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1.
Nat Commun ; 11(1): 1055, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32103022

RESUMO

Activated caspase-1 and caspase-11 induce inflammatory cell death in a process termed pyroptosis. Here we show that Prostaglandin E2 (PGE2) inhibits caspase-11-dependent pyroptosis in murine and human macrophages. PGE2 suppreses caspase-11 expression in murine and human macrophages and in the airways of mice with allergic inflammation. Remarkably, caspase-11-deficient mice are strongly resistant to developing experimental allergic airway inflammation, where PGE2 is known to be protective. Expression of caspase-11 is elevated in the lung of wild type mice with allergic airway inflammation. Blocking PGE2 production with indomethacin enhances, whereas the prostaglandin E1 analog misoprostol inhibits lung caspase-11 expression. Finally, alveolar macrophages from asthma patients exhibit increased expression of caspase-4, a human homologue of caspase-11. Our findings identify PGE2 as a negative regulator of caspase-11-driven pyroptosis and implicate caspase-4/11 as a critical contributor to allergic airway inflammation, with implications for pathophysiology of asthma.


Assuntos
Asma/patologia , Caspases Iniciadoras/metabolismo , Dinoprostona/metabolismo , Macrófagos/imunologia , Piroptose/fisiologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Asma/imunologia , Caspases Iniciadoras/genética , Caspases Iniciadoras/imunologia , Células Cultivadas , Sinergismo Farmacológico , Feminino , Humanos , Indometacina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Misoprostol/farmacologia
2.
Chem Biol Interact ; 321: 108964, 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32006539

RESUMO

Lupeol (1) was isolated from hexane branch extract of Maytenus salicifolia and the Lupeol stearate (2), Lupeol palmitate (3), Lupeol myristate (4), Lupeol laurate (5) and Lupeol caprylate (6) were obtained reacting 1 with an adequate carboxylic acid. Swiss mice were treated with vehicle, carbenoxolone or Lupeol esters before administration of ethanol/HCl or indomethacin. Additionally, the involvement of nitric oxide (NO), sulfhydryl compounds (NP-SH), α-2 adrenergic receptors (α2-AR) and prostaglandins (PGE) in antiulcer effects was investigated using appropriate inhibitors or antagonist. Oxidative and inflammatory parameters were measured after euthanasia and anti-secretory effects was evaluated in pylorus-ligated rats. Ethanol/HCl ulcerated the gastric mucosa by 64.45 ± 6.58 mm2, which the oral treatment with 1, 4 and 6 (10 mg/kg), and 3 and 5 (30 mg/kg) reduced the lesion area. Interestingly, 2 reduced the gastric ulcer by oral route in a potent and dose-dependent manner (ED50 = 0.40 mg/kg), which was accompanied by the increase in reduced glutathione levels and by the reduction of lipids peroxidation and myeloperoxidase and superoxide dismutase activities. Moreover, 2 (0.1 mg/kg) also prevented the ulcerogenesis by intraperitoneal route. The participation of NO, NP-SH, α2-AR and PGE in 2-mediated gastroprotection was confirmed. In indomethacin-induced ulcer, 2 (1 mg/kg, p.o) also reduced the ulcer area and increased the PGE2 levels. However, 2 did not alter the gastric acid secretion. Therefore, these findings indicate that the obtention of 2 potentiated the antiulcer activity of 1 and that this compound can elicit gastroprotective action due a diversified mode of action.


Assuntos
Antiulcerosos/farmacologia , Triterpenos Pentacíclicos/farmacologia , Úlcera Gástrica/prevenção & controle , Animais , Antiulcerosos/administração & dosagem , Antiulcerosos/química , Modelos Animais de Doenças , Esterificação , Etanol/toxicidade , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Ácido Clorídrico/toxicidade , Indometacina/toxicidade , Camundongos , NG-Nitroarginina Metil Éster/metabolismo , Óxido Nítrico/metabolismo , Triterpenos Pentacíclicos/administração & dosagem , Triterpenos Pentacíclicos/química , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo , Relação Estrutura-Atividade
3.
Cochrane Database Syst Rev ; 1: CD010061, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31985831

RESUMO

BACKGROUND: In preterm newborns, the ductus arteriosus frequently fails to close and the infants require medical or surgical closure of the patent ductus arteriosus (PDA). A PDA can be treated surgically; or medically with one of two prostaglandin inhibitors, indomethacin or ibuprofen. Case reports suggest that paracetamol may be an alternative for the closure of a PDA. An association between prenatal or postnatal exposure to paracetamol and later development of autism or autism spectrum disorder has been reported. OBJECTIVES: To determine the effectiveness and safety of intravenous or oral paracetamol compared with placebo or no intervention, intravenous indomethacin, intravenous or oral ibuprofen, or with other cyclo-oxygenase inhibitors for treatment of an echocardiographically diagnosed PDA in preterm or low birth weight infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 10), MEDLINE via PubMed (1966 to 6 November 2017), Embase (1980 to 6 November 2017), and CINAHL (1982 to 6 November 2017). We searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCT) and quasi-randomised trials. SELECTION CRITERIA: We included RCTs in which paracetamol was compared to no intervention, placebo or other agents used for closure of PDA irrespective of dose, duration and mode of administration in preterm (≤ 34 weeks' postmenstrual age) infants. We both reviewed the search results and made a final selection of potentially eligible articles by discussion. We included studies of both prophylactic and therapeutic use of paracetamol. DATA COLLECTION AND ANALYSIS: We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence for the following outcomes when data were available: failure of ductal closure after the first course of treatment; neurodevelopmental impairment; all-cause mortality during initial hospital stay (death); gastrointestinal bleed or stools positive for occult blood; and serum levels of creatinine after treatment (µmol/L). MAIN RESULTS: We included eight studies that reported on 916 infants. One of these studies compared paracetamol to both ibuprofen and indomethacin. Five studies compared treatment of PDA with paracetamol versus ibuprofen and enrolled 559 infants. There was no significant difference between paracetamol and ibuprofen for failure of ductal closure after the first course of drug administration (typical risk ratio (RR) 0.95, 95% confidence interval (CI) 0.75 to 1.21; typical risk difference (RD) -0.02, 95% CI -0.09 to 0.09); I² = 0% for RR and RD; moderate quality of evidence. Four studies (n = 537) reported on gastrointestinal bleed which was lower in the paracetamol group versus the ibuprofen group (typical RR 0.28, 95% CI 0.12 to 0.69; typical RD -0.06, 95% CI -0.09 to -0.02); I² = 0% for RR and RD; number needed to treat for an additional beneficial outcome (NNTB) 17 (95% CI 11 to 50); moderate quality of evidence. The serum levels of creatinine were lower in the paracetamol group compared with the ibuprofen group in four studies (moderate quality of evidence), as were serum bilirubin levels following treatment in two studies (n = 290). Platelet counts and daily urine output were higher in the paracetamol group compared with the ibuprofen group. One study reported on long-term follow-up to 18 to 24 months of age following treatment with paracetamol versus ibuprofen. There were no significant differences in the neurological outcomes at 18 to 24 months (n = 61); (low quality of evidence). Two studies compared prophylactic administration of paracetamol for a PDA with placebo or no intervention in 80 infants. Paracetamol resulted in a lower rate of failure of ductal closure after 4 to 5 days of treatment compared to placebo or no intervention which was of borderline significance for typical RR 0.49 (95% CI 0.24 to 1.00; P = 0.05); but significant for typical RD -0.21 (95% CI -0.41 to -0.02); I² = 0 % for RR and RD; NNTB 5 (95% CI 2 to 50); (low quality of evidence). Two studies (n = 277) compared paracetamol with indomethacin. There was no significant difference in the failure to close a PDA (typical RR 0.96, 95% CI 0.55 to 1.65; I² = 11%; typical RD -0.01, 95% CI -0.09 to 0.08; I² = 17%) (low quality of evidence). Serum creatinine levels were significantly lower in the paracetamol group compared with the indomethacin group and platelet counts and daily urine output were significantly higher in the paracetamol group. AUTHORS' CONCLUSIONS: Moderate-quality evidence according to GRADE suggests that paracetamol is as effective as ibuprofen; low-quality evidence suggests paracetamol to be more effective than placebo or no intervention; and low-quality evidence suggests paracetamol as effective as indomethacin in closing a PDA. There was no difference in neurodevelopmental outcome in children exposed to paracetamol compared to ibuprofen; however the quality of evidence is low and comes from only one study. In view of concerns raised regarding neurodevelopmental outcomes following prenatal and postnatal exposure to paracetamol, long-term follow-up to at least 18 to 24 months' postnatal age must be incorporated in any studies of paracetamol in the newborn population. At least 19 ongoing trials have been registered. Such trials are required before any recommendations for the possible routine use of paracetamol in the newborn population can be made.


Assuntos
Acetaminofen/efeitos adversos , Acetaminofen/uso terapêutico , Permeabilidade do Canal Arterial/tratamento farmacológico , Recém-Nascido de Baixo Peso , Recém-Nascido Prematuro , Inibidores de Ciclo-Oxigenase/uso terapêutico , Humanos , Ibuprofeno/uso terapêutico , Indometacina/uso terapêutico , Recém-Nascido , Razão de Chances , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
Cochrane Database Syst Rev ; 1: CD004213, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31985838

RESUMO

BACKGROUND: Patent ductus arteriosus (PDA) complicates the clinical course of preterm infants and increases the risk of adverse outcomes. Indomethacin has been the standard treatment to close a PDA but is associated with renal, gastrointestinal, and cerebral side effects. Ibuprofen has less effect on blood flow velocity to important organs. OBJECTIVES: Primary objectives To determine the effectiveness and safety of ibuprofen compared to placebo/no intervention, or other cyclo-oxygenase inhibitor drugs in the prevention of PDA in preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 10), MEDLINE via PubMed (1966 to 17 October 2018), Embase (1980 to 17 October 2018), and CINAHL; 1982 to 17 October 2018). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing ibuprofen with placebo/no intervention or other cyclo-oxygenase inhibitor drugs to prevent PDA in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: We extracted outcomes data including presence of PDA on day three or four of life (after 72 hours of treatment), need for surgical ligation or rescue treatment with cyclo-oxygenase inhibitors, mortality, cerebral, renal, pulmonary, and gastrointestinal complications. We performed meta-analyses and reported treatment estimates as typical mean difference (MD), risk ratio (RR), risk difference (RD) and, if statistically significant, number needed to treat to benefit (NNTB) or to harm (NNTH), along with their 95% confidence intervals (CI). We assessed between-study heterogeneity by the I-squared test (I²). We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: In this updated analysis, we included nine trials (N = 1070 infants) comparing prophylactic ibuprofen (IV or oral) with placebo/no intervention or indomethacin. Ibuprofen (IV or oral) probably decreases the risk of PDA on day 3 or 4 (typical RR 0.39, 95% CI 0.31 to 0.48; typical RD -0.26, 95% CI -0.31 to -0.21; NNTB 4, 95% CI 3 to 5; 9 trials; N = 1029) (moderate-quality evidence). In the control group, the spontaneous closure rate was 58% by day 3 to 4 of age. In addition, ibuprofen probably decreases the need for rescue treatment with cyclo-oxygenase inhibitors (typical RR 0.17, 95% CI 0.11 to 0.26; typical RD -0.27, 95% CI -0.32 to -0.22; NNTB 4; 95% CI 3 to 5),and the need for surgical ductal ligation (typical RR 0.46, 95% CI 0.22 to 0.96; typical RD -0.03, 95% CI -0.05 to -0.00; NNTB 33, 95% CI 20 to infinity; 7 trials; N = 925) (moderate-quality evidence). There was a possible decrease in the risk of grade 3 or 4 intraventricular haemorrhage (IVH) in infants receiving prophylactic ibuprofen (typical RR 0.67, 95% CI 0.45 to 1.00; I² = 34%; typical RD -0.04, 95% CI -0.08 to- 0.00; I² = 60%; 7 trials; N = 925) (moderate-quality evidence). High quality evidence showed increased risk for oliguria (typical RR 1.45, 95% CI 1.04 to 2.02; typical RD 0.06, 95% CI 0.01 to 0.11; NNTH 17, 95% CI 9 to 100; 4 trials; N = 747). Low quality results from four studies (N = 202) showed that administering oral ibuprofen may decrease the risk of PDA (typical RR 0.47, 95% CI 0.30 to 0.74) and may increase risk of gastrointestinal bleeding (NNTH 7, 95% CI 4 to 25). No evidence of a difference was identified for mortality, any intraventricular haemorrhage (IVH), or chronic lung disease. AUTHORS' CONCLUSIONS: This review shows that prophylactic use of ibuprofen, compared to placebo or no intervention, probably decreases the incidence of patent ductus arteriosus, the need for rescue treatment with cyclo-oxygenase inhibitors, and for surgical ductal closure. Adverse effects associated with ibuprofen (IV or oral) included increased risks for oliguria, increase in serum creatinine levels, and increased risk of gastrointestinal haemorrhage. There was a reduced risk for intraventricular haemorrhage (grade III - IV) but no evidence of a difference in mortality, chronic lung disease, necrotising enterocolitis, or time to reach full feeds. In the control group, the patent ductus arteriosus had closed spontaneously by day 3 or 4 in 58% of neonates. Prophylactic treatment exposes a large proportion of infants unnecessarily to a drug that has important side effects without conferring any important short-term benefits. Current evidence does not support the use of ibuprofen for prevention of patent ductus arteriosus. Until long-term follow-up results of the trials included in this review have been published, no further trials of prophylactic ibuprofen are recommended. A new approach to patent ductus arteriosus management is an early targeted treatment based on echocardiographic criteria within the first 72 hours of life, that have a high sensitivity for diagnosing a patent ductus arteriosus that is unlikely to close spontaneously. Such trials are currently ongoing in many parts of the world. Results of such trials will be included in updates of our "Ibuprofen for treatment of PDA" review.


Assuntos
Inibidores de Ciclo-Oxigenase/uso terapêutico , Permeabilidade do Canal Arterial/prevenção & controle , Ibuprofeno/efeitos adversos , Ibuprofeno/uso terapêutico , Hemorragia Cerebral/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Enterocolite Necrosante/induzido quimicamente , Inibidores Enzimáticos/uso terapêutico , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Indometacina/uso terapêutico , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
J Biochem Mol Toxicol ; 34(2): e22433, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31916655

RESUMO

Colorectal cancer (CRC) is the third most common fatal cancer. Indomethacin, a nonsteroidal anti-inflammatory drug, is known to reduce the occurrence of CRC. This study evaluated the potential anticolon cancer effects of juglone (5-hydroxy-1,4-naphthoquinone) in combination with indomethacin. Human colon adenocarcinoma cells (HT29) were subjected to treatment with indomethacin, juglone, and a combination of both. Morphological analysis, cell cycle regulation, and dual staining using acridine orange and ethidium bromide in control and treated cells revealed the apoptotic potential of these compounds. Bcl2 and inflammatory molecules (tumor necrosis factor-α, nuclear factor kappa B, and Cox-2) were found to be decreased with a concomitant increase in the expression of proapoptotic molecules (Bad, Bax, cytochrome c, and PUMA) as a result of the molecular regulation of Wnt, Notch, and peroxisome proliferator-activated receptor-γ signaling. Treatment with juglone was not as effective as with indomethacin; however, a combination of both was shown to be more effective, suggesting that juglone may be considered for therapeutic intervention of colon cancer.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Indometacina/farmacologia , Mediadores da Inflamação/metabolismo , Naftoquinonas/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Antineoplásicos/uso terapêutico , Proteínas Reguladoras de Apoptose/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Sinergismo Farmacológico , Células HT29 , Humanos , Indometacina/uso terapêutico , Concentração Inibidora 50 , Naftoquinonas/uso terapêutico , PPAR gama/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Via de Sinalização Wnt
6.
Life Sci ; 243: 117257, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31917992

RESUMO

Electrical field stimulation (EFS) has been used for decades in classical pharmacological preparations in order to characterize the mediators released by neural endings involved in smooth muscle contraction or relaxation. Since most of the human umbilical cord has no innervation, EFS has never been used in this preparation. This study aimed to investigate the effect of EFS on vascular responsiveness from human umbilical cord. Segments of the human umbilical cord were obtained from normotensive parturients and the human umbilical artery (HUA) and the human umbilical vein (HUV) were isolated and mounted in organ bath chambers. Electrical field stimulation-induced contractions in both HUA (2.35 ±â€¯1.31 mN and 3.77 ±â€¯2.31 mN for 8 Hz and 16 Hz respectively, n = 24) and HUV (3.81 ±â€¯2.54 mN and 6.26 ±â€¯4.51 mN for 8 Hz and 16 Hz respectively, n = 25). The addition of tetrodotoxin (1 µM) did not alter the EFS-induced contractions in both tissues (n = 5). Pre-incubation with atropine (10 and 100 µM), glibenclamide (10 µM) and indomethacin (10 µM) did not affect the EFS-induced contractions in both tissues. The contractions of both vessels were significantly reduced by pre-incubation of the tissues with phentolamine (10 and 100 µM). The endothelium removal almost abolished the EFS- induced contractions in both vessels (n = 5). In sandwich preparation, donor tissue (with endothelium) released a factor (s) that promoted contraction of the recipient tissue (endothelium removal) in both HUA and HUV (n = 5, respectively). Our findings indicate a potential role of endothelium-derived catecholamines in modulating HUA and HUV reactivities.


Assuntos
Vasos Sanguíneos/fisiologia , Estimulação Elétrica , Cordão Umbilical/irrigação sanguínea , Adulto , Atropina/farmacologia , Vasos Sanguíneos/efeitos dos fármacos , Glibureto/farmacologia , Humanos , Indometacina/farmacologia , Contração Muscular/efeitos dos fármacos , Tetrodotoxina/farmacologia , Adulto Jovem
7.
AAPS PharmSciTech ; 21(2): 41, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31898765

RESUMO

Coamorphous formulation, a homogeneous monophasic amorphous system composed of multiple components, has been demonstrated as an effective approach for delivering drugs with poor aqueous solubility. In this study, we prepared the coamorphous system composed of two poorly soluble drugs febuxostat (FEB) and indomethacin (IMC) by using cryogenic milling. The combination of these two drugs in the coamorphous form can attain a synergistic effect, especially on gout therapy. Coamorphous solid of FEB and IMC in 1:1 molar ratio exhibited superior physical stability compared with the individual amorphous components, as evidenced by X-ray powder diffractions after 30 days of storage at ambient and elevated temperature. In addition, the FEB-IMC coamorphous system has been demonstrated to show enhanced dissolution performance. The intrinsic dissolution rates of two components in the coamorphous system exhibited the synchronized drug release. Based on the FT-IR spectroscopy, the excellent physical stability and synchronized release of FEB-IMC coamorphous system could be attributed to the heterodimer structure formed by strong hydrogen bonding interactions between these drugs. Furthermore, the supersaturation potential of FEB-IMC coamorphous solids was also investigated through the cosolvent quenching method. The FEB-IMC coamorphous system can effectively inhibit the fast crystallization of FEB in the supersaturated solution. However, the maximum achievable supersaturation of IMC in the coamorphous system decreases to only one fifth of that achieved for the pure amorphous IMC. These results are relevant for understanding the physical stability and complex solution behaviors of the coamorphous formulation.


Assuntos
Febuxostat/química , Supressores da Gota/química , Indometacina/química , Cromatografia Líquida de Alta Pressão , Combinação de Medicamentos , Composição de Medicamentos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Febuxostat/administração & dosagem , Supressores da Gota/administração & dosagem , Ligação de Hidrogênio , Indometacina/administração & dosagem , Pós , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
8.
Am J Physiol Regul Integr Comp Physiol ; 318(2): R468-R479, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31868517

RESUMO

Cyclooxygenase (COX) is proposed to regulate cerebral blood flow (CBF); however, accurate regional contributions of COX are relatively unknown at baseline and particularly during hypoxia. We hypothesized that COX contributes to both basal and hypoxic cerebral vasodilation, but COX-mediated vasodilation is greater in the posterior versus anterior cerebral circulation. CBF was measured in 9 healthy adults (28 ± 4 yr) during normoxia and isocapnic hypoxia (fraction of inspired oxygen = 0.11), with COX inhibition (oral indomethacin, 100mg) or placebo. Four-dimensional flow magnetic resonance imaging measured cross-sectional area (CSA) and blood velocity to quantify CBF in 11 cerebral arteries. Cerebrovascular conductance (CVC) was calculated (CVC = CBF × 100/mean arterial blood pressure) and hypoxic reactivity was expressed as absolute and relative change in CVC [ΔCVC/Δ pulse oximetry oxygen saturation (SpO2)]. At normoxic baseline, indomethacin reduced CVC by 44 ± 5% (P < 0.001) and artery CSA (P < 0.001), which was similar across arteries. Hypoxia (SpO2 80%-83%) increased CVC (P < 0.01), reflected as a similar relative increase in reactivity (% ΔCVC/-ΔSpO2) across arteries (P < 0.05), in part because of increases in CSA (P < 0.05). Indomethacin did not alter ΔCVC or ΔCVC/ΔSpO2 to hypoxia. These findings indicate that 1) COX contributes, in a largely uniform fashion, to cerebrovascular tone during normoxia and 2) COX is not obligatory for hypoxic vasodilation in any regions supplied by large extracranial or intracranial arteries.


Assuntos
Artérias Cerebrais/enzimologia , Circulação Cerebrovascular , Hipóxia/enzimologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Vasodilatação , Adulto , Biomarcadores/sangue , Velocidade do Fluxo Sanguíneo , Artérias Cerebrais/diagnóstico por imagem , Artérias Cerebrais/efeitos dos fármacos , Artérias Cerebrais/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Hipóxia/sangue , Hipóxia/diagnóstico por imagem , Hipóxia/fisiopatologia , Indometacina/administração & dosagem , Masculino , Oxigênio/sangue , Distribuição Aleatória , Vasodilatação/efeitos dos fármacos , Adulto Jovem
9.
mBio ; 10(6)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848271

RESUMO

Cryptococcus neoformans can cause fatal meningoencephalitis in patients with AIDS or other immunocompromising conditions. Current antifungals are suboptimal to treat this disease; therefore, novel targets and new therapies are needed. Previously, we have shown that chitosan is a critical component of the cryptococcal cell wall and is required for survival in the mammalian host and that chitosan deficiency results in rapid clearance from the mammalian host. We had also identified several specific proteins that were required for chitosan biosynthesis, and we hypothesize that screening for compounds that inhibit chitosan biosynthesis would identify additional genes/proteins that influence chitosan biosynthesis. To identify these compounds, we developed a robust and novel cell-based flow cytometry screening method to identify small-molecule inhibitors of chitosan production. We screened the ICCB Known Bioactives library and identified 8 compounds that reduced chitosan in C. neoformans We used flow cytometry-based counterscreens and confirmatory screens, followed by a biochemical secondary screen to refine our primary screening hits to 2 confirmed hits. One of the confirmed hits that reduced chitosan content was the aminoalkylindole BML-190, a known inverse agonist of mammalian cannabinoid receptors. We demonstrated that BML-190 likely targets the C. neoformans G-protein-coupled receptor Gpr4 and, via the cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway, contributes to an intracellular accumulation of cAMP that results in decreased chitosan. Our discovery suggests that this approach could be used to identify additional compounds and pathways that reduce chitosan biosynthesis and could lead to potential novel therapeutics against C. neoformans IMPORTANCE Cryptococcus neoformans is a fungal pathogen that kills ∼200,000 people every year. The cell wall is an essential organelle that protects fungi from the environment. Chitosan, the deacetylated form of chitin, has been shown to be an essential component of the cryptococcal cell wall during infection of a mammalian host. In this study, we screened a set of 480 compounds, which are known to have defined biological activities, for activity that reduced chitosan production in C. neoformans Two of these compounds were confirmed using an alternative method of measuring chitosan, and one of these was demonstrated to impact the cAMP signal transduction pathway. This work demonstrates that the cAMP pathway regulates chitosan biosynthesis in C. neoformans and validates that this screening approach could be used to find potential antifungal agents.


Assuntos
Quitosana/metabolismo , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Indometacina/análogos & derivados , Modelos Biológicos , Morfolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fenômenos Químicos , Descoberta de Drogas , Indometacina/química , Indometacina/farmacologia , Estrutura Molecular , Morfolinas/química , Receptores Acoplados a Proteínas-G/metabolismo
10.
Eur J Pharm Biopharm ; 145: 113-120, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31682903

RESUMO

Lipid-based drug delivery systems (LBDDS) are highly relevant as pharmaceutical formulations significantly enhancing the bioavailability of active pharmaceutical ingredients (APIs). These formulations often are complex mixtures of APIs, various lipids, and other excipients (e.g. surfactants). In their simplest form, LBDDS contain one API being dissolved in a pure lipid, which often is a triglyceride (TG). In this work, solubilities of the APIs indomethacin, ibuprofen, and fenofibrate in pure TGs of different chain lengths (C chain 8-18) and degree of saturation were investigated. Solubilities of APIs in TGs were measured via differential scanning calorimetry, hot-stage microscopy, high-performance liquid chromatography, and Raman spectroscopy. The influence of fatty-acid chain length and degree of saturation on the API solubility in the TGs was investigated. APIs showed a higher solubility in saturated (wIBU = 10.5 wt% at 25 °C in tricaprylin) TGs compared to unsaturated ones (wIBU = 4.0 wt% at 25 °C in triolein). The fatty-acid chain length of TGs only slightly affects the solubility of ibuprofen and fenofibrate, but strongly influences the eutectic temperature of the API/TG mixtures. API solubilities in TGs and TG mixtures (mixtures of tricaprylin and tricaprin) were successfully modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) accounting for the intermolecular API/TG interactions providing a deep understanding of the energetic and structural impact of the TGs on API solubility.


Assuntos
Preparações Farmacêuticas/química , Solubilidade/efeitos dos fármacos , Triglicerídeos/química , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Excipientes/química , Fenofibrato/química , Ibuprofeno/química , Indometacina/química , Lipídeos/química
11.
Life Sci ; 239: 117039, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31704447

RESUMO

AIMS: Obesity is a risk factor for endothelial dysfunction, the severity of which is likely to vary depending on extent and impact of adiposity on the vasculature. This study investigates the roles of cyclooxygenase isoforms and thromboxane receptor activities in the differential endothelial dilatory capacities of arteries derived from omental and subcutaneous adipose tissues in obesity. MAIN METHODS: Small arteries were isolated from omental and subcutaneous adipose tissues obtained from consented morbidly obese patients (n = 65, BMI 45 ±â€¯6 kg m-2 [Mean ±â€¯SD]) undergoing bariatric surgery. Relaxation to acetylcholine was studied by wire myography in the absence or presence of indomethacin (10 µM, cyclooxygenase inhibitor), FR122047 (1 µM, cyclooxygenase-1 inhibitor), Celecoxib (4 µM, cyclooxygenase-2 inhibitor), Nω-Nitro-L-arginine methyl ester (L-NAME, 100 µM, nitric oxide synthase inhibitor) or combination of apamin (0.5 µM) and charybdotoxin (0.1 µM) that together inhibit endothelium-derived hyperpolarizing factor (EDHF). Contractions to U46619 (thromboxane A2 mimetic) were also studied. KEY FINDINGS: Acetylcholine relaxation was significantly attenuated in omental compared with subcutaneous arteries from same patients (p < 0.01). Indomethacin (p < 0.01) and FR122047 (p < 0.001) but not Celecoxib significantly improved the omental arteriolar relaxation. Cyclooxygenase-1 mRNA and U46619 contractions were both increased in omental compared with subcutaneous arteries (p < 0.05). L-NAME comparably inhibited acetylcholine relaxation in both arteries, while apamin+charybdotoxin were less effective in omental compared with subcutaneous arteries. SIGNIFICANCE: The results show that the depot-specific reduction in endothelial dilatory capacity of omental compared with subcutaneous arteries in obesity is in large part due to altered cyclooxygenase-1 and enhanced thromboxane receptor activities, which cause EDHF deficiency.


Assuntos
Ciclo-Oxigenase 1/metabolismo , Artéria Gastroepiploica/efeitos dos fármacos , Receptores de Tromboxanos/metabolismo , Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/metabolismo , Adulto , Apamina/farmacologia , Artérias/efeitos dos fármacos , Celecoxib/farmacologia , Charibdotoxina/farmacologia , Ciclo-Oxigenase 1/fisiologia , Inibidores de Ciclo-Oxigenase/farmacologia , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Endotélio Vascular/efeitos dos fármacos , Feminino , Artéria Gastroepiploica/metabolismo , Humanos , Indometacina/farmacologia , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Obesidade Mórbida/metabolismo , Omento/irrigação sanguínea , Omento/metabolismo , Receptores de Tromboxanos/fisiologia , Vasodilatação/efeitos dos fármacos
12.
AAPS PharmSciTech ; 20(8): 330, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31677079

RESUMO

The present work attempts to develop and optimize the formula of a lipidic nanoemulsion (NE) containing sodium hyaluronate (HNa) and indomethacin (Ind) as HNa-Ind for enhanced transdermal antiarthritic activity. NEs were prepared by the spontaneous emulsification method and characterized by Fourier-transform infrared (FTIR) spectroscopy. The composition of the optimal formulation was statistically optimized using Box-Behnken experimental design method with three independent factors and was characterized for particle size, polydispersity index, and percent transmittance. The selected formula was tested for its in vitro antioxidant activity and in vivo anti-inflammatory activity. The optimized HNa-Ind NE formula was characterized and displayed a particle size of 12.87 ± 0.032 nm, polydispersity index of 0.606 ± 0.082, and 99.4 ± 0.1 percentage of transmittance. FTIR showed no interaction between HNa and Ind as a physical mixture. In addition, the optimized HNa-Ind NE was able to preserve the antioxidant ability of the two drugs, as evidenced through a 2,2-diphenyl-1-picrylhydrazyl (DPPH) inhibition assay used to assess free radical scavenging ability. The cell viability was increased while the free radical scavenging activity was decreased (94.28% inhibition at higher concentrations compared with vitamin C as a reference with an inhibition of 100%). Moreover, the pharmacological anti-inflammatory potential of the optimized HNa-Ind NE formulation was assessed using an in vivo model. Compared with reference drugs (ibuprofen gel 5%), the remarkable activity of the optimized formulation was established using xylene-induced ear edema in mice model, in which the inflamed region reduced by 92.5% upon treatment. The optimized HNa-Ind NE formulation showed considerably higher skin permeation and drug deposition capability compared with the HNa-Ind solution. HNa-Ind NE was demonstrated to be a successful carrier with enhanced antioxidant and anti-inflammatory potential while showing better skin penetration, thus being a promising vehicle for transdermal drug delivery.


Assuntos
Desenvolvimento de Medicamentos/métodos , Ácido Hialurônico/síntese química , Indometacina/síntese química , Nanopartículas/química , Administração Cutânea , Animais , Emulsões , Feminino , Indometacina/metabolismo , Lipídeos , Masculino , Camundongos , Nanopartículas/metabolismo , Tamanho da Partícula , Absorção Cutânea/efeitos dos fármacos , Absorção Cutânea/fisiologia
13.
Pharm Res ; 36(12): 175, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31677137

RESUMO

PURPOSE: Traditional methods for estimating drug-polymer solubility either require fast dissolution in the polymeric matrix, rapid re-crystallization kinetics from supersaturated states or derive from regular solution theories. In this work, we present a new method for determining drug solubility, purely based on thermodynamic considerations, that uses only experimental data from DSC for calculations. METHODS: The new thermodynamic model presented combines DSC analysis and application of Hess's law to determine free energies of conversion of binary mixtures to amorphous solid dispersions, free energies of mixing as well as solubility as a function of temperature. The model drug indomethacin and polymers HPMCAS LF, PVP K29/32 and Eudragit EPO were used in these studies. RESULTS: Free energies were calculated as a function of temperature, for different drug-polymer compositions and the results show that HPMCAS LF solid dispersion with high drug content are less thermodynamically favorable compared to other polymer systems. Solubility of indomethacin in HPMCAS LF, PVP K29/32 and Eudragit EPO was 24, 55 and 56% w/w, respectively, at 25°C. CONCLUSIONS: The thermodynamic model presented has great advantages over traditional methods. It does not require estimation of any interaction parameters, it is almost assumption-free and uses only thermal data for calculations.


Assuntos
Composição de Medicamentos/métodos , Indometacina/química , Modelos Moleculares , Polímeros/química , Cristalização , Estabilidade de Medicamentos , Cinética , Metilcelulose/análogos & derivados , Metilcelulose/química , Ácidos Polimetacrílicos/química , Povidona/química , Solubilidade , Termodinâmica , Temperatura de Transição
14.
Molecules ; 24(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614601

RESUMO

To develop new anti-inflammatory agents, a series of 7-O-amide hesperetin derivatives was designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. All compounds showed inhibitory effect on LPS-induced NO production. Among them, 7-O-(2-(Propylamino)-2-oxoethyl)hesperetin (4d) and 7-O-(2-(Cyclopentylamino)-2-oxoethyl)hesperetin (4k) with hydrophobic side chains exhibited the most potent NO inhibitory activity (IC50 = 19.32 and 16.63 µM, respectively), showing stronger inhibitory effect on the production of pro- inflammatory cytokines tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) than indomethacin and celecoxib at 10 µM. The structure-activity relationships (SARs) suggested that the 7-O-amide unit was buried in a medium-sized hydrophobic cavity of the bound receptor. Furthermore, compound 4d could also significantly suppress the expression of inducible nitric oxide synthase enzymes (iNOS) and cyclooxygenase-2 (COX-2), through the nuclear factor-kappa B (NF-κB) signaling pathway.


Assuntos
Hesperidina/química , Hesperidina/farmacologia , Inflamação/tratamento farmacológico , Óxido Nítrico/biossíntese , Animais , Celecoxib/farmacologia , Ciclo-Oxigenase 2/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hesperidina/síntese química , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Indometacina/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-6/genética , Camundongos , NF-kappa B/genética , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/genética , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/genética
15.
Int J Mol Sci ; 20(20)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31600995

RESUMO

Indomethacin (IMC)-induced gastrointestinal (GI) injuries are more common in rheumatoid arthritis (RA) patients than in other IMC users, and the overexpression of nitric oxide (NO) via inducible NO synthase (iNOS) is related to the seriousness of IMC-induced GI injuries. However, sufficient strategies to prevent IMC-induced GI injuries have not yet been established. In this study, we designed dispersions of rebamipide (RBM) solid nanocrystals (particle size: 30-190 nm) by a bead mill method (RBM-NDs), and investigated whether the oral administration of RBM-NDs is useful to prevent IMC-induced GI injuries. The RBM nanocrystals were spherical and had a solubility 4.71-fold greater than dispersions of traditional RBM powder (RBM-TDs). In addition, the RBM-NDs were stable for 1 month after preparation. The RBM contents in the stomach, jejunum, and ileum of rats orally administered RBM-NDs were significantly higher than in rats administered RBM-TDs. Moreover, the oral administration of RBM-NDs decreased the NO levels via iNOS and area of the GI lesions in IMC-stimulated RA (adjuvant-induced arthritis rat) rats in comparison with the oral administration of RBM-TDs. Thus, we show that the oral administration of RBM-NDs provides a high drug supply to the GI mucosa, resulting in a therapeutic effect on IMC-induced GI injuries. Solid nanocrystalline RBM preparations may offer effective therapy for RA patients.


Assuntos
Alanina/análogos & derivados , Anti-Inflamatórios não Esteroides/efeitos adversos , Hemorragia Gastrointestinal/etiologia , Indometacina/efeitos adversos , Nanopartículas , Quinolonas/administração & dosagem , Alanina/administração & dosagem , Animais , Hemorragia Gastrointestinal/tratamento farmacológico , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Nanopartículas/química , Nanopartículas/ultraestrutura , Óxido Nítrico/metabolismo , Ratos , Difração de Raios X
16.
Medicine (Baltimore) ; 98(40): e17359, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577731

RESUMO

INTRODUCTION: The clinical and genetic characteristics of nephrogenic diabetes insipidus (NDI) were described via assessing 2 cases of NDI patients from a Chinese family. PATIENT CONCERNS: Two patients who manifest polyuria and polydipsia were admitted to hospital for definite diagnosis. DIAGNOSIS: Water deprivation-vasopressin tests showed that the patients may possess renal-origin diabetes insipidus. All the levels of thyroid-stimulating hormone, luteinizing hormone, follicle stimulation hormone, adrenocorticotropic hormone, prolactin, and growth hormone in both patients were normal. These results were certified that both patients possess a nephropathy-type diabetes insipidus. B-mode ultrasonography and urinalysis test demonstrated that the patient's diabetes insipidus is unlikely to originate from renal organic disease. Remarkably, by nucleotide sequencing, we found a novel mutation c.414_418del in arginine-vasopressin receptor 2 (AVPR2) was related to the disease of NDI. INTERVENTIONS: Two patients were treated with oral hydrochlorothiazide and indomethacin. In addition, low salt diet and potassium supplementation throughout the patients' treatment. OUTCOMES: The clinical symptoms of 2 patients were significantly reduced after targeted therapy. CONCLUSION: A mutation in AVPR2 was discovered to be associated with NID. It provides a new target for molecular diagnosis of NDI, enabling families to undergo genetic counseling and obtain prenatal diagnoses.


Assuntos
Diabetes Insípido Nefrogênico/genética , Receptores de Vasopressinas/genética , Grupo com Ancestrais do Continente Asiático , Diabetes Insípido Nefrogênico/diagnóstico , Diabetes Insípido Nefrogênico/tratamento farmacológico , Humanos , Hidroclorotiazida/uso terapêutico , Indometacina/uso terapêutico
17.
Chem Pharm Bull (Tokyo) ; 67(10): 1050-1060, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582625

RESUMO

Universal nanocrystal formulation which can be applied to water-insoluble compounds was proposed and the criteria of its physicochemical properties as an active pharmaceutical ingredients (API) were investigated. Nanocrystal suspension was prepared by a wet-beads milling method. An acceptable Critical Quality Attributes (CQA) of nanocrystal suspension was defined by Z-average less than 500 nm and Polydispersity index (PDI) less than 0.3. Screening studies of dispersing and wetting agents were conducted using three model compounds in different pKa, melting points, etc., to find universal nanocrystal formulation. The effect of four structurally different polymer species (hydroxypropyl cellulose (HPC), hydoroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA)) and their different grades or five different surfactants (docusate sodium (DOSS), sodium lauryl sulfate (SLS), cetyl trimethyl ammonium bromide (CTAB), polysolbate80 (PS80), and polyoxyethylene castor oil (CO-35)) were studied on the re-dispersion stability. It was found that the combination of 4% (w/v) HPC-SSL and 0.2% (w/v) DOSS was the most robust nanocrystal formulation owing to Z-average less than 200 nm and good re-dispersion stability without aggregates at pH 1.2 and pH 6.8. API physicochemical properties were also identified using ten water-insoluble compounds. Consequently, it was found that solubility (water, pH 1.2 and pH 6.8), molecular weight, hydrogen bonding acceptor and the ratio of log D7.4 to C Log P were critical factors.


Assuntos
Composição de Medicamentos , Fenofibrato/química , Indometacina/química , Nanopartículas/química , Nifedipino/química , Físico-Química , Concentração de Íons de Hidrogênio , Tamanho da Partícula , Polímeros/química , Solubilidade , Propriedades de Superfície , Tensoativos/química
18.
J Stroke Cerebrovasc Dis ; 28(12): 104443, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31611169

RESUMO

We herein report the case of a 45-year-old woman who developed a continuous hemicranial headache subsequent to vertebral artery dissection (VAD). After remission of VAD, the patient repeatedly experienced right forehead and temporal region throbbing headache, accompanied by nausea, ocular hyperemia and lacrimation of the right eye, nasal congestion, and rhinorrhea. Magnetic resonance angiography did not reveal the recurrence of dissection. Daily use of indomethacin (190.8 mg/day) showed an excellent effect on the headache, suggesting that the patient had developed hemicrania continua subsequent to VAD.


Assuntos
Cefaleia/etiologia , Dissecação da Artéria Vertebral/complicações , Inibidores de Ciclo-Oxigenase/uso terapêutico , Feminino , Cefaleia/diagnóstico , Cefaleia/tratamento farmacológico , Humanos , Indometacina/uso terapêutico , Pessoa de Meia-Idade , Resultado do Tratamento , Dissecação da Artéria Vertebral/diagnóstico por imagem
19.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(4): 562-565, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31484622

RESUMO

Acute pancreatitis(AP)is an inflammatory condition of the pancreas following the activationt of pancreatic enzymes induced by a variety of factors,with or without other organ dysfunction.The production and release of inflammatory factors is generally considered as a key link during pathogenesis.Non-steroidal anti-inflammatory drugs(NSAIDs)are the most commonly applied agents for inflammatory diseases.Many studies have proved that indomethacin can reduce the risk of pancreatitis after endoscopic retrograde cholangiopancreatography;however,few high-quality evidences have demonstrated the roles of NSAIDs in treating,rather than preventing AP.Most animal experiments have shown that NSAIDs can protect organs,although the currently available findings remained inconsistent.Randomized controlled trials with large sample sizes are warranted to elucidate the roles of NSAIDs in treating AP.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Pancreatite/tratamento farmacológico , Animais , Colangiopancreatografia Retrógrada Endoscópica , Humanos , Indometacina/uso terapêutico
20.
Chem Pharm Bull (Tokyo) ; 67(9): 921-928, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474730

RESUMO

We studied the possibility of using ursodeoxycholic acid (UDCA) as an excipient to create an amorphous composite that can be administered to animals in preclinical studies of experimental drugs. Three UDCA-based amorphous samples composed of nifedipine (NIF), indomethacin (IND), and naproxen (NAP) were found by screening. The UDCA-based formulations were adjudged amorphous by solid-state analysis using X-ray powder diffraction and differential scanning calorimetry. In addition, amorphous samples of NIF-UDCA, IND-UDCA, and NAP-UDCA did not crystallize while in 1% methyl cellulose (MC) solution for 120 min, although an amorphous solid dispersion of NIF-poly(vinylpyrrolidone) (PVP) crystallized rapidly. The low hygroscopicity of UDCA helps NIF maintain an amorphous state in 1% MC solution. The UDCA-based amorphous composites can be administered as suspended formulations to animals in preclinical studies.


Assuntos
Composição de Medicamentos , Preparações Farmacêuticas/química , Ácido Ursodesoxicólico/química , Varredura Diferencial de Calorimetria , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Indometacina/química , Naproxeno/química , Nifedipino/química , Solubilidade
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