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1.
Phytochemistry ; 171: 112234, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31901735

RESUMO

A total of fifteen grayanane diterpenoid glucosides including eight undescribed ones, pierisjaponosides A-H, were isolated from the leaves of Pieris japonica (Thunb.) D. Don ex G. Don (Ericaceae). Their structures were established by extensive spectros copic techniques including HRESIMS and NMR, as well as chemical methods. The absolute configurations of pierisjaponosides A, B, and D were finally established by single-crystal X-ray diffraction with Cu Kα radiation. This is the first time to report the crystal structure of a 5,9-epoxygrayanane diterpenoid glucoside. Pierisjaponoside E represents the first example of a 9ß-hydroxygrayan-1(10)-ene diterpenoid. All the isolated grayanane diterpenoid glucosides were evaluated for their analgesic activities in the acetic acid-induced writhing models in mice, and showed significant analgesic effects. Pierisjaponosides A and C-H, micranthanoside A, pieroside A, and craiobiosides A and B displayed significant analgesic effects with the writhe inhibition rates over 50% at a dose of 5.0 mg/kg. Pierisjaponoside E exhibited significant analgesic activities with the percentage inhibitions of 81.7%, 70.4%, and 52.1% at the doses of 5.0, 1.0, and 0.2 mg/kg, respectively. The preliminary structure-activity relationships of grayanane diterpenoid glucosides as potent analgesics were discussed, giving some clues to design novel analgesics.


Assuntos
Analgésicos/uso terapêutico , Diterpenos/uso terapêutico , Ericaceae/química , Glucosídeos/uso terapêutico , Dor/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Ácido Acético , Analgésicos/química , Analgésicos/isolamento & purificação , Animais , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Feminino , Glucosídeos/química , Glucosídeos/isolamento & purificação , Masculino , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Dor/induzido quimicamente , Medição da Dor , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Folhas de Planta/química , Relação Estrutura-Atividade
2.
Chem Biol Interact ; 317: 108941, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31926916

RESUMO

m-Trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] is an organoselenium molecule that displays multiple pharmacological actions, including the antinociceptive effect. The current study investigated the (m-CF3-PhSe)2 restorative properties in models of acute and chronic inflammatory pain induced by complete Freund's adjuvant (CFA). Male adult Swiss mice received an intraplantar injection of CFA in the hindpaw and 24 h (acute) or 14 days (subchronic) later they were treated with a single or repeated (m-CF3-PhSe)2 schedule via intragastric route, respectively. The mechanical and thermal hypernociceptive behaviors were assessed by von Frey hair and hot plate tests. Samples of injected paw were collected to evaluate the tissue edema and myeloperoxidase (MPO) activity while cerebral contralateral cortex samples were used to determine the inflammatory proteins content (subchronic protocol). The acute (m-CF3-PhSe)2 administration (1 and 10 mg/kg) reduced the hypernociceptive behavior and both paw thickness and MPO activity induced by CFA injection. In the subchronic protocol, the repeated administration with a low effective dosage of (m-CF3-PhSe)2 reduced the mechanical and thermal hypernociception as well as restored the edema and MPO activity in paw samples. In addition, the repeated treatment schedule mitigated the increase in TNF-α, IL-1ß and COX-2 content in cerebral contralateral cortex induced by CFA injection. Collectively, these data showed that (m-CF3-PhSe)2 presents anti-inflammatory properties, which could be mediated by an interplay between peripheral and central mechanisms of action, reinforcing the potential biological properties of the compound.


Assuntos
Inflamação/induzido quimicamente , Compostos de Organossilício/farmacologia , Dor/induzido quimicamente , Dor/tratamento farmacológico , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Comportamento Animal/efeitos dos fármacos , Diclofenaco/administração & dosagem , Diclofenaco/farmacologia , Adjuvante de Freund/toxicidade , Inflamação/tratamento farmacológico , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Compostos de Organossilício/administração & dosagem , Medição da Dor , Sintase do Porfobilinogênio/metabolismo , Carbonilação Proteica , Compostos de Sulfidrila/metabolismo
3.
J Photochem Photobiol B ; 202: 111674, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31778953

RESUMO

The present work showed the preparation of gold (Au NPs) and silver nanoparticles (Ag NPs) using aqueous leaf extract of Clinacanthus nutans Lindau (C. Lindau). The prepared NPs were studied using various microscopic and spectroscopic techniques, which confirmed the formation of crystalline Ag NPs, Au NPs that are stabilized with C. Lindau extract polyphenols. The prepared Au NPs and Ag NPs are studied to assess their comparative analgesic and muscle relaxant activities conducted on BALB/c mice. The muscle relaxant studies displayed that Ag NPs were comparatively higher efficient than Au NPs and methanolic C. Lindau extract in traction examination. Additionally, the analgesic studies exhibited that Ag NPs, Au NPs showed maximum percentage reduction in acetic acid induced writhing at the concentrations of 50, 100 and 150 mg/kg body weight. Further, these results conclude that as prepared Au NPs and Ag NPs prepared from C. Lindau leaf extract demonstrated very good analgesic and muscle relaxant activities for the use of pain management in nursing care.


Assuntos
Acanthaceae/química , Analgésicos/síntese química , Ouro/química , Nanopartículas Metálicas/química , Prata/química , Acanthaceae/metabolismo , Ácido Acético/toxicidade , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Química Verde , Nanopartículas Metálicas/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Relaxamento Muscular/efeitos dos fármacos , Cuidados de Enfermagem , Dor/induzido quimicamente , Dor/tratamento farmacológico , Manejo da Dor/métodos , Extratos Vegetais/química , Folhas de Planta/química , Folhas de Planta/metabolismo
4.
J Photochem Photobiol B ; 202: 111700, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31810039

RESUMO

Zinc oxide (ZnO), an inorganic metal oxide established in the form of nanoparticles, has considerable biological properties. The current research uses Selaginella convolute (S. convolute) leaf extract to establish ZnO NPs and to assess their use in pain management. S. Convolute leaf extract mediated ZnO NPs were characterized by modern techniques and instruments such as Fourier transforms infrared spectroscopy (FTIR), electron microscopy, X-ray diffraction (XRD), and Ultraviolet-vis-spectroscopy (UV-vis), energy dispersive X-ray spectroscopy (EDX), indicating the emergence of spherical NPs of which is around 40 nm. The FTIR spectrum also signified that S. convolute plant extract polyphenols acted as a capping ligand for the fabricated ZnO NPs. Possessed ZnO NPs have shown important characteristics of muscle relaxing and antinociceptive. A concentration dependent acetic acid induced writhing effect was noted for both S. convolute extract and ZnO NPs. S. convolute plant extract and ZnO NPs are found to exhibit highest muscle relaxation effect in both traction and chimney tests and no sedative effect was shown by both ZnO NPs and plant extract. The present results showed that the S. convolute leaves extract is a very effective green reducing agent for the preparation of ZnO NPs and the prepared NPs can be used in pain management in emerging nursing care in future.


Assuntos
Nanopartículas Metálicas/química , Selaginellaceae/química , Óxido de Zinco/química , Ácido Acético/toxicidade , Animais , Química Verde , Locomoção/efeitos dos fármacos , Nanopartículas Metálicas/uso terapêutico , Nanopartículas Metálicas/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Relaxamento Muscular/efeitos dos fármacos , Dor/induzido quimicamente , Dor/tratamento farmacológico , Manejo da Dor , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Folhas de Planta/metabolismo , Selaginellaceae/metabolismo
5.
J Photochem Photobiol B ; 202: 111668, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31734435

RESUMO

Fraxinus rhynchophylla belongs to the family of Oleaceae and also called as Chinese ash wood possesses various pharmacological properties such as neuroprotective, antimicrobial, anti-inflammatory, etc. Therefore we synthesized ZnO nanoparticles using Fraxinus rhynchophylla wood extract as reducing and capping agent. The synthesized nanoparticles were characterized with the aid of UV-Spec, DLS, FT-IR and TEM analysis. Green synthesized ZnO nanoparticles were then assessed for anti-nociceptive property by using various nociception models such as thermal stress-induced, acetic acid, glutamate, capsaicin, and formalin-induced nociception. The sedative effect of synthesized ZnO nanoparticles was evaluated with an open field test. UV-Spectroscopic analysis confirms the formation of ZnO nanoparticles and the characterization studies DLS, FT-IR, and TEM analysis prove it has ideal nanoparticle can be used as a nano-drug. Results of both thermal stress-induced methods hot plate and tail immersion nociception test verified the synthesized ZnO nanoparticles are a potent antinociceptive drug. ZnO nanoparticles effectively reduced the abdominal writhes in acetic acid-induced nociception and it also significantly decreased the nociception activity in another glutamate, capsaicin, and formalin-induced nociception models. Open field experiment proved that synthesized ZnO nanoparticles are less sedative compared to the standard antinociceptive drug morphine. Overall our findings authentically confirm ZnO nanoparticles synthesized from Fraxinus rhynchophylla wood extract is a novel drug that persuasively reduces nociception in different nociceptive induced mice models and can be the best alternative for allopathic drugs which renders severe side effects.


Assuntos
Analgésicos/uso terapêutico , Fraxinus/química , Nanopartículas Metálicas/química , Dor/tratamento farmacológico , Óxido de Zinco/química , Analgésicos/síntese química , Analgésicos/química , Animais , Modelos Animais de Doenças , Formaldeído/toxicidade , Fraxinus/metabolismo , Química Verde , Temperatura Alta , Masculino , Nanopartículas Metálicas/uso terapêutico , Camundongos , Dor/induzido quimicamente , Casca de Planta/química , Casca de Planta/metabolismo , Extratos Vegetais/química
6.
Lancet Haematol ; 7(2): e112-e121, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31866281

RESUMO

BACKGROUND: Chemoimmunotherapy is typically the standard of care for patients with Waldenström macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenström macroglobulinemia. METHODS: This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenström macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenström Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov, number NCT02180724, and is ongoing, but no longer enrolling. FINDINGS: Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0-29·7), 13 (93% [95% CI 66-100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86-98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3-4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3-4 atrial fibrillation occurred in one (1%) patient and grade 3-4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma). INTERPRETATION: This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenström macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies. FUNDING: Acerta Pharma.


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Benzamidas/efeitos adversos , Benzamidas/farmacologia , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/genética , Proteínas de Neoplasias/antagonistas & inibidores , Neutropenia/induzido quimicamente , Dor/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/efeitos adversos , Pirazinas/farmacologia , Qualidade de Vida , Recidiva , Infecções Respiratórias/etiologia , Terapia de Salvação , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/enzimologia , Macroglobulinemia de Waldenstrom/genética
7.
J Ethnopharmacol ; 247: 112265, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31580941

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Hymenaea cangaceira Pinto, Mansano & Azevedo (Fabaceae) is a Brazilian medicinal plant widely known as "Jatobá". In folk medicine, it is used to treat infections, respiratory problems, rheumatism, antitumoral, inflammation and pain, however, no activity has been scientifically validated. AIM OF THE STUDY: This study investigated chemical composition of essential oil from Hymenaea cangaceira (EOHc), antimicrobial, antinociceptive and antioxidant activities besides protection against DNA damage and hemolysis. MATERIAL AND METHODS: The essential oil was obtained by hydrodistillation, and characterized by GC-MS and GC-FID. The evaluation of antimicrobial activity was performed by microdilution method. The evaluation of the antioxidant activity was performed using the radicals DPPH, ABTS, O2- and OH-, and the protection of DNA damage using plasmid pBR322. Different experimental models were used to evaluate the antinociceptive effect (acetic acid and formalin), and evaluate the mechanisms of action involved with pharmacological antagonists (naloxone, atropine and gibenclamide) in mice. The essential oil was evaluated for hemolysis on human erythrocytes. RESULTS: The extraction of EOHc showed a yield of 0.18% on a dry basis, presenting high content of hydrocarbon sesquiterpenes (79.04%), high antioxidant activity and protect DNA from damage, besides presenting antifungal and antibacterial activity against Gram-positive and Gram-negative bacteria in vitro. It was found that the essential oil had no acute toxicity in mice up to 5000 mg/kg oral administration (o.a.), in addition to no hemolysis on human erythrocytes. The reduction of antinociceptive activity was 75%, with the opioid system as the mechanism of action. CONCLUSION: Our results validate the main activities by the traditional use attributed to H. cangaceira for antimicrobial and analgesic activity. In addition, the oil has a potent antioxidant activity, protecting the body against oxidative stress damage, adding new value to an endemic species not known to the industry.


Assuntos
Analgésicos/farmacologia , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Hymenaea/química , Óleos Voláteis/farmacologia , Óleos Vegetais/farmacologia , Ácido Acético/toxicidade , Analgésicos/química , Analgésicos/isolamento & purificação , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Brasil , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Etanol/química , Etnofarmacologia , Formaldeído/toxicidade , Humanos , Medicina Tradicional/métodos , Camundongos , Testes de Sensibilidade Microbiana , Nociceptividade/efeitos dos fármacos , Óleos Voláteis/química , Óleos Voláteis/uso terapêutico , Dor/induzido quimicamente , Dor/diagnóstico , Dor/tratamento farmacológico , Medição da Dor , Óleos Vegetais/química , Óleos Vegetais/isolamento & purificação , Testes de Toxicidade Aguda
8.
Gen Physiol Biophys ; 38(5): 407-416, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31595882

RESUMO

The P2X7 receptor (P2X7R) plays an important role in inflammatory and neuropathic pain. Our recent study indicated that activation of P2X7R in microglial cells of spinal cord contributes to the inflammatory pain induced by BmK I, the major active compound from Buthus martensi Karsch (BmK). In the present study, we further investigated whether P2X7R in satellite glial cells (SGCs) of dorsal root ganglion (DRG) is involved in the BmK I-induced pain in rats. The results found that the expression of P2X7R in SGCs was increased in the ipsilateral side of L4-L5 DRGs after intraplantar injection of BmK I. Moreover, the expression of an inflammatory cytokine IL-1ß was increased in DRG after BmK I injection. Systemic administration of an inhibitor of P2X7R (A-438079) significantly inhibited both spontaneous and evoked nociceptive behaviors induced by BmK I. These results suggest that the P2X7R in SGCs of DRG might contribute to pain induced by toxins that sensitize peripheral sensory nerves.


Assuntos
Gânglios Espinais/patologia , Dor/induzido quimicamente , Dor/patologia , Receptores Purinérgicos P2X7/metabolismo , Células Satélites Perineuronais/metabolismo , Venenos de Escorpião , Animais , Dor/metabolismo , Ratos
9.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31510092

RESUMO

There is accumulating evidence supporting electroacupuncture's (EA) therapeutic effects. In mice, local EA reliably attenuates inflammatory pain and increases the transient receptor potential cation channel, subfamily V, member 1 (TRPV1). However, the effect of distal acupoint EA on pain control has rarely been studied. We used a mouse model to investigate the analgesic effect of distal EA by measuring TRPV1 expression in the brain. Complete Freund's adjuvant (CFA) was injected into mice's hind paws to induce inflammatory pain. The EA-treated group received EA at the LI4 acupoint on the bilateral forefeet on the second and the third days, whereas the control group underwent sham manipulation. Mechanical and thermal pain behavior tests showed that the EA-treated group experienced inflammatory pain alleviation immediately after EA, which did not occur in the sham group. Additionally, following CFA injection, the expression of TRPV1-associated molecules such as phosphorylated protein kinase A (pPKA), extracelluar signal-regulated kinase (pERK), and cAMP-response-element-binding protein (pCREB) increased in the prefrontal cortex (PFC) and the hypothalamus but decreased in the periaqueductal gray (PAG) area. These changes were significantly attenuated by EA but not sham EA. Our results show an analgesic effect of distal EA, which is based on the traditional Chinese medicine theory. The mechanism underlying this analgesic effect involves TRPV1 in the PFC, the hypothalamus, and the PAG. These novel findings are relevant for the evaluation and the treatment of clinical inflammatory pain syndrome.


Assuntos
Pontos de Acupuntura , Eletroacupuntura/métodos , Inflamação/terapia , Dor/prevenção & controle , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Adjuvante de Freund , Inflamação/induzido quimicamente , Camundongos Endogâmicos C57BL , Dor/induzido quimicamente , Manejo da Dor/métodos , Medição da Dor/métodos , Transdução de Sinais , Canais de Cátion TRPV/metabolismo
10.
Int J Pharm ; 569: 118598, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31394185

RESUMO

Topical nonsteroidal anti-inflammatory drugs have been used in treatment of osteoarthritis but their efficacy is marginal. One major reason is because of limited drug direct penetration to affected joint and muscle tissues from the topical application. The main purpose of this study was to evaluate a new topical treatment through enhancing the direct drug penetration to local muscle and joint tissues for improving topical treatment of osteoarthritis. A cationic prodrug, ketoprofen choline chloride (KCC) was synthesized for iontophoretic topical delivery. Anodal iontophoretic delivery of KCC and cathodal iontophoretic delivery of ketoprofen to the knee of live hairless rats were evaluated and the drug concentrations in the joint and muscle tissues over the time were determined. In addition, a knee osteoarthritis rat model was induced with intra-articular injection of monosodium iodoacetate solution. Anodal iontophoretic delivery of KCC, cathodal iontophoretic delivery of ketoprofen, or anodal iontophoretic delivery of sodium chloride were applied to the affected knee joint of each rat group, respectively. Knee joint pain was evaluated through a hind paw weight bearing study and knee joint inflammation was evaluated through measuring of the knee diameter. Iontophoretic delivery of KCC showed much higher drug concentration in the knee joint and muscle tissues, compared to iontophoretic delivery of ketoprofen. Treatment of rat knee joint with anodal iontophoresis of KCC also showed significant pain relief and knee inflammation reduction comparing to the control group, while treatment results from cathodal iontophoresis of ketoprofen were mostly not significantly different from the control group.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Iontoforese , Cetoprofeno/administração & dosagem , Osteoartrite/tratamento farmacológico , Dor/tratamento farmacológico , Animais , Modelos Animais de Doenças , Feminino , Iodoacetatos , Articulação do Joelho/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Osteoartrite/induzido quimicamente , Dor/induzido quimicamente , Ratos , Ratos Pelados
11.
J Ethnopharmacol ; 245: 112156, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31415847

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Uapaca togoensis is a medicinal plant used traditionally in Africa for the treatment of rheumatism, epilepsy, cough, pneumonia, vomitting and fever. Previously, the analgesic activity of its methanol stem bark extract has been scientifically demonstrated. However, the mechanism responsible for this activity remains to be investigated. AIM OF THE STUDY: To elucidate the possible mechanism(s) through which the methanol stem bark extract of Uapaca togoensis (MEUT) exhibits analgesic activity in mice. MATERIALS AND METHODS: Analgesic activity of MEUT was evaluated using acetic acid-induced abdominal writhing test in mice at doses of 250, 500 and 1000 mg/kg orally. For the mechanistic studies, mice were pre-treated with Naloxone (2 mg/kg), Atropine (1 mg/kg), Yohimbine (1 mg/kg), Glibenclamide (10 mg/kg), Prazosin (1 mg/kg) and Yohimbine (1 mg/kg) 15 min prior to MEUT (1000 mg/kg) administration, then assessed using AAWT 1 h later. Data was analysed using One way Anova followed by Bonferroni post hoc test. RESULTS: The extract (at the doses of 250, 500 and 1000 mg/kg) and morphine (10 mg/kg) significantly (p < 0.05) decreased the number of abdominal writhes. Naloxone (opioid receptor antagonist), Atropine (muscarinic receptor antagonist) and Glibenclamide (ATP-sensitive K+ channel blocker) significantly (p < 0.05) reversed the analgesic effect of MEUT. On the other hand, Prazosin and Yohimbine (α1 and α2 receptor antagonists respectively) had no effect on the analgesic action of MEUT. CONCLUSION: The results obtained from this study suggests the possible involvement of opioidergic, cholinergic and sensitive potassium ATP channel pathways in the analgesic activity of the methanol stem bark extract of Uapaca togoensis.


Assuntos
Analgésicos/uso terapêutico , Coffea , Dor/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Ácido Acético , Analgésicos/toxicidade , Animais , Atropina/farmacologia , Feminino , Glibureto/farmacologia , Dose Letal Mediana , Masculino , Metanol/química , Camundongos , Antagonistas Muscarínicos/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/induzido quimicamente , Casca de Planta/química , Extratos Vegetais/toxicidade , Bloqueadores dos Canais de Potássio/farmacologia , Solventes/química
12.
Neurology ; 93(11): e1093-e1103, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31405908

RESUMO

OBJECTIVE: To describe the spectrum, clinical course, and management of neuropathies associated with immune checkpoint inhibitors (ICIs). METHODS: Patients with ICI-related neuropathy (irNeuropathy) were identified and their clinical characteristics compared to neuropathy attributed to cytotoxic agents. RESULTS: We identified 19 patients with irNeuropathies. ICIs included anti-programmed death-1 (PD1), 9; anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), 2; and combination of anti-CTLA4 and anti-PD1, 8. Median number of ICI doses prior to neuropathy onset was 4. Rate of neuropathies following ICI therapy was 0.7%. Underlying malignancies included melanoma (n = 15), lung adenocarcinoma (n = 3), and cholangiocarcinoma (n = 1). Neuropathy phenotypes were cranial neuropathies with or without meningitis (n = 7), nonlength-dependent polyradiculoneuropathies with and without cranial nerve involvement (n = 6), small-fiber/autonomic neuropathy (n = 2), ANCA-associated mononeuritis multiplex (n = 1), sensory neuronopathy (n = 1), length-dependent sensorimotor axonal polyneuropathy (n = 1), and neuralgic amyotrophy (n = 1). Immune-related adverse events involving other organ systems were common (58%). Corticosteroid use for management of neuropathy was associated with improvement in median modified Rankin Scale score (1 vs 0, p = 0.001) and Inflammatory Neuropathy Cause and Treatment Disability score (2 vs 0.5, p = 0.012) (Class IV). Significantly higher proportion of irNeuropathies had acute or subacute and nonlength-dependent presentations (p < 0.001) and rate of hospitalization for irNeuropathy was also higher (p = 0.002) compared to toxic neuropathy from chemotherapy. CONCLUSION: Neuropathy is a rare complication of ICIs that often responds to immunosuppression. Recognition of its wide phenotypic spectrum and distinct clinical characteristics and prompt management with corticosteroids may lead to favorable outcomes.


Assuntos
Gerenciamento Clínico , Genes cdc/imunologia , Dor/tratamento farmacológico , Dor/imunologia , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/imunologia , Fenótipo , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genes cdc/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Dor/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Polineuropatias/diagnóstico , Polineuropatias/tratamento farmacológico , Polineuropatias/imunologia , Sistema de Registros , Estudos Retrospectivos
13.
Am J Clin Dermatol ; 20(5): 711-723, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31264114

RESUMO

BACKGROUND: Atopic dermatitis is highly prevalent in black/African American, Asian, and Hispanic patients, making assessment of these populations in clinical trials important. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. In two pivotal phase III clinical trials in patients aged ≥ 2 years, crisaborole was superior to vehicle in reducing global disease severity. The most common treatment-related adverse event was application site pain. OBJECTIVE: The objective of this study was to investigate the efficacy and safety of crisaborole according to patient race and ethnicity. METHODS: A pooled post hoc analysis by race and ethnicity of the two pivotal trials and a safety extension trial was performed. Race included white or nonwhite (encompassing Asian/native Hawaiian/other Pacific Islander, black/African American, and other/American Indian/Alaskan native); ethnicity included Hispanic/Latino or not Hispanic/Latino. RESULTS: In white, nonwhite, Hispanic/Latino, and not Hispanic/Latino groups at day 29, more crisaborole- than vehicle-treated patients achieved improvements in global disease severity [Investigator's Static Global Assessment of clear/almost clear with a ≥ 2-grade improvement (white: 33.5% vs. 22.3%, nominal p < 0.001; nonwhite: 30.0% vs. 21.3%, nominal p < 0.05; Hispanic/Latino: 35.4% vs. 18.2%, nominal p < 0.01; not Hispanic/Latino: 31.3% vs. 22.8%, nominal p < 0.01)]. Crisaborole treatment also improved atopic dermatitis signs/symptoms and quality of life. Frequency of crisaborole-related adverse events was 7.1-8.5% in the pivotal trials. CONCLUSION: Across races and ethnicities, crisaborole demonstrated efficacy for the treatment of mild-to-moderate atopic dermatitis, with a low frequency of treatment-related adverse events.


Assuntos
Compostos de Boro/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/administração & dosagem , Disparidades nos Níveis de Saúde , Dor/epidemiologia , Administração Cutânea , Adolescente , Adulto , Idoso , Compostos de Boro/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Criança , Pré-Escolar , Grupos de Populações Continentais/estatística & dados numéricos , Dermatite Atópica/diagnóstico , Dermatite Atópica/etnologia , Fármacos Dermatológicos/efeitos adversos , Grupos Étnicos/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pomadas , Dor/induzido quimicamente , Dor/diagnóstico , Medição da Dor , Qualidade de Vida , Índice de Gravidade de Doença , Pele/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
14.
Int J Mol Sci ; 20(13)2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269659

RESUMO

Chronic inflammatory pain is one of the most common complaints that seriously affects patients' quality of life. Previous studies have demonstrated that the analgesic effect of electroacupuncture (EA) stimulation on inflammatory pain is related to its frequency. In this study, we focused on whether the analgesic effects of EA are related to the period of stimulation. Purinergic receptor P2X3 (P2X3) is involved in the pathological process underlying chronic inflammatory pain and neuropathic pain. We hypothesized that 100 Hz EA stimulation alleviated Freund's complete adjuvant (CFA) induced inflammatory pain via regulating P2X3 expression in the dorsal root ganglion (DRG) and/or spinal cord dorsal horn (SCDH). We also assumed that the analgesic effect of EA might be related to the period of stimulation. We found that both short-term (three day) and long-term (14 day) 100 Hz EA stimulation effectively increased the paw withdrawal threshold (PWT) and reversed the elevation of P2X3 in the DRG and SCDH of CFA rats. However, the analgesic effects of 100 Hz EA were not dependent on the period of stimulation. Moreover, P2X3 inhibition or activation may contribute to or attenuate the analgesic effects of 100 Hz EA on CFA-induced inflammatory pain. This result indicated that EA reduced pain hypersensitivity through P2X3 modulation.


Assuntos
Eletroacupuntura/métodos , Adjuvante de Freund , Manejo da Dor/métodos , Dor/induzido quimicamente , Receptores Purinérgicos P2X3/análise , Animais , Gânglios Espinais/patologia , Inflamação/induzido quimicamente , Inflamação/patologia , Inflamação/terapia , Masculino , Dor/patologia , Ratos Sprague-Dawley , Corno Dorsal da Medula Espinal/patologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-31315166

RESUMO

This report summarises Australian passive surveillance data for adverse events following immunisation (AEFI) for 2017 reported to the Therapeutic Goods Administration and describes reporting trends over the 18-year period 1 January 2000 to 31 December 2017. There were 3,878 AEFI records for vaccines administered in 2017; an annual AEFI reporting rate of 15.8 per 100,000 population. There was a 12% increase in the overall AEFI reporting rate in 2017 compared with 2016. This increase in reported adverse events in 2017 compared to the previous year was likely due to the introduction of the zoster vaccine (Zostavax®) provided free for people aged 70­79 years under the National Immunisation Program (NIP) and also the state- and territory-based meningococcal ACWY conjugate vaccination programs. AEFI reporting rates for most other individual vaccines in 2017 were similar to 2016. The most commonly reported reactions were injection site reaction (34%), pyrexia (17%), rash (15%), vomiting (8%) and pain (7%). The majority of AEFI reports (88%) described non-serious events. Two deaths were reported that were determined to have a causal relationship with vaccination; they occurred in immunocompromised people contraindicated to receive the vaccines.


Assuntos
Doenças do Sistema Imunitário/epidemiologia , Vacinação/efeitos adversos , Vacinas/efeitos adversos , Adolescente , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos , Idoso , Austrália/epidemiologia , Criança , Pré-Escolar , Exantema/induzido quimicamente , Exantema/epidemiologia , Feminino , Febre/induzido quimicamente , Febre/epidemiologia , Vacina contra Herpes Zoster , Humanos , Programas de Imunização , Lactente , Reação no Local da Injeção/epidemiologia , Masculino , Pessoa de Meia-Idade , Dor/induzido quimicamente , Dor/epidemiologia , Vigilância da População , Vacinação/normas , Vacinação/estatística & dados numéricos , Vacinas/administração & dosagem , Vômito/induzido quimicamente , Vômito/epidemiologia , Adulto Jovem
16.
Nat Commun ; 10(1): 3087, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300648

RESUMO

The dorsal root ganglia (DRG) contain the somas of first-order sensory neurons critical for somatosensation. Due to technical difficulties, DRG neuronal activity in awake behaving animals remains unknown. Here, we develop a method for imaging DRG at cellular and subcellular resolution over weeks in awake mice. The method involves the installation of an intervertebral fusion mount to reduce spinal movement, and the implantation of a vertebral glass window without interfering animals' motor and sensory functions. In vivo two-photon calcium imaging shows that DRG neuronal activity is higher in awake than anesthetized animals. Immediately after plantar formalin injection, DRG neuronal activity increases substantially and this activity upsurge correlates with animals' phasic pain behavior. Repeated imaging of DRG over 5 weeks after formalin injection reveals persistent neuronal hyperactivity associated with ongoing pain. The method described here provides an important means for in vivo studies of DRG functions in sensory perception and disorders.


Assuntos
Gânglios Espinais/diagnóstico por imagem , Microscopia Intravital/métodos , Percepção da Dor/fisiologia , Células Receptoras Sensoriais/fisiologia , Animais , Técnicas de Observação do Comportamento/instrumentação , Técnicas de Observação do Comportamento/métodos , Comportamento Animal/fisiologia , Cálcio/química , Feminino , Formaldeído/administração & dosagem , Formaldeído/toxicidade , Gânglios Espinais/citologia , Gânglios Espinais/fisiologia , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/genética , Microscopia Intravital/instrumentação , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Imagem Óptica/instrumentação , Imagem Óptica/métodos , Dor/induzido quimicamente , Dor/fisiopatologia , Fótons , Vigília
17.
J Ethnopharmacol ; 243: 112080, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31306693

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Fimbristylis miliacea (L.) Vahl (Cyperaceae) is a grass like herb usually grows as a weed in rice fields and is mainly distributed in tropical or sub-tropical countries of south and south-east Asia, central America, northern Australia and west Africa. The plant has been traditionally used to treat fever as a form of poultice. AIM OF THE STUDY: The present study aimed to investigate antipyretic and anti-nociceptive effects of methanol extract of leaves of Fimbristylis miliacea in mice model. MATERIALS AND METHODS: Antipyretic effect of Fimbristylis miliacea was examined using Baker's yeast induced hyperthermia test. Anti-nociceptive effect was investigated using acetic acid induced writhing test, formalin induced hind paw licking test and hot plate test. RESULTS: The extract at concentration of 400 mg/kg produced significant reduction in body temperature after 0.5 h of administration (4.12 °F, p ≤ 0.001) and continued to decrease (after 4 h, 5.92 °F, p ≤ 0.001). Extracts at 100 mg/kg and 200 mg/kg decreased the temperature by about 2.77 °F (from 99.47 °F to 96.7 °F) and 5.58 °F (98.2 °F-92.62 °F) respectively after 4 h whereas paracetamol dropped by about 7.2 °F (p ≤ 0.001). The extract showed significant decrease in number of writhes at all concentrations. Highest effect was found at 200 mg/kg having 35.7 writhes (p ≤ 0.001), much lower than control (89.2); standard drug diclofenac showed 23.2 writhes. Percent inhibition of writhing were 54.26 and 73.99 for 200 mg/kg and diclofenac respectively. The result of hind paw licking test also corroborated writhing test. Significant reduction in percent inhibition of licking was observed mainly in late phase. Percent inhibition of licking were 93.77 and 51.55 for 400 mg/kg extract and diclofenac respectively. In hot plate test, extract at 400 mg/kg showed significant increase in latency from 10.77 s to 13.59 s (p ≤ 0.05). Extract at this dose after 2 h demonstrated greater percent maximal effect (43.26%) compared to ketorolac (40.19%). CONCLUSION: The experiment confirmed the traditional use of F. miliacea in the treatment of fever with possible anti-nociceptive effects.


Assuntos
Analgésicos/uso terapêutico , Antipiréticos/uso terapêutico , Cyperaceae , Febre/tratamento farmacológico , Dor/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Ácido Acético , Animais , Modelos Animais de Doenças , Feminino , Formaldeído , Masculino , Metanol/química , Camundongos , Dor/induzido quimicamente , Folhas de Planta/química , Saccharomyces cerevisiae , Solventes/química
18.
Pharm Biol ; 57(1): 432-436, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31242794

RESUMO

Context: Since there is still a great need to search for plant species with antinociceptive and anti-inflammatory activities, Diploptropis purpurea (Rich.) Amshoff (Fabaceae) is studied for the first time. Objective: This evaluates the analgesic and anti-inflammatory activities of the stem methanol extract of Diplotropis purpurea (MEDP). Material and methods: The anti-inflammatory and analgesic effects of MEDP of D. purpurea were evaluated in vivo. The antinociceptive activity was assessed in CD1 male mice were treated by oral gavage with 500 mg/kg of MEDP 30 min before submitting to acetic acid-induced abdominal writhing, hot-plate, and formalin tests. Paws oedema induced by carrageenan, histamine or serotonin were performed in male Sprague-Dawley rats to determinate the anti-inflammatory activity. Results: Oral administration of MEDP produced significant antinociceptive effects on the inflammatory phase in the formalin test [12.0 s versus 72.5 s in carboxymethyl cellulose (CMC) control group]. MEDP produced an analgesic effect in the hot-plate model, although the effect was modest compared to tramadol (40 and 60%, respectively). The oral administration of MEDP in a dose of 500 mg/kg showed maximum inhibition (75.1%) after 0.5 h in carrageenan-induced oedema, but it did not modify histamine or serotonin-induced oedemas. Discussion and conclusion: In the peripheral nociception model, acetic acid-induced abdominal writhing, the MEDP did not show a protective effect, but its analgesic effects were evident in the inflammatory phase of the formalin test and in the hot-plate model. These results show that the anti-inflammatory effect was accompanied by a reduction in the perception of painful stimuli.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Edema/tratamento farmacológico , Fabaceae/química , Dor/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Edema/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Metanol/química , Camundongos , Dor/induzido quimicamente , Medição da Dor , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Ratos , Ratos Sprague-Dawley
19.
J Oncol Pharm Pract ; 25(8): 2056-2058, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31203715

RESUMO

INTRODUCTION: Granulocyte-colony stimulating factor (G-CSF) has been approved for use for mobilization of hematopoietic progenitor cells from the marrow into the blood for peripheral blood stem cell collection. Commonly reported side effects of G-CSF include deep throbbing bone pain, severe myalgia and leucocytosis. CASE REPORT: We describe a case of severe hypersensitivity anaphylactoid reaction after filgrastim administration in a healthy stem cell donor. This haploidentical donor was a 38-year old man with sickle cell trait, donating stem cells for his son, a case of sickle cell disease. On administration of G-CSF (10 µg/kg) he developed features of anaphylaxis. MANAGEMENT AND OUTCOME: He was given supportive care with oxygen, IV fluid bolus, anti histaminics and steroids. The donor had complete recovery and underwent successful bone marrow harvest. CONCLUSION: There have been various reports of hypersensitivity anaphylactoid reactions in patients undergoing chemotherapy but those associated with the first dose of G-CSF in healthy stem cell donors have rarely been reported.


Assuntos
Hipersensibilidade a Drogas/etiologia , Filgrastim/efeitos adversos , Doadores de Tecidos , Adulto , Filgrastim/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Humanos , Masculino , Dor/induzido quimicamente
20.
Eur J Pharmacol ; 858: 172443, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31181208

RESUMO

The role of spinal α5 subunit-containing GABAA (α5-GABAA) receptors in chronic pain is controversial. The purpose of this study was to investigate the participation of spinal α5-GABAA receptors in the reserpine-induced pain model. Reserpine administration induced tactile allodynia and muscle hyperalgesia in female and male rats. Intrathecal injection of L-655,708 and TB 21007 (7 days after the last reserpine injection) decreased tactile allodynia and, at a lesser extent, muscle hyperalgesia in female rats. The effects of these drugs produced a lower antiallodynic and antihyperalgesic effect in male than in female rats. Contrariwise, these drugs produced tactile allodynia and muscle hyperalgesia in naïve rats and these effects were lower in naïve male than female rats. Intrathecal L-838,417 prevented or reversed L-655,708-induced antiallodynia in reserpine-treated female rats. Repeated treatment with α5-GABAA receptor small interfering RNA (siRNA), but not scramble siRNA, reduced reserpine-induced allodynia in female rats. Accordingly, α5-GABAA receptor siRNA induced nociceptive hypersensitivity in naïve female rats. Reserpine enhanced α5-GABAA receptors expression in spinal cord and dorsal root ganglia (DRG), while it increased CD11b (OX-42) and glial fibrillary acidic protein (GFAP) fluorescence intensity in the lumbar spinal cord. In contrast, reserpine diminished K+-Cl- co-transporter 2 (KCC2) protein in the lumbar spinal cord. Data suggest that spinal α5-GABAA receptors play a sex-dependent proallodynic effect in reserpine-treated rats. In contrast, these receptors have a sex-dependent antiallodynic role in naïve rats.


Assuntos
Fibromialgia/complicações , Dor/complicações , Dor/tratamento farmacológico , Receptores de GABA-A/metabolismo , Reserpina/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/patologia , Dor/induzido quimicamente , Dor/patologia , Ratos , Ratos Wistar , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Simportadores/metabolismo
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