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1.
Nutrients ; 11(9)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514292

RESUMO

The use of a complete nutritional approach seems increasingly promising to combat chronic inflammation. The choice of healthy sources of carbohydrates, fats, and proteins, associated with regular physical activity and avoidance of smoking is essential to fight the war against chronic diseases. At the base of the analgesic, anti-inflammatory, or antioxidant action of the diets, there are numerous molecules, among which some of a lipidic nature very active in the inflammatory pathway. One class of molecules found in diets with anti-inflammatory actions are ALIAmides. Among all, one is particularly known for its ability to counteract the inflammatory cascade, the Palmitoylethanolamide (PEA). PEA is a molecular that is present in nature, in numerous foods, and is endogenously produced by our body, which acts as a balancer of inflammatory processes, also known as endocannabionoid-like. PEA is often used in the treatment of both acute and chronic inflammatory pathologies, either alone or in association with other molecules with properties, such as antioxidants or analgesics. This review aims to illustrate an overview of the different diets that are involved in the process of opposition to the inflammatory cascade, focusing on capacity of PEA and new formulations in synergy with other molecules.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Suplementos Nutricionais , Etanolaminas/uso terapêutico , Inflamação/prevenção & controle , Ácidos Palmíticos/uso terapêutico , Animais , Anti-Inflamatórios/efeitos adversos , Antioxidantes/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Sinergismo Farmacológico , Etanolaminas/efeitos adversos , Etanolaminas/metabolismo , Humanos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Ácidos Palmíticos/efeitos adversos , Ácidos Palmíticos/metabolismo , Transdução de Sinais
2.
Am J Hosp Palliat Care ; 36(12): 1134-1154, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31113223

RESUMO

Palmitoylethanolamide (PEA) is a nutraceutical endocannabinoid that was retrospectively discovered in egg yolks. Feeding poor children with known streptococcal infections prevented rheumatic fever. Subsequently, it was found to alter the course of influenza. Unfortunately, there is little known about its pharmacokinetics. Palmitoylethanolamide targets nonclassical cannabinoid receptors rather than CB1 and CB2 receptors. Palmitoylethanolamide will only indirectly activate classical cannabinoid receptors by an entourage effect. There are a significant number of prospective and randomized trials demonstrating the pain-relieving effects of PEA. There is lesser evidence of benefit in patients with nonpain symptoms related to depression, Parkinson disease, strokes, and autism. There are no reported drug-drug interactions and very few reported adverse effects from PEA. Further research is needed to define the palliative benefits to PEA.


Assuntos
Etanolaminas/uso terapêutico , Ácidos Palmíticos/uso terapêutico , Animais , Etanolaminas/farmacologia , Humanos , Transtornos Mentais/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Dor/tratamento farmacológico , Ácidos Palmíticos/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico
3.
Drug Metab Dispos ; 47(6): 567-573, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30952677

RESUMO

Rolapitant [(Varubi), 5S,8S)-8-[[(1R)-1-[3,5 bis(trifluoromethyl phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one] is a high-affinity NK1 receptor antagonist that was approved in September 2015 as a treatment for nausea and vomiting caused by chemotherapy. In vivo rolapitant moderately inhibits CYP2D6 for at least 7 days after one 180 mg dose. Due to the long inhibition time, we investigated rolapitant as a possible mechanism-based inactivator of CYP2D6. Rolapitant docked in the active site of CYP2D6 and displayed type I binding to CYP2D6 with a K s value of 1.2 ± 0.4 µM. However, in NADPH-, time-, and concentration-dependent assays of CYP2D6 activity, no evidence for mechanism-based inactivation and no metabolites of rolapitant were observed. Stopped-flow binding studies yielded a kon /koff (K d) value of 6.2 µM. The IC50 value for rolapitant inhibition of CYP2D6 activity was 24 µM, suggesting that inhibition is not due to tight binding of rolapitant to CYP2D6. By Lineweaver-Burk analysis, rolapitant behaved as a mixed, reversible inhibitor. The K i values of 20 and 34 µM were determined by Dixon analysis, with bufuralol and dextromethorphan as reporter substrates, respectively, and drug-drug interaction modeling did not predict the reported in vivo inhibition. The interaction of rolapitant with CYP2D6 was also examined in 1 microsecond molecular dynamics simulations. Rolapitant adopted multiple low-energy binding conformations near the active site, but at distances not consistent with metabolism. Given these findings, we do not see evidence that rolapitant is a mechanism-based inactivator. Moreover, the reversible inhibition of CYP2D6 by rolapitant may not fully account for the moderate inhibition described in vivo.


Assuntos
Inibidores do Citocromo P-450 CYP2D6/uso terapêutico , Citocromo P-450 CYP2D6/metabolismo , Compostos de Espiro/uso terapêutico , Domínio Catalítico/fisiologia , Dextrometorfano/uso terapêutico , Interações Medicamentosas/fisiologia , Etanolaminas/uso terapêutico , Humanos
4.
Medicina (Kaunas) ; 55(4)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939862

RESUMO

Asthma is a common allergic pathology of the respiratory tract that requires the study of mechanisms underlying it, due to severe forms of the disease, which are refractory to therapy. The review is devoted to the search for molecular targets of fatty acid ethanolamides in asthma, in particular palmitoylethanolamide (PEA), which has been successfully used in the treatment of chronic inflammatory and neurodegenerative diseases, in the pathogenesis of which the nervous and immune systems are involved. Recently, the potentially important role of neuro-immune interactions in the development of allergic reactions has been established. Many of the clinical symptoms accompanying allergic airway inflammation are the result of the activation of neurons in the airways, so the attention of researchers is currently focused on neuro-immune interactions, which can play an important role in asthma pathophysiology. A growing number of scientific works confirm that the key molecule in the implementation of these inter-systemic interactions is nerve growth factor (NGF). In addition to its classic role in nervous system physiology, NGF is considered as an important factor associated with the pathogenesis of allergic diseases, particularly asthma, by regulating of mast cell differentiation. In this regard, NGF can be one of the targets of PEA in asthma therapy. PEA has a biological effect on the nervous system, and affects the activation and the degranulation of mast cells.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Asma/tratamento farmacológico , Asma/metabolismo , Etanolaminas/uso terapêutico , Terapia de Alvo Molecular , Fator de Crescimento Neural/metabolismo , Ácidos Palmíticos/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/metabolismo , Asma/imunologia , Eosinófilos/metabolismo , Etanolaminas/metabolismo , Ácidos Graxos/metabolismo , Humanos , Hipersensibilidade/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Mastócitos/metabolismo , Camundongos , Neurônios/metabolismo , Ácidos Palmíticos/metabolismo
5.
Inflammopharmacology ; 27(3): 475-485, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30927159

RESUMO

BACKGROUND: The aim of the study was to assess the safety, tolerability and efficacy of palmitoylethanolamide (PEA) when dosed at 300 mg and 600 mg per day on symptoms of knee osteoarthritis. METHODS: This was a single site, comparative, double-blind placebo controlled study in adults with mild to moderate knee osteoarthritis with 111 participants randomized to receive 300 mg PEA, 600 mg PEA or placebo each day, in divided doses b.i.d, for 8 weeks. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The secondary outcomes were the Numerical Rating Scales (NRS) for pain, the Depression Anxiety Stress Scale (DASS), the Perceived Stress Scale (PSS), the Pittsburg Sleep Quality Index (PSQI), the Short Form Health Survey (SF-36), the use of rescue pain medication and clinical safety assessment. RESULTS: There was a significant reduction in the total WOMAC score in the 300 mg PEA (p = 0.0372) and the 600 mg PEA (p = 0.0012) groups, the WOMAC pain score (300 mg PEA, p = 0.0074; 600 mg PEA, p = < 0.001), the WOMAC stiffness score (PEA 300 mg, p < 0.0490; 600 mg PEA, p = 0.001) and in the WOMAC function score in the 600 mg PEA group (p = 0.033) compared to placebo. The NRS pain evaluations for "worst pain" and "least pain" were significantly reduced in the 300 mg PEA group (p < 0.001, p = 0.005) and the 600 mg PEA group (p < 0.001, p < 0.001) compared to placebo. There was a significant reduction in anxiety (DASS) in both active treatment groups (300 mg PEA, p = 0.042; 600 mg PEA group (p = 0.043) compared to placebo. There were no changes in the clinical markers and the product was well tolerated. CONCLUSIONS: The study demonstrated that palmitoylethanolamide may be a novel treatment for attenuating pain and reducing other associated symptoms of knee osteoarthritis. Further studies on the pharmacological basis of this anti-inflammatory effect are now required.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Etanolaminas/efeitos adversos , Etanolaminas/uso terapêutico , Osteoartrite do Joelho/tratamento farmacológico , Ácidos Palmíticos/efeitos adversos , Ácidos Palmíticos/uso terapêutico , Adulto , Idoso , Transtorno Depressivo Maior/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/fisiopatologia , Dor/tratamento farmacológico , Dor/fisiopatologia , Medição da Dor/métodos , Qualidade de Vida , Resultado do Tratamento
6.
Biochem Biophys Res Commun ; 511(3): 504-509, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30803757

RESUMO

The anti-metastatic effects of cationic liposomes (CL) composed of 87 mol% dimyristoylphosphatidylcholine (DMPC), 8 mol% O,O'-ditetradecanoyl-N-(α-trimethylammonioacetyl) diethanolamine chloride (2C14ECl) and 5 mol% polyoxyethylene(21) dodecyl ether (C12(EO)21) was investigated for human pancreatic cancer (BxPC-3) cells. The inhibitory effect of CL on the migration of BxPC-3 cells was observed based on a wound scratch assay. CL suppressed pseudopodium formation of BxPC-3 cells. The anti-invasive effect of CL against BxPC-3 cells was observed via a Matrigel invasion assay. The anti-invasive effect of CL for BxPC-3 cells was found to occur through the inhibition of MMP2, MMP9, and MMP14. Overall, the results of this study revealed for the first time, the therapeutic effects and anti-metastasis activity of CL in xenograft mouse models for peritoneal metastasis of human pancreatic cancer.


Assuntos
Dimiristoilfosfatidilcolina/uso terapêutico , Etanolaminas/uso terapêutico , Etilaminas/uso terapêutico , Lipossomos/uso terapêutico , Invasividade Neoplásica/prevenção & controle , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Cátions/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/patologia
7.
J Am Acad Dermatol ; 81(2): 558-567, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30802561

RESUMO

Radiation dermatitis is a common sequela of radiation therapy; up to 95% of patients will develop moderate-to-severe skin reactions. No criterion standard currently exists for the treatment of acute radiation-induced skin toxicity. It is therefore imperative to develop a greater understanding of management options available to allow clinicians to make informed decisions when managing radiation oncology patients. This literature review discusses the topical agents that have been studied for the treatment of acute radiation dermatitis, reviews their mechanisms of action, and presents a treatment algorithm for clinicians managing patients experiencing radiation dermatitis.


Assuntos
Algoritmos , Fármacos Dermatológicos/uso terapêutico , Radiodermatite/tratamento farmacológico , Doença Aguda , Corticosteroides/uso terapêutico , Anti-Infecciosos Locais/uso terapêutico , Bandagens , Produtos Biológicos/uso terapêutico , Etanolaminas/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Preparações de Plantas/uso terapêutico , Radiodermatite/etiologia , Radioterapia/efeitos adversos , Sulfadiazina de Prata/uso terapêutico , Sucralfato/uso terapêutico , Vitaminas/uso terapêutico
8.
Acta Pharmacol Sin ; 40(8): 1095-1105, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30643208

RESUMO

ß-Arrestins are a small family of proteins important for signal transduction at G protein-coupled receptors (GPCRs). ß-Arrestins are involved in the desensitization of GPCRs. Recently, biased ligands possessing different efficacies in activating the G protein- versus the ß-arrestin-dependent signals downstream of a single GPCR have emerged, which can be used to selectively modulate GPCR signal transduction in such a way that desirable signals are enhanced to produce therapeutic effects while undesirable signals of the same GPCR are suppressed to avoid side effects. In the present study, we evaluated agonist bias for compounds developed along a drug discovery project of ß2-adrenoceptor agonists. About 150 compounds, including derivatives of fenoterol, 2-amino-1-phenylethanol and 2-amino-2-phenylethanol, were obtained or synthesized, and initially screened for their ß-adrenoceptor-mediated activities in the guinea pig tracheal smooth muscle relaxation assay or the cardiomyocyte contractility assay. Nineteen bioactive compounds were further assessed using both the HTRF cAMP assay and the PathHunter ß-arrestin assay. Their concentration-response data in stimulating cAMP synthesis and ß-arrestin recruitment were applied to the Black-Leff operational model for ligand bias quantitation. As a result, three compounds (L-2, L-4, and L-12) with the core structure of 5-(1-amino-2-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one were identified as a new series of ß-arrestin-biased ß2-adrenoceptor agonists, whereas salmeterol was found to be Gs-biased. These findings would facilitate the development of novel drugs for the treatment of both heart failure and asthma.


Assuntos
Agonistas Adrenérgicos beta/uso terapêutico , Etanolaminas/uso terapêutico , beta-Arrestinas/metabolismo , Agonistas Adrenérgicos beta/síntese química , Animais , Broncodilatadores/síntese química , Broncodilatadores/uso terapêutico , Células CHO , Cricetulus , Descoberta de Drogas , Etanolaminas/síntese química , Cobaias , Células HEK293 , Humanos , Ligantes , Masculino , Traqueia/efeitos dos fármacos
9.
J Pharmacol Exp Ther ; 369(1): 163-172, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30635472

RESUMO

N-Palmitoylethanolamide (PEA), an endocannabinoid-like molecule, participates in controlling behaviors associated with mental disorders as an endogenous neuroprotective factor. On the basis of accumulating evidence and our previous data, we tested the hypothesis that the antidepressant-like effects of PEA observed during chronic unpredictable mild stress (CUMS) are mediated by possible targets in the peroxisome proliferator-activated receptor alpha (PPARα) pathway. In this study, rats were subjected to 35 days of CUMS and treated with drugs such as PEA (2.5, 5.0, or 10 mg/kg, by mouth), fluoxetine (10 mg/kg, by mouth), or the combination of PEA and MK886 (1-[(4-chlorophenyl) methyl]-3-[(1,1-dimethylethyl) thio]-α,α-dimethyl-5-(1-methylethyl)-1H-indole-2-propanoic acid). After behavioral tests, the animals were sacrificed and their hippocampi were dissected for subsequent studies. PEA normalized weight gain, sucrose preferences, locomotor activity in an open-field test, and levels of the PPARα mRNA and protein in the hippocampus, and it reduced serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels in rats subjected to CUMS. PEA reversed the abnormal levels of several oxidative stress biomarkers and increased the concentrations of two neurotrophic factors in the hippocampus of CUMS-induced rats. In addition, PEA alleviated the decrease in hippocampal weight. However, the aforementioned effects of PEA were completely or partially abolished by MK886, a selective PPARα antagonist. On the basis of these findings, the PPARα pathway in the hippocampus is a possible target of the antidepressant effects of PEA, and the maintenance of a stable hypothalamic-pituitary-adrenal axis, the antioxidant defenses, and normalization of neurotrophic factor levels in the hippocampus are involved in this process.


Assuntos
Antidepressivos/farmacologia , Etanolaminas/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , PPAR alfa/metabolismo , Ácidos Palmíticos/farmacologia , Hormônio Adrenocorticotrópico/sangue , Animais , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corticosterona/sangue , Etanolaminas/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Glutationa/metabolismo , Hipocampo/patologia , Masculino , Malondialdeído/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Ácidos Palmíticos/uso terapêutico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/sangue , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Superóxido Dismutase/metabolismo
10.
Malar J ; 18(1): 10, 2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30654808

RESUMO

BACKGROUND: Reduced artemisinin susceptibility and artemisinin-based combination therapy (ACT)-resistance against Plasmodium falciparum and chloroquine (CQ)-resistant P. vivax malaria has been reported in Vietnam. Two therapeutic efficacy studies were conducted in Thuan Bac District (Ninh Thuan Province, Vietnam) in 2015 and 2016 to determine the extent of reduced artemisinin susceptibility and ACT resistant falciparum malaria, and CQ-resistant vivax malaria were present. METHODS: Twenty-seven patients with falciparum malaria were randomized to receive artesunate alone (AS ~ 4 mg/kg/day) for 4 days followed by dihydroartemisinin (DHA) (2.2 mg/kg)-piperaquine (PPQ) (18 mg/kg) daily for 3 days or artemether (AM) (1.7 mg/kg)-lumefantrine (LUM) (12 mg/kg) twice daily for 3 days. Sixteen subjects with vivax malaria received CQ (total 25 mg/kg over 3 days). The therapeutic efficacy study for treating falciparum malaria was complemented with molecular analysis for artemisinin and piperaquine resistance, and in vitro drug susceptibility testing. Patient's drug exposure following both falciparum and vivax treatment studies was determined. RESULTS: Twenty-five of 27 patients treated with the artemisinin regimens completed the 42-day follow-up period. None had parasites present on day 3 after commencing treatment with no incidence of recrudescence (100% curative rate). One patient on AS + DHA-PPQ was lost to follow-up and one patient had Plasmodium falciparum and Plasmodium vivax infection on day 0 by PCR. Of the vivax patients, 15 of 16 completed CQ treatment and two had a recurrence of vivax malaria on day 28, a failure rate of 13.3% (2/15). No mutations in the Pfkelch-13 gene for artemisinin resistance or exo-E415G gene polymorphism and amplification in plasmepsins 2 and 3 for piperaquine resistance were observed. In vitro testing of patient's falciparum parasites indicated susceptibility (low IC50 nM values) to dihydroartemisinin, lumefantrine, piperaquine and pyronaridine. Patient's drug exposure to artesunate and lumefantrine was comparable to published data, however, blood CQ concentrations were lower. CONCLUSIONS: Clinical findings, molecular analysis and in vitro testing revealed that the falciparum parasites at Phuoc Chien Commune were artemisinin susceptible. The clinical failure rate of the 15 vivax patients who completed CQ treatment was 13%. Further studies are required to determine whether CQ-resistant vivax malaria is present at the commune.


Assuntos
Antimaláricos/uso terapêutico , Cloroquina/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária Vivax/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium vivax/efeitos dos fármacos , Adolescente , Adulto , Idoso , Antimaláricos/farmacologia , Criança , Pré-Escolar , Cloroquina/farmacologia , Resistência a Múltiplos Medicamentos/genética , Etanolaminas/farmacologia , Etanolaminas/uso terapêutico , Feminino , Fluorenos/farmacologia , Fluorenos/uso terapêutico , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Vietnã/epidemiologia , Adulto Jovem
11.
Clin Oral Investig ; 23(6): 2743-2750, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30361792

RESUMO

OBJECTIVES: This preliminary randomized double-blind controlled trial was performed to test the efficacy of ultramicronized palmitoylethanolamide treatment in the burning mouth syndrome. MATERIALS AND METHODS: Patients with referred burning mouth intensity greater than 4, according to the Numeric Rating Scale, were included in the study according to established inclusion and exclusion criteria. Patients were randomized into two groups and received either placebo or ultramicronized palmitoylethanolamide 600 mg twice daily for 60 days. Patients were assessed at baseline, 30 and 60 days after treatment start, and 4 months after treatment discontinuation. In order to evaluate the change in the burning mouth sensation over time, the generalized linear mixed model was employed. RESULTS: A total of 35 patients were considered eligible, among which 6 withdrew prior to the end of treatment. A statistically significant reduction of burning mouth sensation (p < 0.0132) was registered at the end of the active treatment in the ultramicronized palmitoylethanolamide group compared to the placebo one. Any side effect related to the active treatment was neither observed nor reported both by patients and by physicians. CONCLUSIONS: The significant decrease of burning sensation in the ultramicronized palmitoylethanolamide group compared to the placebo group suggests to consider this naturally occurring molecule as a viable therapy in the management of burning mouth syndrome. CLINICAL RELEVANCE: The use of an effective compound to manage the burning mouth syndrome, devoid of adverse effects for the patient and that does not interfere with other pharmacological therapies, could find wide employability from clinicians.


Assuntos
Síndrome da Ardência Bucal/tratamento farmacológico , Etanolaminas/uso terapêutico , Ácidos Palmíticos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
12.
Front Immunol ; 9: 2671, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30505308

RESUMO

Easy-to-achieve interventions to promote healthy longevity are desired to diminish the incidence and severity of infections, as well as associated disability upon recovery. The dietary supplement palmitoylethanolamide (PEA) exerts anti-inflammatory and neuroprotective properties. Here, we investigated the effect of prophylactic PEA on the early immune response, clinical course, and survival of old mice after intracerebral E. coli K1 infection. Nineteen-month-old wild type mice were treated intraperitoneally with two doses of either 0.1 mg PEA/kg in 250 µl vehicle solution (n = 19) or with 250 µl vehicle solution only as controls (n = 19), 12 h and 30 min prior to intracerebral E. coli K1 infection. The intraperitoneal route was chosen to reduce distress in mice and to ensure exact dosing. Survival time, bacterial loads in cerebellum, blood, spleen, liver, and microglia counts and activation scores in the brain were evaluated. We measured the levels of IL-1ß, IL-6, MIP-1α, and CXCL1 in cerebellum and spleen, as well as of bioactive lipids in serum in PEA- and vehicle-treated animals 24 h after infection. In the absence of antibiotic therapy, the median survival time of PEA-pre-treated infected mice was prolonged by 18 h compared to mice of the vehicle-pre-treated infected group (P = 0.031). PEA prophylaxis delayed the onset of clinical symptoms (P = 0.037). This protective effect was associated with lower bacterial loads in the spleen, liver, and blood compared to those of vehicle-injected animals (P ≤ 0.037). PEA-pre-treated animals showed diminished levels of pro-inflammatory cytokines and chemokines in spleen 24 h after infection, as well as reduced serum concentrations of arachidonic acid and of one of its metabolites, 20-hydroxyeicosatetraenoic acid. In the brain, prophylactic PEA tended to reduce bacterial titers and attenuated microglial activation in aged infected animals (P = 0.042). Our findings suggest that prophylactic PEA can counteract infection associated detrimental responses in old animals. Accordingly, PEA treatment slowed the onset of infection symptoms and prolonged the survival of old infected mice. In a clinical setting, prophylactic administration of PEA might extend the potential therapeutic window where antibiotic therapy can be initiated to rescue elderly patients.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Escherichia coli/metabolismo , Etanolaminas/uso terapêutico , Inflamação/dietoterapia , Meningite devida a Escherichia coli/dietoterapia , Meningite devida a Escherichia coli/prevenção & controle , Ácidos Palmíticos/uso terapêutico , Envelhecimento/imunologia , Animais , Cerebelo/microbiologia , Citocinas/metabolismo , Suplementos Nutricionais , Modelos Animais de Doenças , Estimativa de Kaplan-Meier , Meningite devida a Escherichia coli/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Baço/microbiologia , Estatísticas não Paramétricas , Taxa de Sobrevida
13.
Minerva Med ; 109(5): 358-362, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30338679

RESUMO

BACKGROUND: Painful distal symmetric polyneuropathy (pDSPN) is one of the most common and invalidating complications of diabetes mellitus, both of type 1 and type 2. Mechanisms responsible for the occurrence of the pDSPN are multifactorial and involve metabolic pathways regulating inflammation, microvessel circulation, axonal degeneration and so on. Several therapeutic approaches have been proposed to treat pain and each of them showed positive effects associated to drug-related side effects. METHODS: Twenty-five consecutive patients with diagnosis of diabetes mellitus and pDSPN and tried to manage pain with a dietary supplement composed of a mixture of natural extracts (ß-caryophyllene, myrrh, carnosic acid) and PEA. This is a nutraceutical with potential multiple effects on metabolic, pain and vascular compartments, a profile considered useful in pDSPN. Patients were enrolled and polyneuropathy evaluated by means of nerve conduction study. Pain was assessed using VAS score scale and MNSI. Each patient was evaluated at T0 (time of enrollment) and at T1 (after 16 weeks of treatment). RESULTS: Supplement administration was well tolerated and induced unexpectedly significant amelioration of polyneuropathy with increase amplitude and reduction of pain. No side effects were reported. CONCLUSIONS: This fixed combination could well be considered as a potential nutraceutical option to manage pDSPN in diabetic patients.


Assuntos
Neuropatias Diabéticas/dietoterapia , Suplementos Nutricionais , /administração & dosagem , Adulto , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/fisiopatologia , Etanolaminas/administração & dosagem , Etanolaminas/uso terapêutico , Feminino , Humanos , Masculino , Medição da Dor , Ácidos Palmíticos/administração & dosagem , Ácidos Palmíticos/uso terapêutico , Sesquiterpenos/administração & dosagem , Sesquiterpenos/uso terapêutico , Índice de Gravidade de Doença , Nervo Sural/fisiopatologia , Terpenos/administração & dosagem , Terpenos/uso terapêutico , Resultado do Tratamento , Adulto Jovem
14.
Malar J ; 17(1): 347, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30290808

RESUMO

BACKGROUND: Artemether-lumefantrine (AL) and artesunate-amodiaquine are first-line treatment for uncomplicated malaria in many endemic countries, including Mali. Dihydroartemisinin-piperaquine (DHA-PQ) is also an alternative first-line artemisinin-based combination therapy, but only few data are available on DHA-PQ efficacy in sub-Saharan Africa. The main aim of this study was to compare clinical efficacy of DHA-PQ versus AL, using the World Health Organization (WHO) 42-day in vivo protocol. METHODS: The efficacy of three-dose regimens of DHA-PQ was compared to AL combination in a randomized, comparative open label trial using the WHO 42-day follow-up protocol from 2013 to 2015 in Doneguebougou and Torodo, Mali. The primary endpoint was to access the PCR-corrected Adequate Clinical and Parasitological Responses at day 28. RESULTS: A total of 317 uncomplicated malaria patients were enrolled, with 159 in DHA-PQ arm and 158 in AL arm. The parasite positivity rate decreased from 68.4% (95% CI 60.5-75.5) on day 1 to 3.8% (95% CI 1.4-8.1) on day 2 for DHA-PQ and 79.8% (95% CI 72.3-85.7) on day 1 to 9.5% (95% CI 5.4-15.2) on day 2 for AL, (p = 0.04). There was a significant difference in the uncorrected ACPR between DHA-PQ and AL, both at 28-day and 42-day follow-up with 97.4% (95% CI 93.5-99.3) in DHA-PQ vs 84.5% (95% CI 77.8-89.8) in AL (p < 0.001) and 94.2% (95% CI 89.3-97.3) in DHA-PQ vs 73.4% (95% CI 65.7-80.2) in AL, respectively (p < 0.001). After molecular correction, there was no significant difference in ACPRc between DHA-PQ and AL, both at the 28-day and 42-day follow-up with 99.4% (95% CI 96.5-100) in DHA-PQ versus 98.1% (95% CI 94.5-99.6) in AL (p = 0.3) and 99.3% (95% CI 96.5-100) in DHA-PQ vs 97.4% (95% CI 93.5-99.3) in AL (p = 0.2). There was no significant difference between DHA-PQ and AL in QTc prolongation 12.1% vs 7%, respectively (p = 0.4). CONCLUSION: The results showed that dihydroartemisinin-piperaquine and artemether-lumefantrine were clinically efficacious on Plasmodium falciparum parasites in Mali.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária Falciparum/prevenção & controle , Quinolinas/uso terapêutico , Adolescente , Adulto , Combinação Arteméter e Lumefantrina , Criança , Pré-Escolar , Combinação de Medicamentos , Etanolaminas/uso terapêutico , Feminino , Fluorenos/uso terapêutico , Humanos , Lactente , Masculino , Mali , Pessoa de Meia-Idade , Plasmodium falciparum/efeitos dos fármacos , Adulto Jovem
15.
Malar J ; 17(1): 350, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30290825

RESUMO

BACKGROUND: In 2009, the Papua New Guinea (PNG) Department of Health adopted artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PPQ) as the first- and second-line treatments for uncomplicated malaria, respectively. This study was conducted to assess the efficacy of both drugs following adoption of the new policy. METHODS: Between June 2012 and September 2014, a therapeutic efficacy study was conducted in East Sepik and Milne Bay Provinces of PNG in accordance with the standard World Health Organization (WHO) protocol for surveillance of anti-malarial drug efficacy. Patients ≥ 6 months of age with microscopy confirmed Plasmodium falciparum or Plasmodium vivax mono-infections were enrolled, treated with AL or DHA-PPQ, and followed up for 42 days. Study endpoints were adequate clinical and parasitological response (ACPR) on days 28 and 42. The in vitro efficacy of anti-malarials and the prevalence of selected molecular markers of resistance were also determined. RESULTS: A total of 274 P. falciparum and 70 P. vivax cases were enrolled. The day-42 PCR-corrected ACPR for P. falciparum was 98.1% (104/106) for AL and 100% (135/135) for DHA-PPQ. The day-42 PCR-corrected ACPR for P. vivax was 79.0% (15/19) for AL and 92.3% (36/39) for DHA-PPQ. Day 3 parasite clearance of P. falciparum was 99.2% with AL and 100% with DHA-PPQ. In vitro testing of 96 samples revealed low susceptibility to chloroquine (34% of samples above IC50 threshold) but not to lumefantrine (0%). Molecular markers assessed in a sub-set of the study population indicated high rates of chloroquine resistance in P. falciparum (pfcrt SVMNT: 94.2%, n = 104) and in P. vivax (pvmdr1 Y976F: 64.8%, n = 54). CONCLUSIONS: AL and DHA-PPQ were efficacious as first- and second-line treatments for uncomplicated malaria in PNG. Continued in vivo efficacy monitoring is warranted considering the threat of resistance to artemisinin and partner drugs in the region and scale-up of artemisinin-based combination therapy in PNG.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Etanolaminas/uso terapêutico , Fluorenos/uso terapêutico , Malária Falciparum/prevenção & controle , Malária Vivax/prevenção & controle , Quinolinas/uso terapêutico , Adolescente , Adulto , Combinação Arteméter e Lumefantrina , Criança , Pré-Escolar , Combinação de Medicamentos , Feminino , Humanos , Lactente , Concentração Inibidora 50 , Masculino , Pessoa de Meia-Idade , Papua Nova Guiné , Plasmodium falciparum/efeitos dos fármacos , Plasmodium vivax/efeitos dos fármacos , Adulto Jovem
16.
Inflamm Res ; 67(10): 891-901, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30121836

RESUMO

OBJECTIVE AND DESIGN: Temporomandibular disorder (TMD) is a common painful condition in the temporomandibular joint (TMJ). Joint inflammation is believed to be a chief cause of pain in patients with TMD, through the release of pro-inflammatory cytokines that induce peripheral sensitization of nerve terminals followed by microglial stimulation. MATERIALS AND SUBJECT: TMJ was induced in rats with the injection of complete Freund's adjuvant (CFA) emulsion into the left TMJ capsule. TREATMENT: The present study would assess the effects of micronized palmitoylethanolamide (m-PEA) on glial activation and trigeminal hypersensitivity. METHODS: Ten mg/kg m-PEA or corresponding vehicle was administered 1 h after CFA and mechanical allodynia and edema were evaluated at 24 and 72 h after CFA injection. RESULTS: CFA-injected animals showed TMJ edema and ipsilateral mechanical allodynia accompanied by a robust growth in GFAP protein-positive satellite glial cells and activation of resident macrophages in the TG. Moreover, m-PEA administration significantly reduced the degree of TMJ damage and pain, macrophage activation in TG and up-regulation of Iba1. CONCLUSIONS: The results confirm that m-PEA could represent a novel approach for monitoring pain during trigeminal nerve sensitization.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Artralgia/tratamento farmacológico , Etanolaminas/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuroglia/efeitos dos fármacos , Ácidos Palmíticos/uso terapêutico , Articulação Temporomandibular , Animais , Artralgia/induzido quimicamente , Artralgia/metabolismo , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Adjuvante de Freund , Proteína Glial Fibrilar Ácida/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Masculino , Neuroglia/metabolismo , Ratos Sprague-Dawley
17.
PLoS One ; 13(8): e0202534, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30133539

RESUMO

Characterization of cytochrome P450 2D6 (CYP2D6) and the impact of the major identified allelic variants on the activity of one of the most dominating drug-metabolising enzymes is essential to increase drug safety and avoid adverse reactions. Microsecond molecular dynamics simulations have been performed to capture the dynamic signatures of this complex enzyme and five allelic variants with diverse enzymatic activity. In addition to the apo simulations, three substrates (bufuralol, veliparib and tamoxifen) and two inhibitors (prinomastat and quinidine) were included to explore their influence on the structure and dynamical features of the enzyme. Our results indicate that the altered enzyme activity can be attributed to changes in the hydrogen bonding network within the active site, and local structural differences in flexibility, position and shape of the binding pocket. In particular, the increased (CYP2D6*53) or the decreased (CYP2D6*17) activity seems to be related to a change in dynamics of mainly the BC loop due to a modified hydrogen bonding network around this region. In addition, the smallest active site volume was found for CYP2D6*4 (no activity). CYP2D6*2 (normal activity) showed no major differences in dynamic behaviour compared to the wild-type.


Assuntos
Citocromo P-450 CYP2D6/química , Inativação Metabólica/genética , Simulação de Dinâmica Molecular , Alelos , Benzimidazóis/química , Benzimidazóis/uso terapêutico , Domínio Catalítico/efeitos dos fármacos , Citocromo P-450 CYP2D6/genética , Dextrometorfano/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Etanolaminas/química , Etanolaminas/uso terapêutico , Heme/química , Humanos , Ligação de Hidrogênio/efeitos dos fármacos , Especificidade por Substrato , Tamoxifeno/química , Tamoxifeno/uso terapêutico
18.
Cochrane Database Syst Rev ; 7: CD012171, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-30043448

RESUMO

BACKGROUND: Ear wax (cerumen) is a normal bodily secretion that can become a problem when it obstructs the ear canal. Symptoms attributed to wax (such as deafness and pain) are among the commonest reasons for patients to present to primary care with ear trouble.Wax is part of the ear's self-cleaning mechanism and is usually naturally expelled from the ear canal without causing problems. When this mechanism fails, wax is retained in the canal and may become impacted; interventions to encourage its removal may then be needed. Application of ear drops is one of these methods. Liquids used to remove and soften wax are of several kinds: oil-based compounds (e.g. olive or almond oil); water-based compounds (e.g. sodium bicarbonate or water itself); a combination of the above or non-water, non-oil-based solutions, such as carbamide peroxide (a hydrogen peroxide-urea compound) and glycerol. OBJECTIVES: To assess the effects of ear drops (or sprays) to remove or aid the removal of ear wax in adults and children. SEARCH METHODS: We searched the Cochrane ENT Trials Register; Cochrane Register of Studies; PubMed; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 23 March 2018. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which a 'cerumenolytic' was compared with no treatment, water or saline, an alternative liquid treatment (oil or almond oil) or another 'cerumenolytic' in adults or children with obstructing or impacted ear wax. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. The primary outcomes were 1) the proportion of patients (or ears) with complete clearance of ear wax and 2) adverse effects (discomfort, irritation or pain). Secondary outcomes were: extent of wax clearance; proportion of people (or ears) with relief of symptoms due to wax; proportion of people (or ears) requiring further intervention to remove wax; success of mechanical removal of residual wax following treatment; any other adverse effects recorded and cost. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. MAIN RESULTS: We included 10 studies, with 623 participants (900 ears). Interventions included: oil-based treatments (triethanolamine polypeptide, almond oil, benzocaine, chlorobutanol), water-based treatments (docusate sodium, carbamide peroxide, phenazone, choline salicylate, urea peroxide, potassium carbonate), other active comparators (e.g. saline or water alone) and no treatment. Nine of the studies were more than 15 years old.The overall risk of bias across the 10 included studies was low or unclear. PRIMARY OUTCOME: proportion of patients (or ears) with complete clearance of ear waxSix studies (360 participants; 491 ears) contributed quantitative data and were included in our meta-analyses.Active treatment versus no treatmentOnly one study addressed this comparison. The proportion of ears with complete clearance of ear wax was higher in the active treatment group (22%) compared with the no treatment group (5%) after five days of treatment (risk ratio (RR) 4.09, 95% confidence interval (CI) 1.00 to 16.80); one study; 117 ears; NNTB = 8) (low-quality evidence).Active treatment versus water or salineWe found no evidence of a difference in the proportion of patients (or ears) with complete clearance of ear wax when the active treatment group was compared to the water or saline group (RR 1.47, 95% CI 0.79 to 2.75; three studies; 213 participants; 257 ears) (low-quality evidence). Two studies applied drops for five days, but one study only applied the drops for 15 minutes. When we excluded this study in a sensitivity analysis it did not change the result.Water or saline versus no treatmentThis comparison was only addressed in the single study cited above (active versus no treatment) and there was no evidence of a difference in the proportion of ears with complete wax clearance when comparing water or saline with no treatment after five days of treatment (RR 4.00, 95% CI 0.91 to 17.62; one study; 76 ears) (low-quality evidence).Active treatment A versus active treatment BSeveral single studies evaluated 'head-to-head' comparisons between two active treatments. We found no evidence to show that one was superior to any other.Subgroup analysis of oil-based active treatments versus non-oil based active treatmentsWe found no evidence of a difference in this outcome when oil-based treatments were compared with non-oil-based active treatments. PRIMARY OUTCOME: adverse effects: discomfort, irritation or painOnly seven studies planned to measure and did report this outcome. Only two (141 participants;176 ears) provided useable data. There was no evidence of a significant difference in the number of adverse effects between the types of ear drops in these two studies. We summarised the remaining five studies narratively. All events were mild and reported in fewer than 30 participants across the seven studies (low-quality evidence).Secondary outcomesThree studies reported 'other' adverse effects (how many studies planned to report these is unclear). The available information was limited and included occasional reports of dizziness, unpleasant smell, tinnitus and hearing loss. No significant differences between groups were reported. There were no emergencies or serious adverse effects reported in any of the 10 studies.There was very limited or no information available on our remaining secondary outcomes. AUTHORS' CONCLUSIONS: Although a number of studies aimed to evaluate whether or not one type of cerumenolytic is more effective than another, there is no high-quality evidence to allow a firm conclusion to be drawn and the answer remains uncertain.A single study suggests that applying ear drops for five days may result in a greater likelihood of complete wax clearance than no treatment at all. However, we cannot conclude whether one type of active treatment is more effective than another and there was no evidence of a difference in efficacy between oil-based and water-based active treatments.There is no evidence to show that using saline or water alone is better or worse than commercially produced cerumenolytics. Equally, there is also no evidence to show that using saline or water alone is better than no treatment.


Assuntos
Cerume , Meato Acústico Externo , Higiene , Tensoativos/uso terapêutico , Adulto , Antipirina/uso terapêutico , Benzocaína/uso terapêutico , Peróxido de Carbamida , Carbonatos/uso terapêutico , Criança , Clorobutanol/uso terapêutico , Colina/análogos & derivados , Colina/uso terapêutico , Ácido Dioctil Sulfossuccínico/uso terapêutico , Combinação de Medicamentos , Etanolaminas/uso terapêutico , Humanos , Peróxidos/uso terapêutico , Soluções Farmacêuticas/uso terapêutico , Óleos Vegetais/uso terapêutico , Potássio/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Salicilatos/uso terapêutico , Cloreto de Sódio/uso terapêutico , Ureia/análogos & derivados , Ureia/uso terapêutico , Água
19.
Pediatr Pulmonol ; 53(10): 1348-1355, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29905977

RESUMO

BACKGROUND: Dry powder inhalers (DPI) are effective but forceful inhalation required to fluidize the powder may be difficult for children and patients with airway disease. Inspiromatic is a new generation active DPI that actively suspends drugs in synchrony with inhalation. We evaluated safety and efficacy of Formoterol delivery via Inspiromatic, compared to Aerolizer, a conventional DPI, in pediatric asthmatic subjects. METHODS: A phase I/II, randomized, single-center, double-blind, double-dummy, placebo-controlled, cross-over study. Subjects aged 8-18 years with FEV1 40-80% predicted were included. Patients were randomized to inhale Formoterol via the Inspiromatic, immediately followed by the placebo via the Aerolizer or vice versa, in a double-blind fashion. Spirometry, blood pressure, and heart rate were measured at baseline and 15, 30, and 60 min after drug administration. Capsule emptying, comfort of use, confidence in efficacy, and patient satisfaction were assessed. At a subsequent visit, three months later, patients inhaled the active drug via the other DPI. RESULTS: Twenty-nine patients, aged 12.6 (±2.3) years, mean (SD), completed the study. Baseline FEV1 was 69.1 (±6.7) % at visit one and 65.3 (±9) % at visit two. Maximal FEV1 increase was 16.6 (±7.1) % with Inspiromatic and 15.5 (±7.5) % with Aerolizer (P = 0.47). No differences in heart rate or blood pressure were observed; 24/28 capsules were emptied using the Inspiromatic and 19/28 with the Aerolizer (P = 0.5); 21/28 preferred the Inspiromatic and 7/28 the Aerolizer (P < 0.001). There were no adverse events. CONCLUSIONS: Formoterol inhalation via the Inspiromatic is safe and as efficacious as with the Aerolizer. The device is well accepted by asthmatic subjects.


Assuntos
Asma/tratamento farmacológico , Broncodilatadores/administração & dosagem , Inaladores de Pó Seco , Fumarato de Formoterol/administração & dosagem , Administração por Inalação , Adolescente , Asma/fisiopatologia , Pressão Sanguínea , Broncodilatadores/uso terapêutico , Criança , Estudos Cross-Over , Método Duplo-Cego , Etanolaminas/uso terapêutico , Feminino , Volume Expiratório Forçado , Fumarato de Formoterol/uso terapêutico , Frequência Cardíaca , Humanos , Masculino , Satisfação do Paciente , Espirometria
20.
Eur J Pharmacol ; 833: 425-431, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-29913125

RESUMO

The purpose of this study was to evaluate in vitro the effect of the combination of BRL 37344 (ß3-adrenoceptor agonist) with tadalafil (phosphodiesterase type 5 inhibitor) or rolipram (phosphodiesterase type 4 inhibitor) in an experimental model of detrusor overactivity. The experiments were carried out in two phases using bladder strips of mice. In the first phase, on the top of 40 mM potassium-induced contraction, strips isolated from control mice were exposed to increasing concentrations of each study drug. In another series of experiments, prior to contraction, strips were incubated with either tadalafil or rolipram, followed by the addition of increasing concentrations of BRL 37344. In the second phase, the same protocols were performed with animals previously treated with L-NAME for 30 days. Chronic L-NAME administration leads to detrusor overactivity due to nitric oxide synthase inhibition. In phase one, preincubation with tadalafil enhanced relaxation response to BRL 37344 at two concentrations. Pretreatment with rolipram had no effect on BRL 37344-induced relaxation. In L-NAME-treated mice, rolipram induced more relaxation than the other drugs, enhancing relaxation response to BRL 37344 at almost all concentrations, but no synergistic effect with tadalafil was observed. The relaxant effect of BRL 37344 was enhanced by rolipram but not by tadalafil, suggesting that PDE4 inhibition, especially when associated with ß3-adrenoceptor stimulation, could represent a potential treatment for overactive bladder.


Assuntos
Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 5/farmacologia , Bexiga Urinária Hiperativa/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Etanolaminas/farmacologia , Etanolaminas/uso terapêutico , Humanos , Masculino , Camundongos , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/fisiopatologia , NG-Nitroarginina Metil Éster/toxicidade , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Rolipram/farmacologia , Rolipram/uso terapêutico , Tadalafila/farmacologia , Tadalafila/uso terapêutico , Resultado do Tratamento , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/induzido quimicamente , Bexiga Urinária Hiperativa/fisiopatologia
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