RESUMEN
OBJECTIVE: Endogenous prostaglandins are involved in hemostasis, renal excretion of electrolytes, and implicated in dysmenorrhea. Piroxicam and Nitroglycerin are common drugs used in treating dysmenorrhea by inhibiting the cyclooxygenase pathway involved in prostaglandin production. However, studies comparing the effects of these drugs on prostaglandin-modulated hemostasis and renal function are lacking. METHODS: Fifteen female rats (120-160g) were divided into 3 groups (20 per group), namely Control (distilled water, 0.3 mL), Piroxicam treated (3mg/kg) and Nitroglycerin treated (1 mg/kg). Di-estrous phase was confirmed in animals in each group using the Pipette smear method. Treatment was administered for 4 days covering the estrous cycle. Bleeding and clotting time were assessed and blood concentrations of sodium, potassium, urea and platelet counts were evaluated in all phases. Data were analyzed using one-way ANOVA and Newman-Keuls post-hoc test. Statistical significance was considered at p<0.0. RESULTS: The nitroglycerin-treated group showed significant increases in blood potassium during di-estrous while the piroxicam-treated group showed significant increases in blood potassium, urea and clotting time with a significant decrease in sodium levels during di-estrous compared to controls. Results obtained in other phases were not significant compared to controls. CONCLUSIONS: The study showed that Nitroglycerin produces minimum alteration of blood and electrolyte indices compared to piroxicam during di-estrous.
Asunto(s)
Nitroglicerina , Piroxicam , Humanos , Femenino , Ratas , Animales , Piroxicam/farmacología , Piroxicam/uso terapéutico , Ratas Wistar , Nitroglicerina/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Prostaglandinas , Dismenorrea , Urea/farmacología , Sodio , Electrólitos , PotasioRESUMEN
OBJECTIVE: To evaluate the participation of the phosphatidylinositol 3-kinase pathway in the liver damage caused by nimesulide. METHODS: Liver damage been induced by nimesulide. Mice were treated with either 2% dimethyl sulfoxide or AS605240, a phosphatidylinositol 3-kinase gamma pathway antagonist. Blood samples were collected for function assays of liver. The liver was removed for analysis of liver weight/animal weight ratio, histopathological parameters, oxidative and nitrous stress, cytokine levels, and the immunostaining for cyclooxygenase 2 and nuclear factor kappa B. KEY FINDINGS: Liver injured by nimesulide and treated with phosphatidylinositol 3-kinase gamma inhibitor significantly reversed (P < 0.05) the damage; it decreased the liver weight/animal weight ratio, histopathological scores, and neutrophil infiltration, consequently reducing oxidative stress. In addition, we show that phosphatidylinositol 3-kinase gamma is associated with hepatic damage induced by nimesulide, because it altered liver function and increased the protein immunostaining of cyclooxygenase 2 and nuclear factor kappa B in the liver tissue of nimesulide-treated animals. CONCLUSIONS: The findings from the present study allows us to infer that nimesulide causes liver damage through the phosphatidylinositol 3-kinase gamma pathway.
Asunto(s)
Fosfatidilinositol 3-Quinasa/metabolismo , Sulfonamidas , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Inhibidores de la Ciclooxigenasa/toxicidad , Dimetilsulfóxido/farmacología , Depuradores de Radicales Libres/farmacología , Ratones , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Quinoxalinas/farmacología , Sulfonamidas/farmacología , Sulfonamidas/toxicidad , Tiazolidinedionas/farmacología , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate the main chemical components and the anti-inflammatory activity of extracts of Adelia ricinella L. aerial parts. METHODS: Three extracts obtained by soxhlet extraction and ethanol/water mixtures were evaluated in their chemical composition by UPLC-DAD-MS/MS. The in vitro anti-inflammatory activity of the prepared extracts was assessed through three different assays: COX-1 and COX-2 enzymatic inhibition, cell-based COX assays on RAW264.7 macrophages (ATCC) measuring the COX-2 protein expression by Western blot and the measurement of the PGE2 concentration in the supernatants of the culture medium. Also was determinate the effect of the three extracts on the RAW 264.7 cell viability. KEY FINDINGS: Few differences in the phytochemical profile were found between the three prepared extracts, identifying a blend of thirteen flavonoids derived from luteolin and apigenin, with orientin as main constituent. Plant extracts (alcoholic and aqueous) did not affect the macrophage cell viability (IC50 > 256 µg/ml) and significantly reduced COX-1 and COX-2 enzyme activities. Additionally, COX-2 expression and PGE2 release were suppressed after 24 h of LPS stimulation and treatment with plant extracts (8-64 µg/ml). CONCLUSIONS: A. ricinella extracts showed the ability to reduce the inflammatory effect exerted by LPS in murine macrophages. However, further studies should confirm their anti-inflammatory activity.
Asunto(s)
Apigenina , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Euphorbiaceae/química , Flavonoides , Glucósidos , Luteolina , Animales , Antiinflamatorios/farmacología , Apigenina/aislamiento & purificación , Apigenina/farmacología , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 1/análisis , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/análisis , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Glucósidos/aislamiento & purificación , Glucósidos/farmacología , Luteolina/aislamiento & purificación , Luteolina/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Componentes Aéreos de las Plantas , Extractos Vegetales/química , Extractos Vegetales/farmacología , Células RAW 264.7RESUMEN
Prostaglandin E2 (PGE2) is known to increase glioblastoma (GBM) cell proliferation and migration while cyclooxygenase (COX) inhibition decreases proliferation and migration. The present study investigated the effects of COX inhibitors and PGE2 receptor antagonists on GBM cell biology. Cells were grown with inhibitors and dose response, viable cell counting, flow cytometry, cell migration, gene expression, Western blotting, and gelatin zymography studies were performed. The stimulatory effects of PGE2 and the inhibitory effects of ibuprofen (IBP) were confirmed in GBM cells. The EP2 and EP4 receptors were identified as important mediators of the actions of PGE2 in GBM cells. The concomitant inhibition of EP2 and EP4 caused a significant decrease in cell migration which was not reverted by exogenous PGE2. In T98G cells exogenous PGE2 increased latent MMP2 gelatinolytic activity. The inhibition of COX1 or COX2 caused significant alterations in MMP2 expression and gelatinolytic activity in GBM cells. These findings provide further evidence for the importance of PGE2 signalling through the EP2 and the EP4 receptor in the control of GBM cell biology. They also support the hypothesis that a relationship exists between COX1 and MMP2 in GBM cells which merits further investigation as a novel therapeutic target for drug development.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Movimiento Celular , Proliferación Celular , Inhibidores de la Ciclooxigenasa/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/patología , Apoptosis , Biomarcadores de Tumor/genética , Ciclo Celular , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Humanos , Invasividad Neoplásica , Células Tumorales CultivadasRESUMEN
Coccoloba cowellii Britton (Polygonaceae) is an endemic and critically endangered plant that only grows in Camagüey, a province of Cuba. In this study, a total of 13 compounds were identified in a methanolic leaf extract, employing a dereplication of the UHPLC-HRMS data by means of feature-based molecular networking (FBMN) analysis in the Global Natural Products Social Molecular Network (GNPS), together with the interpretation of the MS/MS data and comparison with the literature. The major constituents were glucuronides and glycosides of myricetin and quercetin, as well as epichatechin-3-O-gallate, catechin, epicatechin and gallic acid, all of them being reported for the first time in C. cowellii leaves. The leaf extract was also tested against various microorganisms, and it showed a strong antifungal effect against Candida albicans ATCC B59630 (azole-resistant) (IC50 2.1 µg/mL) and Cryptococcus neoformans ATCC B66663 (IC50 4.1 µg/mL) with no cytotoxicity (CC50 > 64.0 µg/mL) on MRC-5 SV2 cells, determined by the resazurin assay. Additionally, the extract strongly inhibited COX-1 and COX-2 enzyme activity using a cell-free experiment in a dose-dependent manner, being significantly more active on COX-1 (IC50 4.9 µg/mL) than on COX-2 (IC50 10.4 µg/mL). The constituents identified as well as the pharmacological activities measured highlight the potential of C. cowellii leaves, increasing the interest in the implementation of conservation strategies for this species.
Asunto(s)
Antibacterianos/farmacología , Antifúngicos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Fitoquímicos/farmacología , Extractos Vegetales/farmacología , Polygonaceae/química , Tripanocidas/farmacología , Bacterias/efectos de los fármacos , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Hongos/efectos de los fármacos , Humanos , Pulmón/citología , Pulmón/efectos de los fármacos , Hojas de la Planta/química , Trypanosoma/efectos de los fármacosRESUMEN
Solidagenone (SOL) is a labdane-type diterpenoid found in Solidago chilensis, a plant traditionally used to treat skin diseases, kidney pain and ovarian inflammation. In this study, the topical anti-inflammatory activity of SOL was evaluated using in vivo and in silico assays. Croton oil-, arachidonic acid (AA)- and phenol-induced ear oedema mouse models were applied in the in vivo studies. Myeloperoxidase (MPO) and N-acetyl-ß-D-glucosaminidase (NAG) activities and tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and nitric oxide (NO) levels were determined, as well as histopathological analyses were conducted. Interaction profiles between SOL and cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), glucocorticoid receptor, estradiol-17-ß-dehydrogenase and prostaglandin-E(2)-9-reductase were established using molecular docking. SOL significantly inhibited croton oil-, AA- and phenol-induced ear oedema (P < .001) at doses of 0.1, 0.5 and 1.0 mg/ear. The MPO and NAG activities and TNF-α, IL-6 and NO levels were decreased (P < .001). The histopathological data revealed that inflammatory parameters (oedema thickness, leucocyte infiltration and vasodilatation) were reduced by treatment with SOL at doses of 0.1, 0.5 and 1.0 mg/ear. The docking study showed that SOL interacts with COX-1 and prostaglandin-E(2)-9-reductase through hydrogen bonding, inhibiting these enzymes. These results indicate that SOL may be a promising compound for the treatment of cutaneous inflammatory disorders and has potential as a topical anti-inflammatory agent.
Asunto(s)
Inhibidores de la Ciclooxigenasa/farmacología , Dermatitis/prevención & control , Edema/prevención & control , Furanos/farmacología , Hidroxiprostaglandina Deshidrogenasas/antagonistas & inhibidores , Proteínas de la Membrana/antagonistas & inhibidores , Naftalenos/farmacología , Extractos Vegetales/farmacología , Piel/efectos de los fármacos , Solidago , Acetilglucosaminidasa/metabolismo , Animales , Ciclooxigenasa 1/metabolismo , Inhibidores de la Ciclooxigenasa/aislamiento & purificación , Inhibidores de la Ciclooxigenasa/metabolismo , Dermatitis/metabolismo , Dermatitis/patología , Modelos Animales de Enfermedad , Edema/inducido químicamente , Edema/metabolismo , Edema/patología , Furanos/aislamiento & purificación , Furanos/metabolismo , Enlace de Hidrógeno , Hidroxiprostaglandina Deshidrogenasas/metabolismo , Interleucina-6/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Simulación del Acoplamiento Molecular , Naftalenos/aislamiento & purificación , Naftalenos/metabolismo , Óxido Nítrico/metabolismo , Peroxidasa/metabolismo , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/metabolismo , Unión Proteica , Transducción de Señal , Piel/metabolismo , Piel/patología , Solidago/química , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVE: To examine the effects of early echocardiography-targeted ibuprofen treatment of large patent ductus arteriosus (PDA) on survival without cerebral palsy at 24 months of corrected age. STUDY DESIGN: We enrolled infants born at <28 weeks of gestation with a large PDA on echocardiography at 6-12 hours after birth to ibuprofen or placebo by 12 hours of age in a multicenter, double blind, randomized-controlled trial. Open-label ibuprofen was allowed for prespecified criteria of a hemodynamically significant PDA. The primary outcome was survival without cerebral palsy at 24 months of corrected age. RESULTS: Among 337 enrolled infants, 109 had a small or closed ductus and constituted a reference group; 228 had a large PDA and were randomized. The primary outcome was assessed at 2 years in 108 of 114 (94.7%) and 102 of 114 (89.5%) patients allocated to ibuprofen or placebo, respectively. Survival without cerebral palsy occurred in 77 of 108 (71.3%) after ibuprofen, 73 of 102 (71.6%) after placebo (adjusted relative risk 0.98, 95% CI 0.83-1.16, P = .83), and 77 of 101 (76.2%) in reference group. Infants treated with ibuprofen had a lower incidence of PDA at day 3. Severe pulmonary hemorrhage during the first 3 days occurred in 2 of 114 (1.8%) infants treated with ibuprofen and 9 of 114 (7.9%) infants treated with placebo (adjusted relative risk 0.22, 95% CI 0.05-1.00, P = .05). Open-label rescue treatment with ibuprofen occurred in 62.3% of infants treated with placebo and 17.5% of infants treated with ibuprofen (P < .001), at a median (IQR) age of 4 (3, 5) and 4 (4, 12) days, respectively. CONCLUSIONS: Early echocardiography-targeted ibuprofen treatment of a large PDA did not change the rate of survival without cerebral palsy. TRIAL REGISTRATION: Eudract 2011-003063-30 and ClinicalTrials.gov: NCT01630278.
Asunto(s)
Parálisis Cerebral/epidemiología , Inhibidores de la Ciclooxigenasa/uso terapéutico , Conducto Arterioso Permeable/tratamiento farmacológico , Ibuprofeno/uso terapéutico , Recien Nacido Extremadamente Prematuro , Preescolar , Método Doble Ciego , Conducto Arterioso Permeable/mortalidad , Humanos , Lactante , Recién NacidoRESUMEN
Our previous study showed that kaempferitrin, the main flavonoid from Bauhinia forficata Link leaves, induces diuresis and saluresis when orally given to rats. Since afzelin (AFZ) and kaempferol (KFL) are active compounds from the biometabolism of kaempferitrin, the diuretic and renal protective properties of these two compounds were evaluated. While the acute treatment with AFZ evoked a diuretic action associated with an increase in Cl- excretion and a Ca2+-sparing effect, KFL did not present any activity. The pretreatment with a muscarinic receptor blocker or with an inhibitor of the cyclooxygenase fully avoided AFZ-induced diuresis. AFZ also induced a prolonged (7-day treatment) diuretic effect in normotensive (NTR) and hypertensive rats (SHR), with an increase of urinary Na+ and Cl- excretion, while it decreased the elimination of Ca2+. AFZ was able to decrease ROS and nitrite generation on kidney homogenates in comparison with the SHR group treated with the vehicle, as well as mitigated the changes in the renal corpuscle region (glomerulus and Bowman's capsule). Moreover, AFZ significantly reduced calcium oxalate crystal formation in urine, with inhibition rates of 41% for the NTR and 92% for the SHR group. Taken together, this study shows that AFZ exerts acute and prolonged diuretic effects plus protective renal properties.
Asunto(s)
Diuréticos/farmacología , Hipertensión/tratamiento farmacológico , Quempferoles/farmacología , Enfermedades Renales/prevención & control , Manósidos/farmacología , Proantocianidinas/farmacología , Sustancias Protectoras/farmacología , Animales , Antioxidantes/farmacología , Bauhinia/química , Calcio/metabolismo , Cloruros/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Enfermedades Renales/patología , Estructura Molecular , Antagonistas Muscarínicos/farmacología , Hojas de la Planta/química , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The Candida parapsilosis complex has been associated with highly refractory infections mainly due to the presence of biofilms. High glucose levels enable the development of this virulence factor which can aggravate the clinical condition of patients with diabetes mellitus, those using parenteral nutrition, with invasive medical device, including others. Combined antifungal therapy, such as azole and cyclooxygenase inhibitors, may be an alternative in such infections since they modulate prostaglandin production favoring the adhesion and development of biofilms. Thus, the present study aimed to evaluate the influence of glucose supplementation in the formation and detection of Candida parapsilosis complex biofilms and to treat them using fluconazole and a cyclooxygenase inhibitor in combination. Protein spectra evaluation allowed the differentiation between species from the complex (score > 2) in our studies. All isolates were able to form active biofilms at different glucose concentrations. In addition, a significant reduction in biofilm formation was observed when fluconazole and acetylsalicylic acid were combined. The ultrastructural analysis presented typical biofilm characteristics by species from the complex. These data support new combined therapies for the treatment of fungal infections, especially with those which are resistant and therapeutic failure is associated with virulence factors.
Asunto(s)
Aspirina/farmacología , Biopelículas/efectos de los fármacos , Candida parapsilosis/efectos de los fármacos , Fluconazol/farmacología , Antifúngicos/farmacología , Aspirina/administración & dosificación , Candida parapsilosis/fisiología , Inhibidores de la Ciclooxigenasa/farmacología , Fluconazol/administración & dosificación , Glucosa/metabolismo , Pruebas de Sensibilidad MicrobianaRESUMEN
In the search for new drugs, strategies such as bioisosterism have been evidenced, in which the modification of molecules is already known to be active. Thus, metal complexes of known drugs have been highlighted, with examples of significant improvements in therapeutic efficacy. In this way, this work aimed at the synthesis of new zinc complexes with nonsteroidal anti-inflammatory drugs (NSAIDs), as well as the chemical characterization and the previous toxicity by cytotoxicity with Artemia salina, and evaluating the ability of these compounds to interact with DNA. As result, two new zinc II ternary complexes containing the NSAIDs diclofenac (Diclof) and ibuprofen (Ibup) and nicotinamide neutral linker (Nic) were obtained by the two-step solvent metal-ligand complexation method. Molecular structures were determined by NMR, FTIR, HR-MS, UV-Vis and X-ray diffraction, which demonstrated that both complexes are binuclear systems of general formula [Zn2(R-COO-)4(Nic)2]. Plasmidial DNA breakdown capacities were evaluated by producing single and double breaks (DNA FII and FIII) from plasmid incubation with complex solutions in the concentration range 0 to 400 µmol·L-1 in experiments with the presence and absence of light. Both experiments did not show significant differences (P ≤ 0.05) in induced DNA cleavage activity between the maximum study concentrations (400 µmol·L-1) and the negative controls for both complexes. The types of complex 1 and 2 interactions with the secondary DNA structure were determined by titrating a CT-DNA solution with complex solutions and monitored by circular dichroism spectrometry. The results showed that both complexes interact with the grooves of the secondary structure of CT-DNA by electrostatic attraction, but without evidence of alteration in the primary structure. Acute toxicity tests against Artemia salina showed that both complexes did not produce lethality >10% of the population up to a maximum concentration of 1200 µg·mL-1 within an exposure interval of 24 h. Thus, two new compounds were synthesized, characterized and had their previous toxicities determined. These compounds are promising new drugs, with the next step being evaluations of their activity.
Asunto(s)
Artemia/crecimiento & desarrollo , Complejos de Coordinación/toxicidad , Inhibidores de la Ciclooxigenasa/toxicidad , Diclofenaco/química , Ibuprofeno/química , Niacinamida/química , Zinc/química , Animales , Antiinflamatorios no Esteroideos , Artemia/efectos de los fármacos , Complejos de Coordinación/química , Cristalografía por Rayos X , Inhibidores de la Ciclooxigenasa/química , División del ADN , Estructura Molecular , Pruebas de Toxicidad AgudaRESUMEN
The development of analgesic drugs is still a necessity due to the inefficiency of the current treatments for some pathological conditions and also due to the adverse effects produced by these drugs. The aim of this study was to deepen the pharmacological study of two new hybrids NSAIDs tetrahydropyran derivatives, regarding their antinociceptive effects on acute pain in mice. Male swiss mice were evaluated in the acetic acid-induced abdominal writhing, formalin, tail-flick, open-field, glutamate- and capsaicin-induced paw licking tests, and in vitro Cox inhibition assay, besides the acute toxicological evaluation. The compounds had an effect on the acetic acid-induced abdominal writhing, formalin (both phases), and tail-flick tests. In the study of the mechanism of action was observed reversion of the antinociceptive effect of the compounds from the previous administration of naloxone, L-NAME (L-nitro-arginine methyl ester), ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), glibenclamide, and nor-binaltorphimine, by the intrathecal and intraperitoneal routes. The prior administration of MK-801 suggests that the modulation of NMDA receptor contributes to the antinociceptive effect of compounds. In summary, hybrid compounds presented central antinociceptive effect, demonstrating participation of the NO-cGMP-K+ ATP pathway, κ-opioid, and NMDA receptors. In addition, the compounds showed inhibition of cyclo-oxygenase enzymes and adverse effects were not observed with dose 300 times greater than the dose used experimentally.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Adenosina Trifosfato/metabolismo , Analgésicos Opioides/farmacología , Animales , GMP Cíclico/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Maleato de Dizocilpina/farmacología , Formaldehído/farmacología , Gliburida/farmacología , Humanos , Masculino , Ratones , NG-Nitroarginina Metil Éster/farmacología , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Dolor/tratamiento farmacológico , Dolor/metabolismo , Dimensión del Dolor/métodos , Canales de Potasio/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
The stingless bee, Melipona fasciculata Smith (Apidae, Meliponini), is a native species from Brazil. Their products have high biotechnological potential, however there are no studies about the biological activities of pollen collected by M. fasciculata. In this context, the present study investigated the chemical composition, anti-oxidant, anti-inflammatory, and analgesic activities of hydroethanolic pollen extracts collected by M. fasciculata in three cities in Maranhão State, Brazil. We verified the antioxidant activity of the extracts and inhibitory activity against the cyclooxygenase enzyme using in vitro assays and in allowed to select the extract with higher efficiency to be used on in vivo assays. In these trials, the selected extract showed high anti-inflammatory activity as well as nociceptive effects at central and peripheral level, suggesting that this extract acts on inhibition of histamine release and decreased synthesis of prostaglandins and the in-silico study suggested that polyphenols and acids fatty acids in the extract may be associated with these activities. The results of the present study report the high biological potential of pollen extract and we conclude that the pollen collected by M. fasciculata can be considered as the object of research for new pharmacological alternatives.
Asunto(s)
Analgésicos/química , Antiinflamatorios/química , Inhibidores de la Ciclooxigenasa/química , Extractos Vegetales/química , Polen/química , Analgésicos/farmacología , Animales , Antiinflamatorios/farmacología , Abejas , Brasil , Inhibidores de la Ciclooxigenasa/farmacología , Ácidos Grasos/química , Ácidos Grasos/farmacología , Masculino , Ratones , Extractos Vegetales/farmacología , Plantas/química , Polifenoles/química , Polifenoles/farmacologíaRESUMEN
Different NSAIDs are used as antinociceptive in various analgesic assays, among which should be mentioned: ibuprofen, ketorolac , ketoprofen, meloxicam , paracetamol and others. It has been shown that NSAIDs possess antinociceptive activity by blocking cyclooxygenase enzymes (COXs). The present study was designed to evaluate the possible involvement of the nitridergic pathway due to L-NAME and the opioidergic route by NTX in the antinoception induced by NSAIDs using a murine pain model the tail flick test in an automatic tail flick algesiometer. The antinociception was evaluated by means of isobolographic analysis. The interaction between the combination of NSAIDs, via i.p., on basis of their ED25, demonstrated that the coadministration of the drugs were synergistic with the exception of the lack of effect in combination of meloxicam with ibuprofen and with ketorolac, since the result was additive. These data validate that the NSAIDs administered alone or in combinations produce antinociception in which other mechanisms of action must be added to the simple inhibition of COXs. In addition, the pretreatment of the mice with L-NAME and NTX does not change previous isobolographic parameters of the mixture of NSAIDs.
Asunto(s)
Analgésicos Opioides/farmacología , Antiinflamatorios no Esteroideos/farmacología , Óxido Nítrico/metabolismo , Acetaminofén/farmacología , Animales , Inhibidores de la Ciclooxigenasa/farmacología , Ibuprofeno/farmacología , Cetoprofeno/farmacología , Ketorolaco/farmacología , Ratones , Dolor/tratamiento farmacológico , Dolor/metabolismo , Dimensión del Dolor/métodosRESUMEN
In the design of 1-phenylbenzimidazoles as model cyclooxygenase (COX) inhibitors, docking to a series of crystallographic COX structures was performed to evaluate their potential for high-affinity binding and to reproduce the interaction profile of well-known COX inhibitors. The effect of ligand-specific induced fit on the calculations was also studied. To quantitatively compare the pattern of interactions of model compounds to the profile of several cocrystallized COX inhibitors, a geometric parameter, denominated ligand-receptor contact distance (LRCD), was developed. The interaction profile of several model complexes showed similarity to the profile of COX complexes with inhibitors such as iodosuprofen, iodoindomethacin, diclofenac, and flurbiprofen. Shaping of high-affinity binding sites upon ligand-specific induced fit mostly determined both the affinity and the binding mode of the ligands in the docking calculations. The results suggest potential of 1-phenylbenzimidazole derivatives as COX inhibitors on the basis of their predicted affinity and interaction profile to COX enzymes. The analyses also provided insights into the role of induced fit in COX enzymes. While inhibitors produce different local structural changes at the COX ligand binding site, induced fit allows inhibitors in diverse chemical classes to share characteristic interaction patterns that ensure key contacts to be achieved. Different interaction patterns may also be associated with different inhibitory mechanisms.
Asunto(s)
Bencimidazoles/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Bencimidazoles/química , Cristalografía por Rayos X , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacología , Bases de Datos de Proteínas , Indometacina/química , Indometacina/farmacología , Ligandos , Simulación del Acoplamiento Molecular , Prostaglandina-Endoperóxido Sintasas/química , TermodinámicaRESUMEN
OBJECTIVES: Infection, inflammation and bone resorption are closely related events in apical periodontitis development. Therefore, we sought to investigate the role of cyclooxygenase (COX) in osteoclastogenesis and bone metabolism signaling in periapical bone tissue after bacterial lipopolysaccharide (LPS) inoculation into root canals. METHODOLOGY: Seventy two C57BL/6 mice had the root canals of the first molars inoculated with a solution containing LPS from E. coli (1.0 mg/mL) and received selective (celecoxib) or non-selective (indomethacin) COX-2 inhibitor. After 7, 14, 21 and 28 days the animals were euthanized and the tissues removed for total RNA extraction. Evaluation of gene expression was performed by qRT-PCR. Statistical analysis was performed using analysis of variance (ANOVA) followed by post-tests (α=0.05). RESULTS: LPS induced expression of mRNA for COX-2 (Ptgs2) and PGE2 receptors (Ptger1, Ptger3 and Ptger4), indicating that cyclooxygenase is involved in periapical response to LPS. A signaling that favours bone resorption was observed because Tnfsf11 (RANKL), Vegfa, Ctsk, Mmp9, Cd36, Icam, Vcam1, Nfkb1 and Sox9 were upregulated in response to LPS. Indomethacin and celecoxib differentially modulated expression of osteoclastogenic and other bone metabolism genes: celecoxib downregulated Igf1r, Ctsk, Mmp9, Cd36, Icam1, Nfkb1, Smad3, Sox9, Csf3, Vcam1 and Itga3 whereas indomethacin inhibited Tgfbr1, Igf1r, Ctsk, Mmp9, Sox9, Cd36 and Icam1. CONCLUSIONS: We demonstrated that gene expression for COX-2 and PGE2 receptors was upregulated after LPS inoculation into the root canals. Additionally, early administration of indomethacin and celecoxib (NSAIDs) inhibited osteoclastogenic signaling. The relevance of the cyclooxygenase pathway in apical periodontitis was shown by a wide modulation in the expression of genes involved in both bone catabolism and anabolism.
Asunto(s)
Inhibidores de la Ciclooxigenasa/farmacología , Cavidad Pulpar/metabolismo , Lipopolisacáridos/farmacología , Osteogénesis/fisiología , Tejido Periapical/efectos de los fármacos , Tejido Periapical/metabolismo , Prostaglandina-Endoperóxido Sintasas/fisiología , Animales , Antiinflamatorios no Esteroideos/farmacología , Resorción Ósea/metabolismo , Celecoxib/farmacología , Ciclooxigenasa 2/análisis , Escherichia coli/metabolismo , Expresión Génica , Indometacina/farmacología , Lipopolisacáridos/análisis , Masculino , Ratones Endogámicos C57BL , Osteogénesis/efectos de los fármacos , Prostaglandina-Endoperóxido Sintasas/análisis , Prostaglandina-Endoperóxido Sintasas/efectos de los fármacos , Receptores de Prostaglandina E/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Regulación hacia ArribaRESUMEN
Inflammation is the response of the body to noxious stimuli such as infections, trauma, or injury. Experimental studies have shown that vanillic acid has anti-inflammatory effects. The objective of this study was to investigate the anti-inflammatory and antipyretic properties of the derivative of vanillic acid, isopropyl vanillate (ISP-VT), in mice. The results of this study indicated that ISP-VT reduced paw edema induced by carrageenan, dextran sulfate (DEX), compound 48/80, serotonin, bradykinin (BK), histamine (HIST), and prostaglandin E2 (PGE2). Furthermore, ISP-VT reduced recruitment of leukocytes and neutrophils and reduced its adhesion and rolling, and decreased myeloperoxidase enzyme activity (MPO), cytokine levels (tumor necrosis factor-α and interleukin-6), and vascular permeability. ISP-VT also significantly reduced the expression of cyclooxygenase-2 (COX-2) in subplantar tissue of mice. ISP-VT inhibited COX-2 selectively compared to the standard drug. Our results showed that although ISP-VT binds to COX-1, it is less toxic than indomethacin, as evidenced by MPO analysis of gastric tissue. Treatment with the ISP-VT significantly reduced rectal temperature in yeast-induced hyperthermia in mice. Our results showed that the main mechanism ISP-VT-induced anti-inflammatory activity is by inhibition of COX-2. In conclusion, our results indicate that ISP-VT has potential as an anti-inflammatory and antipyretic therapeutic compound.
Asunto(s)
Antiinflamatorios/administración & dosificación , Carragenina/efectos adversos , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inflamación/tratamiento farmacológico , Fenoles/efectos adversos , Ácido Vanílico/química , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Anticuerpos Monoclonales/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacología , Modelos Animales de Enfermedad , Femenino , Inflamación/inducido químicamente , Inflamación/metabolismo , Inyecciones Intraperitoneales , Masculino , Ratones , Modelos Moleculares , Fenoles/síntesis química , Fenoles/química , Fenoles/farmacología , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
Nitric oxide-releasing aspirins (NO-aspirins) are aspirin derivatives that are safer than the parent drug in the gastrointestinal context and have shown superior cytotoxic effects in several cancer models. Despite the rationale for their design, the influence of nitric oxide (NOâ¢) on the effects of NO-aspirins has been queried. Moreover, different isomers exhibit varying antitumor activity, apparently related to their ability to release NOâ¢. Here, we investigated the effects and mode of action of NO-aspirins in non-small-cell lung cancer (NSCLC) cells, comparing two isomers, NCX4016 and NCX4040 (-meta and -para isomers, respectively). NCX4040 was more potent in decreasing NSCLC cell viability and migration and exhibited significant synergistic effects in combination with erlotinib (an epidermal growth factor receptor inhibitor) in erlotinib-resistant cells. We also studied the relationship among the effects of NO-aspirins, NO⢠release, and PGE2 levels. NCX4040 released more NO⢠and significantly decreased PGE2 synthesis relative to NCX4016; however, NO⢠scavenger treatment reversed the antiproliferative effects of NCX4016, but not those of NCX4040. By contrast, misoprostol (a PGE2 receptor agonist) significantly reversed the antiproliferative effect of NCX4040, but not those of NCX4016. Furthermore, misoprostol reversed the antimigratory effects of NCX4040. Overall, these results indicate that PGE2 inhibition is important in the mode of action of NO-aspirins.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Aspirina/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Óxido Nítrico/metabolismo , Antiinflamatorios no Esteroideos/química , Aspirina/análogos & derivados , Aspirina/química , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/química , Dinoprostona/biosíntesis , Sinergismo Farmacológico , Clorhidrato de Erlotinib/farmacología , Humanos , Neoplasias Pulmonares/metabolismo , Estructura Molecular , Nitrocompuestos/farmacologíaRESUMEN
Endothelial dysfunction contributes to the development of ungulate's laminitis. Although extensively studied in equines, the endothelial function is not fully examined in bovine digital veins (BDVs). BDVs were studied under isometric conditions to describe the acetylcholine (ACh) endothelium-dependent relaxation. Concentration-response curves were constructed to phenylephrine, ACh, and sodium nitroprusside (SNP). Relaxation responses were evaluated using either phenylephrine or depolarizing high-potassium Krebs solution (DKS) as precontraction agents. Endothelium denudation and incubation with L-NAME (300 µM), indomethacin (10 µM) or both were used to explore endothelial-mediated mechanisms. Endothelium denudation did not modify phenylephrine and SNP responses, however, significantly (p < 0.05) converted a relaxation (63.2 ± 5%) response to ACh into a contraction (30.3±9%). The ACh-evoked relaxation was significantly (p < 0.05) reduced in the presence of indomethacin (37.5 ± 6%) and L-NAME (6.40 ± 2%). The presence of both inhibitors abolished the ACh-evoked relaxation. Although DKS caused a higher precontraction than phenylephrine, ACh-evoked relaxation (22.4 ± 3.4%) was still observed and was reduced by the combination of inhibitors (7.0 ± 1.0%). The ACh endothelium-dependent relaxation in BDVs is essentially mediated by nitric oxide and endothelium-derived prostanoids. The BDV endothelium function is a dynamic component in the control of the bovine digital blood flow, particularly under endothelial dysfunction conditions when venoconstriction might lead to postcapillary resistance increase.
Asunto(s)
Endotelio Vascular/metabolismo , Óxido Nítrico/fisiología , Prostaglandinas/fisiología , Vasodilatación , Venas/metabolismo , Acetilcolina/farmacología , Animales , Bovinos , Inhibidores de la Ciclooxigenasa/farmacología , Relación Dosis-Respuesta a Droga , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Femenino , Pezuñas y Garras/irrigación sanguínea , Indometacina/farmacología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Nitroprusiato/farmacología , Fenilefrina/farmacología , Prostaglandina-Endoperóxido Sintasas/metabolismo , Prostaglandinas/metabolismo , Venas/efectos de los fármacos , Venas/fisiologíaRESUMEN
Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used medications associated with nephrotoxicity, especially when used chronically. Factors such as advanced age and comorbidities, which in themselves already lead to a decrease in glomerular filtration rate, increase the risk of NSAID-related nephrotoxicity. The main mechanism of NSAID action is cyclooxygenase (COX) enzyme inhibition, interfering on arachidonic acid conversion into E2 prostaglandins E2, prostacyclins and thromboxanes. Within the kidneys, prostaglandins act as vasodilators, increasing renal perfusion. This vasodilatation is a counter regulation of mechanisms, such as the renin-angiotensin-aldosterone system works and that of the sympathetic nervous system, culminating with compensation to ensure adequate flow to the organ. NSAIDs inhibit this mechanism and can lead to acute kidney injury (AKI). High doses of NSAIDs have been implicated as causes of AKI, especially in the elderly. The main form of AKI by NSAIDs is hemodynamically mediated. The second form of NSAID-induced AKI is acute interstitial nephritis, which may manifest as nephrotic proteinuria. Long-term NSAID use can lead to chronic kidney disease (CKD). In patients without renal diseases, young and without comorbidities, NSAIDs are not greatly harmful. However, because of its dose-dependent effect, caution should be exercised in chronic use, since it increases the risk of developing nephrotoxicity.
Resumo Os anti-inflamatórios não esteroidais (AINEs) são medicamentos comumente utilizados, associados à nefrotoxicidade, sobretudo quando utilizados cronicamente. Fatores como idade avançada e comorbidades, que por si só já levam à diminuição da taxa de filtração glomerular, aumentam o risco de nefrotoxicidade dos AINEs. O principal mecanismo de ação dos AINEs é a inibição da enzima ciclooxigenase (COX), interferindo na conversão do ácido araquidônico em prostaglandinas E2, prostaciclinas e tromboxanos. Nos rins, as prostaglandinas atuam como vasodilatadoras, aumentando a perfusão renal. Essa vasodilatação atua como uma contrarregulação de mecanismos, como a atuação do sistema renina-angiotensina-aldosterona e do sistema nervoso simpático, culminando com uma compensação para assegurar o fluxo adequado ao órgão. O uso de AINEs inibe esse mecanismo, podendo causar lesão renal aguda (LRA). Altas doses de AINEs têm sido implicadas como causas de LRA, especialmente em idosos. A principal forma de LRA por AINEs é a hemodinamicamente mediada. A segunda forma de apresentação da LRA induzida por AINES é a nefrite intersticial aguda, que pode se manifestar com proteinúria nefrótica. O uso de AINEs em longo prazo pode ocasionar doença renal crônica (DRC). Nos pacientes sem doenças renais, jovens e sem comorbidades, os AINEs não apresentam grandes malefícios. Entretanto, por seu efeito dose-dependente, deve-se ter grande cautela no uso crônico, por aumentar risco de desenvolver nefrotoxicidade.