicine ; 16: 3725-3739, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34103913

RESUMO

Purpose: Transarterial chemoembolization is the preferred treatment for patients with middle and advanced-stage hepatocellular carcinoma (HCC); however, most hepatic artery embolization agents have various disadvantages. The purpose of this study was to evaluate phytantriol-based liquid crystal injections for potential use in treatment of HCC. Methods: Using sinomenine (SN) and 5-fluorouracil (5-FU) as model drugs, three precursor in situ liquid crystal injections based on phytantriol (P1, P2, and P3) were prepared, and their in vitro biocompatibility, anticancer activity, and drug release investigated, to evaluate their feasibility for use in treatment of HCC. The properties of the precursor injections and subsequent cubic liquid crystal gels were observed by visual and polarizing microscopy, in an in vitro gelation experiment. Biocompatibility was evaluated by in vitro hemolysis, histocompatibility, and cytotoxicity assays. Results: Precursor injections were colorless liquids that formed transparent cubic liquid crystal gels on addition of excess water. The three precursor injections all caused slight hemolysis, without agglutination, and were mildly cytotoxic. Histocompatibility experiments showed that P1 had good histocompatibility, while P2 and P3 resulted in strong inflammatory responses, which subsequently resolved spontaneously. In vitro anti-cancer testing showed that SN and 5-FU inhibited HepG2 cells in a time- and concentration-dependent manner and had synergistic effects. Further, in vitro release assays indicated that all three preparations had sustained release effects, with cumulative release of >80% within 48 h. Conclusion: These results indicate that SN and 5-FU have synergistic inhibitory effects on HepG2 cells, which has not previously been reported. Moreover, we describe a biocompatible precursor injection, useful as a drug carrier for the treatment of liver cancer, which can achieve targeting, sustained release, synergistic chemotherapy, and embolization. These data indicate that precursor injections containing SN and 5-FU have great potential for use in therapy for liver cancer.


Assuntos
Fluoruracila/uso terapêutico , Cristais Líquidos/química , Neoplasias Hepáticas/tratamento farmacológico , Morfinanos/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Morte Celular , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Álcoois Graxos/química , Fluoruracila/farmacologia , Géis , Hemólise , Células Hep G2 , Humanos , Injeções , Morfinanos/farmacologia , Ratos Sprague-Dawley , Água/química
9.
J Pharm Biomed Anal ; 203: 114171, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34087551

RESUMO

INTRODUCTION: A range of opioids are commonly prescribed to manage chronic pain, but individual patient responses vary greatly, especially in older populations. One source of that variability are differences in absorption, metabolism and excretion, i.e. pharmacokinetics. Blood, plasma and serum concentrations of opioids allow that variability to be quantified and may be used to optimise opioid dosing. As an aid to that process, there is an unmet need to rapidly quantify several opioids and their metabolites in a single analytical method. AIMS: To develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of tramadol, oxycodone, fentanyl and their major metabolites in various human matrices. METHODS: Sample preparation involved adding three deuterated internal standards followed by protein precipitation with 100 % acetonitrile, evaporation and reconstitution. Separation of analytes via LC was achieved on a reversed phase column via binary gradient elution using 0.005 % formic acid in water and 100 % acetonitrile as mobile phases. Analytes were detected via MS/MS with multiple reaction monitoring (MRM). RESULTS: The method was accurate with the inter-day and intra-day accuracy of quality control samples (QCs) below 15 %. It was also precise with inter-day and intra-day coefficient of variation below 15 %. The lower limit of quantification (LLOQ) was 0.2 ng/mL for all analytes except tramadol and its metabolites, where the LLOQ was 10 ng/mL. Recovery was greater than 88 % for all analytes, except for O-desmethyltramadol (81 %). Analytes were stable over four freeze-thaw cycles, for 24 h on the bench top and for 24 h post-preparation. The inter- and intra-day variability of concentrations determined in blood and plasma were within 84-124%, whereas the inter- and intra-day variability for blood samples prepared using volumetric absorptive micro-sampling (VAMS) compared to those prepared from whole blood ranged between 83-122%. CONCLUSION: A LC-MS/MS method is described that is able to accurately and precisely quantify a number of commonly prescribed opioids and their major metabolites in plasma and whole blood, including whole blood collected using VAMS.


Assuntos
Oximorfona , Tramadol , Idoso , Cromatografia Líquida , Fentanila/análogos & derivados , Humanos , Morfinanos , Oxicodona , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Tramadol/análogos & derivados
10.
Support Care Cancer ; 29(12): 7577-7586, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34120247

RESUMO

PURPOSE: Naloxegol, an oral once-daily peripherally acting mu-opioid receptor antagonist, is indicated for the treatment of opioid-induced constipation (OIC) with inadequate response to laxative(s), in cancer and non-cancer patients. This study mainly aimed to assess in real-life conditions the efficacy and safety of naloxegol in cancer pain patients and the evolution of their quality of life. METHODS: A non-interventional, 4-week follow-up study was conducted in 24 French oncology and pain centers between 2018 and 2019. Eligible patients were aged ≥ 18 years, treated with opioids for cancer pain, and started naloxegol for OIC with inadequate response to laxatives. The rate of the response to naloxegol (primary criterion) was assessed at W4. The evolution of quality of life was measured using the Patient Assessment of Constipation Quality of Life (PAC-QOL). RESULTS: A total of 124 patients were included (mean age, 62 ± 12 years; ECOG ≤ 2, 79%; primary cancer, lung 18%, breast 16%, prostate 11%, head and neck 9%, digestive 9%…; metastatic stage, 80%). At inclusion, the median opioid dosage was 60 mg of oral morphine or equivalent. At W4, the response rate was 73.4% (95% CI [63.7-83.2%]), and 62.9% (95% CI [51.5-74.2%]) of patients had a clinically relevant change in quality of life (decrease in PAC-QOL score ≥ 0.5 point). Adverse events related to naloxegol were reported in 8% of patients (7% with gastrointestinal events; one serious diarrhea). CONCLUSION: This real-world study shows that naloxegol is effective and well tolerated in cancer pain patients with OIC and that their quality of life improves under treatment.


Assuntos
Dor do Câncer , Neoplasias , Constipação Induzida por Opioides , Idoso , Analgésicos Opioides/efeitos adversos , Dor do Câncer/tratamento farmacológico , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Morfinanos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Polietilenoglicóis/efeitos adversos , Qualidade de Vida
11.
Curr Top Med Chem ; 21(14): 1224-1234, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34126903

RESUMO

BACKGROUND: Recent evidence has been demonstrated that Sinomenine (SIN) exerts antitumor activity in vitro. However, the clinical utility of SIN remains limited mainly because of its poor bioavailability. Exosomes are nanoscale vesicles that play crucial roles in intracellular communications through functionally active substances such as DNA and RNA. Exosomes have been utilized as nanocarriers for targeted drug delivery of different anticancer drugs. METHODS: The present study aimed to evaluate the effectiveness of combined Exosomes-SIN for the treatment of hepatocellular carcinoma (HCC) in a rat model. To do so, we prepared a mixture of SIN and exosomes (Exo-SIN) to improve the bioavailability of SIN to treat liver cancer. The in vitro releasing profile of the Exo-SIN was examined. RESULTS: We observed a continuous, slow release of SIN from Exo-SIN in simulated body fluid as well as tumor microenvironment. In the cytotoxicity test, Exo-SIN exhibited a significantly stronger inhibition in HepG2 cells compared to free SIN. The flow cytometry assessments showed that Exo-SIN could suppress HepG2 cell migration in a Transwell assay and induce cell cycle arrest and cellular apoptosis. Western blotting showed that survivin, a crucial protein for the survival of living cells, was significantly downregulated after treatment with Exo-SIN. CONCLUSION: In conclusion, our data suggested that Exo-SIN could serve as a potential, effective delivery platform for hepatic carcinoma therapy.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Neoplasias Hepáticas/tratamento farmacológico , Morfinanos/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais , Exossomos/química , Humanos , Neoplasias Hepáticas/patologia , Morfinanos/química , Ratos , Ratos Sprague-Dawley
12.
Biochem Biophys Res Commun ; 560: 192-198, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34000468

RESUMO

The medial prefrontal cortex (mPFC) plays a vital role in the processing of emotional events. It has been shown that activation of the glutamatergic transmission in prelimbic subregion of the mPFC (PL-PFC) evoked anxiety-like behavior in rodents. We previously reported that local perfusion of a selective agonist to delta-opioid receptor (DOP), KNT-127, attenuated the veratrine-induced elevation of extracellular glutamate in the PL-PFC and anxiety-like behavior in mice. These results suggested the possibility that KNT-127 suppresses glutamate release from the presynaptic site in the PL-PFC. To examine this possibility directly, we performed whole-cell patch-clamp recording from principal neurons in the PL-PFC and examined the spontaneous and electrically-evoked excitatory postsynaptic currents (EPSC)s. We found that bath application of KNT-127 significantly decreased the frequency of spontaneous and miniature EPSCs. Conversely, amplitude, rise time, and decay time of spontaneous and miniature EPSCs were not affected by bath application of KNT-127. Also, KNT-127 increased paired-pulse ratios of electrically-evoked EPSCs in the PL-PFC principal neurons tested. Further, we analyzed the firing properties of pyramidal neurons in the PL-PFC and found that KNT-127 treatment significantly reduced the number of action potentials and firing threshold. These results suggested that KNT-127 suppresses glutamatergic synaptic transmission by inhibiting glutamate release from the presynaptic site and reduces neuronal excitability in the mouse PL-PFC. We propose the possibility that these suppressing effects of KNT-127 on PL-PFC activity are part of the underlying mechanisms of its anxiolytic-like effects.


Assuntos
Morfinanos/farmacologia , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Receptores Opioides delta/agonistas , Transmissão Sináptica/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia
13.
Chem Commun (Camb) ; 57(48): 5981-5984, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34027538

RESUMO

Although sinomenine (SIN) has been used to treat several inflammation-related diseases in the clinic for decades, the detailed anti-inflammatory mechanism remains elusive. Here, we present a chemoproteomic study that supports a polypharmacological mode of action for SIN to inhibit inflammation. Notably, functional validation revealed multiple new protein regulators whose knockdown could significantly affect inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Morfinanos/farmacologia , Proteômica , Animais , Anti-Inflamatórios/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Morfinanos/química , Células RAW 264.7
14.
J Chromatogr Sci ; 59(7): 606-617, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-33969409

RESUMO

OBJECTIVE: Sinomenii Caulis (QingFengTeng) and Ramulus Cinnamomi (GuiZhi) are traditional Chinese drugs that have been used for anti-inflammation. In this study, the team plans to find out the material basis of a Chinese herb combination composed of the two herbs with different ratios. METHODS: The extracts of the herbal compound with various ratios obtained from ethanol extraction were analyzed by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) and gas chromatography coupled mass spectrometry to identify the basic chemical compounds. Simultaneously, the contents of the eight main components (sinomenine, magnoflorine, laurifoline, dauricine, coumarin, cinnamyl alcohol, cinnamic acid and cinnamaldehyde) from herb formula were determined by gradient elution by high-performance liquid chromatography. Furthermore, the content of sinomenine and cinnamaldehyde were determined by isocratic elution, respectively. RESULTS: Eighteen compounds in the herb formula were identified by UHPLC-Q-TOF-MS. The components in the GuiZhi are mostly volatile oils and the kinds of compounds isolated from the formula in the ratio of 4:1 were the most. Wherein eight compounds were identified as the main detection targets in the content determination. CONCLUSION: The extraction rate of sinomenine in QingFengTeng was related to the proportion of GuiZhi in the drug pairs. Synchronously, the addition of sinomenine in different proportions also had some influence on the extraction of cinnamaldehyde in GuiZhi. Furthermore, the series of methods was successfully applied to the simultaneous determination of chemical compounds in different samples of QingFengTeng-GuiZhi decoction.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas , Cromatografia Gasosa-Espectrometria de Massas/métodos , Acroleína/análogos & derivados , Acroleína/análise , Acroleína/química , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/química , Morfinanos/análise , Morfinanos/química , Óleos Voláteis/química
15.
Eur J Pharmacol ; 903: 174132, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33933466

RESUMO

Opioid-induced constipation is the most prevalent adverse effect of opioid drugs. Peripherally acting mu opioid receptor antagonists (PAMORAs), including naloxegol, are indicated for the treatment of opioid-induced constipation. The aim of this study was the in vitro and in vivo pharmacological characterization of naloxegol in comparison with naloxone. In vitro experiments were performed to measure calcium mobilization in cells coexpressing opioid receptors and chimeric G proteins and mu receptor interaction with G protein and ß-arrestin 2 using bioluminescence resonance energy transfer. In vivo experiments were performed in mice to measure pain threshold using the tail withdrawal assay and colonic transit using the bead expulsion assay. In vitro, naloxegol behaved as a selective and competitive mu receptor antagonist similarly to naloxone, being 3-10-fold less potent. In vivo, naloxone was effective in blocking fentanyl actions when given subcutaneously (sc), but not per os (po). In contrast, naloxegol elicited very similar effects with sc or po administration counteracting in a dose dependent manner the constipating effects of fentanyl without interfering with the fentanyl mediated analgesia. Thus, a useful PAMORA action could be obtained with naloxegol both after po and sc administration.


Assuntos
Constipação Intestinal/tratamento farmacológico , Morfinanos/farmacologia , Antagonistas de Entorpecentes/farmacologia , Polietilenoglicóis/farmacologia , Administração Oral , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Células CHO , Cálcio/metabolismo , Constipação Intestinal/induzido quimicamente , Cricetulus , Fentanila/administração & dosagem , Fentanila/efeitos adversos , Fentanila/farmacologia , Injeções Subcutâneas , Masculino , Camundongos , Morfinanos/administração & dosagem , Morfina/farmacologia , Naloxona/administração & dosagem , Naloxona/farmacologia , Antagonistas de Entorpecentes/administração & dosagem , Dor/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/efeitos dos fármacos
16.
Chem Rec ; 21(9): 2344-2353, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33955153

RESUMO

The morphinans are an important class of structurally fascinating and physiologically important natural products as exemplified by the famous opium alkaloids of the morphine family. Although this class of secondary metabolites from the juice of the opium poppy capsule was already used for medicinal purposes thousands of years ago, chemical modifications are still being applied to the core structure today in order to achieve the most specific effect on the various receptor subtypes possible with the fewest possible side effects. The unusual architecture of the morphinan core has also proven to be a highly challenging target for total synthesis. This review highlights electrosynthetic approaches towards natural and semisynthetic morphinan alkaloids. The historical progress in applying anodic aryl-aryl couplings to the construction of the morphinan framework is described in chronological order while particular benefits and challenges concerning the electrochemical transformations are grouped together, including the influence of substitution patterns, protecting groups, and reaction conditions.


Assuntos
Morfinanos , Papaver , Morfina
17.
Sci Rep ; 11(1): 8647, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33883646

RESUMO

Corneal neovascularization (CNV) causes higher-order aberrations, corneal edema, ocular inflammation, and corneal transplant rejection, thereby decreasing visual acuity. In this study, we investigated the effects of topical administration of the kappa opioid receptor agonist nalfurafine (TRK-820) on CNV. To induce CNV, intrastromal corneal sutures were placed on the corneal stroma of BALB/c mice for 2 weeks. Nalfurafine (0.1 µg/2 µL/eye) was topically administered to the cornea once or twice daily after CNV induction. The CNV score, immune cell infiltration, and mRNA levels of angiogenic and pro-inflammatory factors in neovascularized corneas were evaluated using slit-lamp microscopy, immunohistochemistry, flow cytometry, and polymerase chain reaction. The mRNA expression of the kappa opioid receptor gene Oprk1 was significantly upregulated following CNV induction. Topical administration of nalfurafine twice daily significantly suppressed CNV and lymphangiogenesis, as well as reduced the mRNA levels of angiogenic and pro-inflammatory factors in the neovascularized corneas. Moreover, nalfurafine administration twice daily reduced the numbers of infiltrating leukocytes, neutrophils, macrophages, and interferon-γ-producing CD4+ T cells in the neovascularized corneas. In this study, we demonstrated that topical administration of nalfurafine suppressed local CNV in a mouse model along with the activation of KOR, suggesting that nalfurafine may prevent and control CNV in humans.


Assuntos
Neovascularização da Córnea/tratamento farmacológico , Substância Própria/efeitos dos fármacos , Inflamação/tratamento farmacológico , Morfinanos/administração & dosagem , Receptores Opioides kappa/agonistas , Compostos de Espiro/administração & dosagem , Administração Tópica , Animais , Edema da Córnea/tratamento farmacológico , Edema da Córnea/metabolismo , Neovascularização da Córnea/metabolismo , Substância Própria/metabolismo , Expressão Gênica/efeitos dos fármacos , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , RNA Mensageiro/metabolismo
18.
Forensic Sci Int Genet ; 53: 102510, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33799050

RESUMO

Genetic disposition can cause variation in oxycodone pharmacokinetic characteristics and decrease or increase the expected clinical response. In forensic medicine, determination of cause of death or assessing time between drug intake and death can be facilitated by knowledge of parent and metabolite concentrations. In this study, the aim was to investigate if CYP2D6 genotyping can facilitate interpretation by investigating the frequency of the four CYP2D6 phenotypes, poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultra-rapid metabolizer in postmortem cases, and to study if the CYP2D6 activity was associated with a certain cause of death, concentration, or metabolic ratio. Cases positive for oxycodone in femoral blood (n = 174) were genotyped by pyrosequencing for CYP2D6*3, *4, and *6 and concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined by LC-MS/MS (LLOQ 0.005 µg/g). Digital droplet PCR was used to determine the copy number variation for CYP2D6*5. Cases were categorized by cause of death. It was found that poor and intermediate CYP2D6 metabolizers had significantly higher oxycodone and noroxycodone concentrations compared to extensive and ultra-rapid metabolizers. CYP2D6 phenotype were equally distributed between cause of death groups, showing that no phenotype was overrepresented in any of the cause of death groups. We also found that the concentration ratio between oxymorphone and oxycodone depended on the CYP2D6 activity when death was unrelated to intoxication. In general, a low metabolite to parent ratio indicate an acute intake. By using receiver operating characteristic (ROC) analysis, we conclude that an oxymorphone/oxycodone ratio lower than 0.075 has a high sensitivity for separating intoxications with oxycodone from other intoxications and non-intoxications. However, the phenotype needs to be known to reach a high specificity. Therefore, the ratio should not be used as a biomarker on its own to distinguish between different causes of death but needs to be complemented by genotyping.


Assuntos
Analgésicos Opioides/sangue , Citocromo P-450 CYP2D6/genética , Oxicodona/sangue , Testes Farmacogenômicos , Adolescente , Adulto , Idoso , Analgésicos Opioides/farmacocinética , Variações do Número de Cópias de DNA , Feminino , Genética Forense , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Morfinanos/sangue , Oxicodona/farmacocinética , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
19.
Sci Rep ; 11(1): 9300, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33927244

RESUMO

Chronic pain is a significant public health problem that afflicts nearly 30% of the global population, but current pharmacotherapies are insufficient. Previous report indicated that N-demethylsinomenine, an active metabolite of sinomenine, is efficacious against postoperative pain. The present study investigated whether N-demethylsinomenine is effective for chronic painful conditions or whether repeated treatment alters its effect. Both chronic constriction injury (CCI) surgery and complete Freund's adjuvant (CFA) intraplantar injection induced significant and reliable mechanical allodynia at least for 7 days. Acute treatment with N-demethylsinomenine (10-40 mg/kg, i.p.) dose-dependently attenuated the mechanical allodynia both in CCI-induced neuropathic pain and CFA-induced inflammatory pain in mice. The potency of N-demethylsinomenine for reducing CFA-induced mechanical allodynia was slightly higher than sinomenine. During the period of repeated treatment, N-demethylsinomenine maintained its anti-allodynic effect against both neuropathic and inflammatory pain without producing carry-over effect. Pretreatment with bicuculline, a selective γ-aminobutyric acid type A (GABAA) receptor antagonist, almost completely blocked the anti-allodynia of N-demethylsinomenine (40 mg/kg) both in CCI and CFA-treated mice. Our findings indicated that N-demethylsinomenine exhibits GABAA receptor-mediated anti-allodynic effects in mouse models of neuropathic and inflammatory pain, suggesting it may be a useful novel pharmacotherapy for the control of chronic pain.


Assuntos
Analgésicos/uso terapêutico , Dor Crônica/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Morfinanos/uso terapêutico , Neuralgia/tratamento farmacológico , Analgésicos/administração & dosagem , Animais , Bicuculina/farmacologia , Modelos Animais de Doenças , Antagonistas de Receptores de GABA-A/farmacologia , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Morfinanos/administração & dosagem , Receptores de GABA-A/metabolismo
20.
Zhongguo Zhong Yao Za Zhi ; 46(1): 214-224, 2021 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-33645073

RESUMO

To systemically evaluate the efficacy and safety of sinomenine combined with methotrexate(SIN+MTX) in the treatment of rheumatoid arthritis(RA). Literature databases of Wanfang, CNKI, VIP, SinoMed, PubMed, Cochrane Library and Web of Science were retrieved comprehensively for relevant clinical trials. The literature retrieval time was from database establishment to February 4, 2020. The quality of literatures was assessed by the Cochrane Evaluation Handbook 5.1.0, and qualified literature was reviewed and analyzed by using the RevMan 5.3 statistical software. Twenty randomized controlled trials met the inclusion criteria, and were enrolled in the Meta-analysis. The results showed that SIN+MTX remarkably reduced DAS28(MD=-0.85, 95%CI[-1.03,-0.67], P<0.000 01), and improved total efficiency(P<0.000 01). SIN+MTX could inhibit swollen joint count(MD=-1.19, 95%CI[-1.75,-0.63], P<0.000 1), tender joint count(MD=-1.58, 95%CI[-2.89,-0.28], P=0.02) and reduce morning stiffness time(MD=-8.44, 95%CI[-11.82,-5.07], P<0.000 01) compared with control group. The results showed that SIN+MTX was equal to control group in grip strength(SMD=0.20,95%CI[-1.11,1.51],P=0.77). SIN+MTX remarkably alleviated the erythrocyte sedimentation rate(MD=-9.87, 95%CI[-14.52,-5.22], P<0.000 1), C-reactive protein(SMD=-0.30, 95%CI[-0.51,-0.09], P=0.005), and rheumatoid factor(MD=-11.23,95%CI[-13.81,-8.65],P<0.000 01). The frequency of adverse reactions were reduced compared with that in the control group(P<0.000 01). Current clinical studies demonstrate that the efficacy and safety of SIN+MTX in the treatment of RA were superior to control group. However, due to the low quality and quantity of the included studies, high-quality randomized controlled trials are necessary to support the clinical evidences.


Assuntos
Antirreumáticos , Artrite Reumatoide , Medicamentos de Ervas Chinesas , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Metotrexato/efeitos adversos , Morfinanos
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