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1.
Chem Biol Interact ; 311: 108790, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31400342

RESUMO

Preclinical assays play a key role in research in research on the neurobiology of pain and the development of novel analgesics. Drugs available for the treatment of inflammatory pain are not fully effective and show adverse effects. Thus, we investigated the antinociceptive, anti-inflammatory and anti-hyperalgesic effects of bis(3-amino-2-pyridine) diselenide (BAPD), a new analgesic drug prototype. BAPD effects were investigated using nociception models induced by chemical (glutamate), immunologic (Freund's Complete Adjuvant - CFA) and thermal stimuli in Swiss mice. Mice were orally (p.o.) treated with BAPD (0.1-50 mg/kg) 30 min prior to the glutamate and hot-plate tests and a time-course (0.5 up to 8 h) of the antinociceptive effect of BAPD (50 mg/kg, p. o.) was evaluated in a CFA model. In the CFA model, BAPD effects on cyclooxygenase-2 (COX-2), tumor necrosis factor (TNFα) and interferon-γ (INF-γ) expression, myeloperoxidase (MPO) activity, oxidative (2,2'-Azino-bis-3-ethylbenzothiazoline 6-sulfonic acid and 2,2-diphe- nyl-1-picrylhydrazyl levels) and histological parameters were evaluated. The safety of the compound (50 and 300 mg/kg, p. o.) was verified for 72 h. BAPD reduced the licking time induced by glutamate and caused an increase in latency response to thermal stimulus. Naloxone reversed the antinociceptive effect of BAPD. Paw edema formation induced by glutamate or CFA injection was reduced by BAPD. Mechanical hyperalgesia induced by CFA was attenuated by BAPD. BAPD did not protect against the increase in MPO activity and decrease of the 2,2'-Azino-bis-3-ethylbenzothiazoline 6-sulfonic acid and 2,2-diphe- nyl-1-picrylhydrazyl levels induced by CFA. BAPD protected against histological alterations and reduction on the levels of gene expression COX-2 and INF-γ in the paw of mice exposed to CFA. BAPD was safe at the doses and time evaluated. BAPD exerts acute antinociceptive, anti-inflammatory and anti-hyperalgesic actions, suggesting that it may represent an alternative in the future development of new therapeutic strategies.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/metabolismo , Interferon gama/metabolismo , Nociceptividade/efeitos dos fármacos , Receptores Opioides/metabolismo , Analgésicos/química , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Ciclo-Oxigenase 2/genética , Edema/tratamento farmacológico , Edema/patologia , Comportamento Exploratório/efeitos dos fármacos , Pé/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/farmacologia , Interferon gama/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Dor/tratamento farmacológico , Dor/patologia , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Opioides/genética , Testes de Toxicidade Aguda , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
2.
Eur J Med Chem ; 177: 269-290, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158744

RESUMO

Neuropathic pain is a chronic pain caused by a lesion or disease affecting the somatosensory nervous system. To date, no specific treatment has been developed to cure this pain. Antidepressants and anticonvulsant drugs are used, but they do not demonstrate universal efficacy, and they often cause detrimental adverse effects. Some studies highlighted the efficacy of sildenafil, a well-known inhibitor of phosphodiesterase 5 (PDE5, (IC50 = 3.3 nM)), in models of pain. Based on these results, we focused our attention on MY 5445, another known PDE5 inhibitor. Homologues, isosteres and structural analogues of MY 5445 were designed and all synthesized compounds were evaluated for their inhibitory activity toward PDE5. Selectivity profiles towards other PDE1-4 isoenzymes, water solubility and stability in acidic medium of the most potent PDE5 inhibitors were determined and the aminophthalazine 16h and its mimetic 41n (3-aminoindazole) were evaluated in comparison to MY 5445 (4b) in vivo in a model of neuropathic pain induced by sciatic nerve cuffing in mice (3 and 0.5 mg/kg, ip twice a day). Both compounds showed the same efficacy on neuropathic allodynia as MY 5445, and thus produced a significant relief of mechanical hypersensitivity after 12 days of treatment.


Assuntos
Analgésicos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Ftalazinas/uso terapêutico , Analgésicos/síntese química , Analgésicos/química , Animais , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Inibidores da Fosfodiesterase 5/síntese química , Inibidores da Fosfodiesterase 5/química , Ftalazinas/síntese química , Ftalazinas/química , Solubilidade , Relação Estrutura-Atividade
3.
Biochemistry (Mosc) ; 84(2): 101-118, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31216970

RESUMO

TRPA1 is a cation channel located on the plasma membrane of many types of human and animal cells, including skin sensory neurons and epithelial cells of the intestine, lungs, urinary bladder, etc. TRPA1 is the major chemosensor that also responds to thermal and mechanical stimuli. Substances that activate TRPA1, e.g., allyl isothiocyanates (pungent components of mustard, horseradish, and wasabi), cinnamaldehyde from cinnamon, organosulfur compounds from garlic and onion, tear gas, acrolein and crotonaldehyde from cigarette smoke, etc., cause burning, mechanical and thermal hypersensitivity, cough, eye irritation, sneezing, mucus secretion, and neurogenic inflammation. An increased activity of TRPA1 leads to the emergence of chronic pruritus and allergic dermatitis and is associated with episodic pain syndrome, a hereditary disease characterized by episodes of debilitating pain triggered by stress. TRPA1 is now considered as one of the targets for developing new anti-inflammatory and analgesic drugs. This review summarizes information on the structure, function, and physiological role of this channel, as well as describes known TRPA1 ligands and their significance as therapeutic agents in the treatment of inflammation-associated pain.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Inflamação Neurogênica/tratamento farmacológico , Dor/tratamento farmacológico , Canal de Cátion TRPA1/antagonistas & inibidores , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/química , Humanos , Ligantes , Estrutura Molecular , Inflamação Neurogênica/metabolismo , Dor/metabolismo , Canal de Cátion TRPA1/química , Canal de Cátion TRPA1/metabolismo
4.
Mar Drugs ; 17(6)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31159276

RESUMO

Currently a few compounds isolated from marine sources have become drugs, mainly directed towards cancer and pain. Compounds from marine sources have exquisite potencies against eukaryotic cells, as they act as protective agents against attack by predators in the marine environment. Their toxicities act as a "double-edged sword" as they are often too toxic for direct use in humans and thus have to be chemically modified. By linking suitably modified compounds to monoclonal antibodies directed against specific epitopes in mammalian cancer cells, they can be delivered to a specific cell type in humans. This review updates and extends an article published in early 2017, demonstrating how by careful chemical modifications, highly toxic compounds, frequently peptidic in nature, can be utilized as antitumor drug candidates. The antibody-drug- conjugates (ADCs) discussed are those that are currently in clinical trials listed in the NIH Clinical Trials Registry as, "currently active, recruiting or in some cases, recently completed". There are also some ADCs discussed that are at the advanced preclinical stage, that in some cases, are repurposing current drug entities, and the review finishes with a short discussion of the aplyronines as potential candidate warheads as a result of scalable synthetic processes.


Assuntos
Toxinas Marinhas/química , Toxinas Marinhas/uso terapêutico , Neoplasias/tratamento farmacológico , Analgésicos/química , Analgésicos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Humanos , Imunoconjugados/uso terapêutico , Dor/tratamento farmacológico
5.
Dokl Biochem Biophys ; 485(1): 123-125, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31201630

RESUMO

Previously, we synthesized a dimeric dipeptide mimetic of the brain-derived neurotrophic factor (BDNF) loop 4, GSB-106, which, similarly to BDNF, activated TrkB, PI3K/AKT, and MAPK/ERK. When administered systemically, it exhibited neuroprotective, antidepressant, and antidiabetic activities and stimulated neurogenesis and synaptogenesis. In this study, we established that GSB-106 also exhibits the analgesic activity, typical for BDNF, which was revealed in rats in hot plate and tail flick tests 0.5-48 h after intraperitoneal injection at doses of 0.1 and 1 mg/kg.


Assuntos
Analgésicos , Fator Neurotrófico Derivado do Encéfalo , Dipeptídeos , Peptidomiméticos , Analgésicos/química , Analgésicos/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/química , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Dipeptídeos/química , Dipeptídeos/farmacologia , Humanos , Masculino , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Estrutura Secundária de Proteína , Ratos
6.
Eur J Med Chem ; 177: 47-62, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129453

RESUMO

The class of tetrahydro-1H-3-benzazepines was systematically modified in 1-, 3- and 7-position. In particular, a F-atom was introduced in ß- or γ-position of the 4-phenylbutyl side chain in 3-position. Ligands with the F-atom in γ-position possess higher GluN2B affinity than analogs bearing the F-atom in ß-position. This effect was attributed to the reduced basicity of ß-fluoro amines. 3-Benzazepines with a benzylic OH moiety show moderate GluN2B affinity, but considerable selectivity over the σ2 receptor. However, removal of the benzylic OH moiety led to increased GluN2B affinity, but reduced GluN2B/σ2 selectivity. With respect to GluN2B affinity the phenol 17b with a γ-fluorophenylbutyl moiety in 3-position represents the most interesting fluorinated ligand (Ki(GluN2B) = 16 nM). Most of the synthesized ligands reveal either similar GluN2B and σ1 affinity or higher σ1 affinity than GluN2B affinity. The methyl ether 16b shows high σ1 affinity (Ki(σ1) = 6.6 nM) and high selectivity over a broad panel of receptors and transporters. The high antiallodynic activity in the mouse capsaicin assay proved the σ1 antagonistic activity of 16b.


Assuntos
Analgésicos/uso terapêutico , Benzazepinas/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Hiperalgesia/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores sigma/antagonistas & inibidores , Analgésicos/síntese química , Analgésicos/química , Analgésicos/toxicidade , Animais , Benzazepinas/síntese química , Benzazepinas/química , Benzazepinas/toxicidade , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Humanos , Ligantes , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piperidinas/uso terapêutico , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 177: 188-197, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136893

RESUMO

Carbonic Anhydrases have been recently validated as novel therapeutic targets in neuropathic pain. In this study, we combine the anticonvulsant propriety of spyrohydantoin and the CA inhibitor moiety of benzenesulfonamide to synthesize a novel series of spyrohydantoin bearing sulfonamides with strong activity against hCA II and VII. These isoforms are present in the nervous system and largely expressed both at the central as well as at peripheral level and can be modulated for pain relief. The crystal structures of hCA II in complex with selected compounds 5a-c demonstrate the importance of the tail in the binding modes within the isoform. Finally, in vivo, in an animal model of oxaliplatin induced neuropathy, compounds with organoselenium tails (8b-c) showed potent neuropathic pain attenuating effects. Taken together, these data strongly suggest the translational utility of these inhibitors as novel pain relievers.


Assuntos
Analgésicos/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Hidantoínas/uso terapêutico , Neuralgia/tratamento farmacológico , Sulfonamidas/uso terapêutico , Analgésicos/síntese química , Analgésicos/química , Animais , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Cristalografia por Raios X , Desenho de Drogas , Humanos , Hidantoínas/síntese química , Hidantoínas/química , Masculino , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
8.
Cell Mol Biol (Noisy-le-grand) ; 65(4): 37-42, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31078150

RESUMO

Inflammation and insomnia are two types of symptoms very likely occur in life, seriously perplexing people's work and life. How to alleviate these symptoms is an urgent medical problem. Lucidone D (LUC) is a terpene from the ethanol extract of Ganoderma lucidum fruiting body. Triterpenoids are also the main pharmacological components of Ganoderma lucidum. In recent years, people pay more and more attention to its anti-inflammatory effect. In this study, LPS induced RAW264.7 macrophage inflammatory response model was used to evaluate the anti-inflammatory activity of LUC. The results showed that LUC could significantly inhibit the production of inflammatory mediators NO, which may play a role by down-regulating the expression level of iNOS and COX-2 proteins. Meanwhile, the production of TNF-α and IL-6 was significantly inhibited. These results indicate that LUC has obvious anti-inflammatory activity. Writhing and sedation tests in ICR male mice showed that LUC showed significant analgesic and sedative effects. In conclusion, these results suggest the anti-inflammatory, analgesic and sedative effects of LUC in vitro and in vivo.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Hipnóticos e Sedativos/farmacologia , Reishi/química , Terpenos/farmacologia , Analgésicos/química , Animais , Anti-Inflamatórios/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Citocinas/biossíntese , Hipnóticos e Sedativos/química , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Pentobarbital , Células RAW 264.7 , Latência do Sono/efeitos dos fármacos , Terpenos/química
9.
Molecules ; 24(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052248

RESUMO

Incarvillea compacta Maxim is a traditional Tibetan plant widely used to treat rheumatic pain and bruises. We conducted qualitative analyses by liquid chromatography-mass spectrometry and quantitative analyses of the total phenols, flavonoids, and alkaloids content of different extracts of I. compacta Maxim. Antioxidant and analgesic activity were analyzed. The results showed that the methanol extract had the highest content of the various ingredients. A total of 25 constituents were identified, of which compounds 1-23 were found for the first time in this plant. The water extract had the highest capacity to clear free radicals in the antioxidant test. The water extract had dose-dependent analgesic effects in the first and second phase in a formalin test. The latency of pain from a hot-plate test was augmented by the water extract when the dose was greater than or equal to 30 g/kg. The water extract significantly decreased the amount of writhing in a dose-dependent manner compared with the control group in the acetic acid-induced writhing test. These results showed that I. compacta Maxim is a new antioxidant and analgesic agent, and this study provides information on its ingredients for further study.


Assuntos
Analgésicos/química , Analgésicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Bignoniaceae/química , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Cromatografia Líquida , Flavonoides/química , Flavonoides/farmacologia , Espectrometria de Massas , Estrutura Molecular , Fenóis , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Solventes , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Tibet
10.
Life Sci ; 228: 176-188, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31059688

RESUMO

AIM: Inflammatory algesia and pyresia are common pathological consequences of physiological defense. Phenacetin introduced as effective analgesic anti-pyretic agent, was proscribed from therapeutic use because of associated systemic toxicity. The aim of the study was to evaluate the potency of 1,2,3-triazole conjugation in reducing toxicity and increasing efficacy of the phenacetin nucleus. MAIN METHODS: The amide bond implicated as the cause of phenacetin toxicity was bioisosterically replaced with 1,2,3-triazoles to yield a series of PhTCs(PhTC1, PhTC2 and PhTC3). The toxicology of the synthesized conjugates in reference to phenacetin was evaluated in accordance with OECD test guidelines 420, 425 and 407. For the purpose of evaluating anti-inflammatory potency carrageenan induced paw edema and croton oil induced ear edema models were evaluated. Anti-nociceptive efficacy was assessed using Eddy's hot plate and acetic acid induced writhing experimental models. For anti-pyretic efficacy, the conjugates were submitted to Brewer's yeast antipyretic assay. KEY FINDINGS: Toxicological examination of PhTCs in comparison to phenacetin revealed that, phenacetin treatment caused considerable nephrotoxicity and hepatotoxicity in experimental models PhTCs were devoid of such toxic manifestations. Results of pharmacological assays showed that the entire series of PhTCs possessed better anti-inflammatory, anti-nociceptive and anti-pyretic potential than phenacetin. Furthermore it was revealed that the pharmacological profile of PhTC1 with triazole substitution at para position of the phenol ring exhibited potency even better than that exhibited by the reference standards. CONCLUSION: Bioisosteric replacement of amide bond by 1,2,3-triazole in the phenacetin moiety yields conjugates with superior efficacy and diminished toxicity, thus opening neo avenues in treatment of inflammatory syndromes.


Assuntos
Analgésicos/química , Analgésicos/farmacologia , Fenacetina/análogos & derivados , Fenacetina/farmacologia , Triazóis/química , Triazóis/farmacologia , Analgésicos/toxicidade , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/toxicidade , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Fenacetina/toxicidade , Ratos Wistar , Triazóis/toxicidade
11.
Eur J Med Chem ; 174: 226-235, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31042618

RESUMO

A new set of 5-chlorobenzoxazole- and 5-chlorobenzothiazole-based derivatives containing the azepane ring as a basic moiety was designed, synthesized and evaluated through binding assays to measure their affinity and selectivity towards σ1 and σ2 receptors. Compounds 19, 22 and 24, with a four units spacer between the bicyclic scaffold and the azepane ring, showed nanomolar affinity towards both receptor subtype and the best Ki values (Ki σ1 = 1.27, 2.30, and 0.78 and Ki σ2 = 7.9, 3.8, and 7.61 nM, respectively). Evaluation of cytotoxic and apoptotic effects in MCF-7 human cancer cells was useful to assess σ2 receptor activity, while an in vivo mice model of inflammatory pain allowed to analyze σ1 receptor pharmacological properties. In vitro and in vivo results suggested that compound 19 is a σ1/σ2 agonist, compound 24 a σ1 antagonist/σ2 agonist, whereas compound 22 might act as σ1 antagonist/σ2 partial agonist. Due to their pharmacological profile, a potential therapeutic application in cancer of aforesaid novel σ1/σ2 receptor ligands, especially 22 and 24, is proposed.


Assuntos
Analgésicos/uso terapêutico , Benzotiazóis/uso terapêutico , Benzoxazóis/uso terapêutico , Receptores sigma/agonistas , Receptores sigma/antagonistas & inibidores , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Benzotiazóis/síntese química , Benzotiazóis/química , Benzotiazóis/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/química , Benzoxazóis/farmacologia , Humanos , Ligantes , Células MCF-7 , Camundongos , Estrutura Molecular
12.
J Headache Pain ; 20(1): 37, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30995909

RESUMO

BACKGROUND: In the past decade, migraine research has identified novel drug targets. In this review, we discuss recent data on emerging anti-migraine therapies. MAIN BODY: The development of ditans, gepants and anti-calcitonin gene-related peptide monoclonal antibodies for the treatment of migraine is one of the greatest advances in the migraine field. Lasmiditan, rimegepant and ubrogepant will extend our therapeutic armamentarium for managing acute migraine attacks when triptans are not effective or contraindicated due to cardiovascular disorders. The monoclonal antibodies are migraine specific prophylactic drugs with high responder rates and favorable adverse event profiles. Furthermore, they offer convenient treatment regimens of 4- or 12-week intervals. CONCLUSION: Collectively, novel migraine therapies represent a major progress in migraine treatment and will undoubtedly transform headache medicine.


Assuntos
Analgésicos/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Triptaminas/uso terapêutico , Analgésicos/química , Animais , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/química , Humanos , Transtornos de Enxaqueca/diagnóstico , Piridinas/química , Piridinas/uso terapêutico , Pirróis/química , Pirróis/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Triptaminas/química
13.
Int J Pharm ; 563: 293-303, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30951860

RESUMO

The current study aimed to develop an effective transdermal nanovesicular carrier of diflunisal that provides enhanced delivery through the skin. Two types of nanovesicles, ethosomes and transfersomes, were investigated and compared to conventional liposomes. Ethosomes with variable ethanol contents (10, 30 and 50%) and transfersomes using different edge activators, including sodium deoxycholate, sodium cholate and sodium taurocholate, were prepared and characterized. The obtained vesicles revealed good entrapment efficiencies (46.73-65.99%), nanometric vesicle sizes (453.10-796.80 nm) and negative zeta potential values (-45.40 to -86.90 mV). Ethosomes with 30% ethanol and sodium deoxycholate-containing transfersomes were incorporated into hydrogels to evaluate their in vitro release and permeation patterns. Nanovesicular hydrogels exhibited more sustained diflunisal release than did corresponding dispersions. Compared to liposomal hydrogel, both carriers proved the superiority of diflunisal permeation and flux across the skin. Confocal laser scanning microscopy showed improved penetration of rhodamine-loaded nanovesicles through skin layers with a wider distribution and higher fluorescence intensity. Compared to liposomes, selected nanovesicles exhibited remarkable antinociceptive and anti-inflammatory effects manifested by significant reduction in number of writhings and significantly higher inhibition of paw oedema. Hence, the developed nanovesicles could be considered promising carriers for transdermal delivery of diflunisal for pain and inflammation management.


Assuntos
Analgésicos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Diflunisal/administração & dosagem , Hidrogéis/administração & dosagem , Absorção Cutânea/efeitos dos fármacos , Ácido Acético , Administração Cutânea , Analgésicos/química , Animais , Anti-Inflamatórios/química , Carragenina , Diflunisal/química , Liberação Controlada de Fármacos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Hidrogéis/química , Lipossomos , Masculino , Camundongos , Dor/induzido quimicamente , Dor/tratamento farmacológico , Ratos Wistar , Pele/metabolismo
14.
Int J Pharm ; 563: 395-405, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30978486

RESUMO

Fast dissolution of nonsteroidal anti-inflammatory drugs (NSAIDs) is a prerequisite from patient perspective. However, most NSAIDs are slowly dissolving acidic compounds. Caffeine, a commonly used analgesic adjuvant with NSAIDs showed high potential as eutectic co-former for acidic compounds. The study investigated eutectic forming potential of caffeine with meloxicam, aceclofenac and flurbiprofen. Each drug was co-ground with caffeine in various ratios and the products were characterized by thermal analysis to determine the optimum eutectic composition from phase diagram and Tamman's triangle. The optimum systems were subjected to X-ray powder diffraction (XRPD), Fourier-transform infrared (FTIR) and dissolution studies. Co-ground systems at dose ratio were also assessed for drug dissolution and anti-inflammatory effect using carrageenan induced rat paw edema method. Eutexia was confirmed by thermal analysis with the optimum composition being 1:1, 1:1 and 1:2 (NSAID: caffeine) for aceclofenac, flurbiprofen and meloxicam, respectively. Eutexia did not alter FTIR spectra with minor changes being recorded in XRPD patterns. The eutectic systems underwent fast liberation of drugs with fast dissolution being retained even at dose ratios. Dissolution enhancement was associated with enhanced anti-inflammatory response. The study introduced caffeine as eutectic forming analgesic for fixed dose combination with NSAIDs to enhance drug dissolution and anti-inflammatory effect.


Assuntos
Analgésicos , Anti-Inflamatórios não Esteroides , Cafeína , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Cafeína/administração & dosagem , Cafeína/química , Carragenina , Diclofenaco/administração & dosagem , Diclofenaco/análogos & derivados , Diclofenaco/química , Liberação Controlada de Fármacos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Flurbiprofeno/administração & dosagem , Flurbiprofeno/química , Masculino , Meloxicam/administração & dosagem , Meloxicam/química , Difração de Pó , Ratos Wistar , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura de Transição , Difração de Raios X
15.
Medicina (Kaunas) ; 55(4)2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959829

RESUMO

Background and objectives: The clinical use of non-steroidal anti-inflammatory drugs is limited due to high incidence of adverse drug reactions. The pyrrole heterocycle is included in the chemical structure of a number of drugs with various activities and shows relatively good tolerability and safety. The objectives of our study were to evaluate the analgesic and anti-inflammatory activity, as well as possible organ toxicity, of 2-[3-acetyl-5-(4-chloro-phenyl)-2-methyl-pyrrol-1-yl]-3-(1H-indol-3-yl)-propionic acid (compound 3g), a novel N-pyrrolylcarboxylic acid structurally similar to celecoxib. Materials and methods: All experiments were performed on 6-week-old male Wistar rats divided into parallel groups (n = 8). Antinociception was assessed using animal pain models with thermal and chemical stimuli (paw withdrawal, tail-flick, and formalin tests). Criteria for the analgesic effect were increased latency in the paw withdrawal and tail-flick tests and decreased paw licking time in the formalin test compared to animals treated with saline (control). Anti-inflammatory activity was measured using a carrageenan-induced paw edema model; the criterion for anti-inflammatory effect was decreased edema compared to control. Blood samples were obtained after animals were sacrificed to assess possible organ toxicity. Statistical analysis was performed with IBM SPSS 20.0. Results: 2-[3-Acetyl-5-(4-chloro-phenyl)-2-methyl-pyrrol-1-yl]-3-(1H-indol-3-yl)-propionic acid had analgesic action against chemical stimulus after single and multiple administration and against thermal stimulus after single administration. Compound 3g significantly suppressed carrageenan-induced paw edema after both single and continuous administration. After continuous administration, hematological tests showed that compound 3g decreased leukocyte and platelet levels and elevated serum creatinine levels. Conclusions: Antinociception with the tested compound is most likely mediated by spinal, peripheral, and anti-inflammatory mechanisms. Possible tolerance of the analgesic action at the spinal level develops after continuous administration. Anti-inflammatory activity is significant and probably the leading cause of antinociception. After multiple administration, compound 3g showed signs of potential nephrotoxicity and antiplatelet activity, as well as suppression of leukocyte levels.


Assuntos
Analgésicos/química , Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Celecoxib/análogos & derivados , Celecoxib/farmacologia , Avaliação Pré-Clínica de Medicamentos , Indóis/química , Indóis/farmacologia , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Análise de Variância , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Carragenina/administração & dosagem , Carragenina/farmacologia , Celecoxib/administração & dosagem , Celecoxib/efeitos adversos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Eritrócitos/efeitos dos fármacos , Hemoglobinas/análise , Leucócitos/efeitos dos fármacos , Masculino , Modelos Animais , Medição da Dor , Pirróis/química , Ratos , Ratos Wistar
16.
BMC Complement Altern Med ; 19(1): 79, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940120

RESUMO

BACKGROUND: Methanol extract (MECN) of Clinacanthus nutans Lindau leaves (family Acanthaceae) demonstrated peripherally and centrally mediated antinociceptive activity via the modulation of opioid/NO-mediated, but cGMP-independent pathway. In the present study, MECN was sequentially partitioned to obtain petroleum ether extract of C. nutans (PECN), which was subjected to antinociceptive study with aims of establishing its antinociceptive potential and determining the role of opioid receptors and L-arginine/nitric oxide/cyclic-guanosine monophosphate (L-arg/NO/cGMP) pathway in the observed antinociceptive activity. METHODS: The antinociceptive potential of orally administered PECN (100, 250, 500 mg/kg) was studied using the abdominal constriction-, hot plate- and formalin-induced paw licking-test in mice (n = 6). The effect of PECN on locomotor activity was also evaluated using the rota rod assay. The role of opioid receptors was determined by pre-challenging 500 mg/kg PECN (p.o.) with antagonist of opioid receptor subtypes, namely ß-funaltrexamine (ß-FNA; 10 mg/kg; a µ-opioid antagonist), naltrindole (NALT; 1 mg/kg; a δ-opioid antagonist) or nor-binaltorphimine (nor-BNI; 1 mg/kg; a κ-opioid antagonist) followed by subjection to the abdominal constriction test. In addition, the role of L-arg/NO/cGMP pathway was determined by prechallenging 500 mg/kg PECN (p.o.) with L-arg (20 mg/kg; a NO precursor), 1H-[1, 2, 4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ; 2 mg/kg; a specific soluble guanylyl cyclase inhibitor), or the combinations thereof (L-arg + ODQ) for 5 mins before subjection to the abdominal constriction test. PECN was also subjected to phytoconstituents analyses. RESULTS: PECN significantly (p < 0.05) inhibited nociceptive effect in all models in a dose-dependent manner. The highest dose of PECN (500 mg/kg) also did not significantly (p > 0.05) affect the locomotor activity of treated mice. The antinociceptive activity of PECN was significantly (p < 0.05) inhibited by all antagonists of µ-, δ-, and κ-opioid receptors. In addition, the antinociceptive activity of PECN was significantly (p < 0.05) reversed by L-arg, but insignificantly (p > 0.05) affected by ODQ. HPLC analysis revealed the presence of at least cinnamic acid in PECN. CONCLUSION: PECN exerted antinocicpetive activity at peripheral and central levels possibly via the activation of non-selective opioid receptors and modulation of the NO-mediated/cGMP-independent pathway partly via the synergistic action of phenolic compounds.


Assuntos
Acanthaceae/química , Analgésicos/farmacologia , GMP Cíclico/metabolismo , Óxido Nítrico/metabolismo , Extratos Vegetais/farmacologia , Receptores Opioides/efeitos dos fármacos , Alcanos , Analgésicos/química , Animais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Extratos Vegetais/química , Folhas de Planta/química , Receptores Opioides/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Eur J Med Chem ; 170: 261-275, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30904783

RESUMO

The 5-HT7 receptor has recently gained much attention due to its involvement in multiple physiological functions and diseases. The insufficient quality of the available molecular probes prompted design of fluorinated 3-(1-alkyl-1H-imidazol-5-yl)-1H-indoles as a new generation of selective 5-HT7 receptor agonists. A potent and drug-like agonist, 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-4-fluoro-1H-indole (AGH-192, 35, Ki 5-HT7R = 4 nM), was identified by optimizing the halogen bond formation with Ser5.42 as the supposed partner. The compound was characterized by excellent water solubility, high selectivity over related CNS targets, high metabolic stability, oral bioavailability and low cytotoxicity. Rapid absorption into the blood, medium half-life and a high peak concentration in the brain Cmax = 1069 ng/g were found after i.p. (2.5 mg/kg) administration in mice. AGH-192 may thus serve as the long-sought tool compound in the study of 5-HT7 receptor function, as well as a potential analgesic, indicated by the antinociceptive effect observed in a mouse model of neuropathic pain.


Assuntos
Imidazóis/química , Imidazóis/farmacocinética , Indóis/química , Indóis/farmacocinética , Neuralgia/tratamento farmacológico , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacocinética , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/química , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Células HEK293 , Halogenação , Humanos , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Indóis/administração & dosagem , Indóis/uso terapêutico , Masculino , Camundongos , Modelos Moleculares , Neuralgia/metabolismo , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/uso terapêutico
18.
Molecules ; 24(5)2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30866543

RESUMO

Neuronal nicotinic acetylcholine receptors are cell membrane-bound ion channels that are widely distributed in the central nervous system. The α4ß2 subtype of neuronal nicotinic acetylcholine receptor plays an important role in modulating the signaling pathways for pain. Previous studies have shown that agonists, partial agonists, and positive allosteric modulators for the α4ß2 receptors are effective in relieving pain. Desformylflustrabromine is a compound that acts as an allosteric modulator of α4ß2 receptors. The aim of this study was to assess the effects of desformylflustrabromine on chemically induced pain. For this purpose, the formalin-induced pain test and the acetic acid-induced writhing response test were carried out in CD-1 mice. Both tests represent chemical assays for nociception. The results show that desformylflustrabromine is effective in producing an analgesic effect in both tests used for assessing nociception. These results suggest that desformylflustrabromine has the potential to become a clinically used drug for pain relief.


Assuntos
Analgésicos/administração & dosagem , Hidrocarbonetos Bromados/administração & dosagem , Alcaloides Indólicos/administração & dosagem , Dor/tratamento farmacológico , Receptores Nicotínicos/metabolismo , Ácido Acético/efeitos adversos , Regulação Alostérica , Analgésicos/química , Analgésicos/farmacologia , Animais , Formaldeído/efeitos adversos , Hidrocarbonetos Bromados/química , Hidrocarbonetos Bromados/farmacologia , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Masculino , Camundongos , Estrutura Molecular , Dor/induzido quimicamente
19.
Eur J Med Chem ; 166: 400-416, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30739823

RESUMO

Grayanane diterpenoids, possessing a unique 5/7/6/5 tetracyclic system, exist exclusively in plants of the Ericaceae family. Owing to their various skeletons, complex structures, and diverse bioactivities, grayanoids have been the topic of research in many phytochemical and pharmacological laboratories, offering opportunities for the development of new drugs with analgesic, anti-inflammatory, and protein tyrosine phosphatase 1B (PTP1B) properties. Recently, a number of new grayanane diterpenoids with unprecedented carbon skeletons have been obtained from plants of the Ericaceae family, and they exhibit diverse biological properties, such as agalgesic, antinociceptive, anticancer, antiviral, antifeedant, insecticidal, toxicity, and PTP1B. In this review, 162 new grayanoids with 14 carbon skeletons from the Ericaceae family over the past seven years (2012-October 2018) are discussed, including their occurrence and distribution, skeleton types, structural features, biological activities, and structure-activity relationships (SARs). Also, strategies for the structural elucidation are summarized to provide useful information for medicinal chemists in developing potent anticancer, antiviral, analgesic, anti-inflammatory, and novel PTP1B agents.


Assuntos
Diterpenos/química , Diterpenos/farmacologia , Ericaceae/química , Analgésicos/química , Analgésicos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antivirais/química , Antivirais/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos
20.
Int J Pharm ; 559: 341-347, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30710660

RESUMO

Topical preparations of capsaicin, the major pungent ingredient of hot pepper, are being used for management of pain and inflammatory disorders. Purpose of this study was to use nanoemulsion as an effective topical drug carrier for in vivo delivery of capsaicin. An oil-in-water nanoemulsion containing capsaicin was prepared by spontaneous emulsification method. Optimized formulation showed a median droplet diameter (d50) of 13-14 nm and was stable for more than 8 months in room and harsh temperature (i.e. 4 and 45 °C). The nanoemulsion was then formulated into topical cream and gel to compare its efficacy and safety profiles with conventional cream of capsaicin. Skin irritation study showed that topical application of capsaicin nanoemulsion was safe and no sign of edema and erythema was observed. The preparation significantly decreased inflammation of rats paw edema compared to the commercial cream and control group, especially in 2nd and 3rd hours of the test. Also, pretreated rats with capsaicin nanoemulsion gel showed very good resistance to the pain caused by heat stimulus. In total, the selected nanoemulsion showed great potential as carrier for topical delivery of capsaicin for improving its analgesic and anti-inflammatory effects. It was also found that the topical gel outperforms the topical cream as dosage form for the nanoemulsion.


Assuntos
Analgésicos/química , Anti-Inflamatórios/química , Capsaicina/química , Capsaicina/farmacologia , Emulsões/química , Nanopartículas/química , Azeite de Oliva/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Química Farmacêutica/métodos , Portadores de Fármacos/química , Edema/tratamento farmacológico , Emulsões/farmacologia , Géis/química , Géis/farmacologia , Inflamação/tratamento farmacológico , Masculino , Azeite de Oliva/farmacologia , Dor/tratamento farmacológico , Coelhos , Ratos , Ratos Wistar , Absorção Cutânea/efeitos dos fármacos
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