RESUMO
The gut mucosal barrier plays a key role in the physiology of gastrointestinal (GI) tract, preventing under homeostatic conditions, the epithelial cells of the gastric mucosa from hydrochloric acid and intestinal mucosa from alkaline secretion, food toxins and pathogenic microbiota. Previous studies have documented that blockade of both isoforms of cyclooxygenase (COX): constitutive (COX-1) and inducible (COX-2), as well NO synthase in the stomach exacerbated the gastric damage induced by various ulcerogens, however, such as effects of non-selective and selective inhibition of COX-1, COX-2 and NOS enzymes on colonic damage have been little studied. The supplementation of NO by intragastric (i.g.) treatment with NO-releasing compound NO-aspirin (NO-ASA) or substrate for NO synthase L-arginine ameliorated the damage of upper GI-tract, but whether similar effect can be observed in colonic mucosa associated with the experimental colitis, and if above mentioned compounds can be effective in aggravation or protection of experimental colitis remains less recognized. In this study rats with experimental colitis induced by intrarectal administration of 2,4,6-trinitrobenzosulphonic acid (TNBS) were daily treated for 7 days with: 1) vehicle (i.g.), 2) ASA 40 mg/kg (i.g.), 3) rofecoxib 10 mg/kg (i.g.), 4) resveratrol 10 mg/kg (i.g.), 5) NO-ASA 40 mg/kg (i.g.), 6) L-arginine 200 mg/kg (i.g.) with or without of L-NNA 20 mg/kg (i.p.). The macroscopic and microscopic area of colonic damage was determined planimetrically, the colonic blood flow (CBF) was assessed by Laser flowmetry, and the oxidative stress biomarkers malondialdehyde and 4-hydroxynonenal (MDA+4-HNE), the antioxidative factors superoxide dismutase (SOD) and glutathione (GSH), as well as proinflammatory cytokines in the colonic mucosa (tumor necrosis factor alpha (TNF-α) and interleukin-1beta (IL-1ß)) were measured. We have documented that administration of TNBS produced gross and microscopic colonic damage and significantly decreased CBF (p<0.05). Treatment with ASA significantly increased the area of colonic damage (p<0.05), an effect accompanied by a significant decrease in the CBF, the significant increment of MDA+4-HNE, and the attenuation of the antioxidative properties in colonic mucosa, documented by a significant decrease of SOD activity and GSH concentration, and elevation of the colonic tissue levels of TNF-α and IL-1ß comparing to control Veh-treated TNBS rats. Administration of rofecoxib or resveratrol also significantly increased the colonic damage and significantly decreased the CBF, causing an increase in MDA+4-HNE and mucosal content of TNF-α and IL-1α and a significant decrease of the SOD activity and GSH content (p<0.05), however, these changes were significantly less pronounced as compared with ASA. On the contrary, the treatment with NO-ASA, or L-arginine, significantly diminished the area of colonic lesions, the MDA+4-HNE concentration, attenuated the TNF-α and IL-1ß levels, while increasing the CBF, SOD activity and GSH content (p<0.05). The concomitant treatment of L-NNA with rofecoxib or resveratrol reversed an increase in area of colonic damage and accompanying changes in CBF, colonic mucosa TNF-α and IL-1ß levels, the MDA+4-HNE concentration, and SOD activity and GSH content comparing to those observed in TNBS rats treated with these COX-inhibitors alone (p<0.05). In contrast, co-treatment with L-NNA and NO-ASA or L-arginine failed to significantly affect the decrease of colonic lesions accompanied by the rise in CBF, the attenuation of MDA+4-HNE concentration, TNF-α and IL-1ß levels, SOD activity and GSH content exerted by NO-ASA- or L-arginine treatment of the respective control TNBS-rats without L-NNA administration. These observations suggest that 1) the increase of NO availability either from NO-releasing donors such as NO-ASA or NO precursors such as L-arginine, can inhibit the inflammatory and microvasculature alterations, as well as increase in lipid peroxidation due to the enhanced efficacy of these compounds to increase the antioxidative properties of colonic mucosa, 2) unlike ASA which exacerbated the severity of colitis, the treatment with rofecoxib, the specific 'safer' COX-2 inhibitor or resveratrol, the polyphenolic compound known to act as the dual COX-1 and COX-2 inhibitor, can attenuate the colonic damage during course of TNBS colitis possibly via anti-inflammatory and antioxidative properties, and 3) the blockade of endogenous NO activity by L-NNA which also exacerbated the severity of mucosal damage in colitis, can abolish the sparing effect of rofecoxib and resveratrol indicating the NO bioavailability plays an important role in enhanced efficacy of both specific and dual COX inhibitors to ameliorate the experimental colitis.
Assuntos
Colite , Inibidores de Ciclo-Oxigenase 2 , Ratos , Animais , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Óxido Nítrico/farmacologia , Resveratrol/farmacologia , Citocinas , Ciclo-Oxigenase 2/metabolismo , Fator de Necrose Tumoral alfa , Ciclo-Oxigenase 1 , Ratos Wistar , Anti-Inflamatórios não Esteroides/uso terapêutico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Estresse Oxidativo , Superóxido Dismutase/metabolismo , Óxido Nítrico Sintase , Arginina/farmacologia , BiomarcadoresRESUMO
INTRODUCTION: Diclofenac has increased cardiovascular risks, but its risk profile compared with other COX-2 inhibitors remains unknown. AIMS: The aim of this study was to compare the cardiovascular risks of diclofenac versus other older and newer COX-2 inhibitors (coxibs). METHODS: Using Danish nationwide health registries (1999-2020), we conducted a series of emulated trials (n = 264). Eligible adults had no recent NSAID prescriptions, contraindications or conditions with low adherence. We included initiators of diclofenac (n = 1,600,202), meloxicam (n = 10,903), etodolac (n = 238,538), celecoxib (n = 77,591), and etoricoxib (n = 12,122). We computed the adjusted intention-to-treat incidence rate ratio (aIRR) with 95% confidence interval (CI) of major adverse cardiovascular events (MACE) within 30 days of initiation (5562 events). RESULTS: MACE was 20% increased among initiators of diclofenac compared with other older COX-2 inhibitors (aIRR 1.19, 95% CI 1.10-1.28), driven by cardiac death (aIRR 1.57, 95% CI 1.21-2.03). The effect appeared strongest for women (aIRR 1.28, 95% CI 1.15-1.43), individuals with high baseline cardiovascular risk (aIRR 1.32, 95% CI 1.05-1.66), and when comparing high-dose diclofenac with low doses of the other older COX-2 inhibitors (aIRR 1.31, 95% CI 1.13-1.52). The results reflected increased rates compared with both meloxicam (aIRR 1.46, 95% CI 0.94-2.26) and etodolac (aIRR 1.18, 95% CI 1.09-1.28). Diclofenac initiators had similar increased rates of MACE compared with coxibs (aIRR 0.96, 95% CI 0.85-1.08), consistent for celecoxib (aIRR 1.02, 95% CI 0.88-1.19) and etoricoxib (aIRR 0.85, 95% CI 0.66-1.10). CONCLUSIONS: The increased cardiovascular risks associated with diclofenac initiation were higher than for other older COX-2 inhibitors (meloxicam/etodolac) and comparable to coxibs (celecoxib/etoricoxib).
Assuntos
Doenças Cardiovasculares , Inibidores de Ciclo-Oxigenase 2 , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Celecoxib/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Diclofenaco/efeitos adversos , Etodolac , Etoricoxib/efeitos adversos , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Meloxicam/efeitos adversos , Fatores de RiscoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Saussurea laniceps Hand.-Mazz. (Compositae) is a representative "snow lotus" herb well known in Chinese folk medicine to treat inflammation-related diseases such as arthritis. S. laniceps (SL) shows anti-inflammatory and analgesic potencies and contains various constituents potentially with cyclooxygenase-2 (COX-2) selective inhibition. The herb is a valuable source of natural alternatives to synthetic COX-2 selective nonsteroidal anti-inflammatory drugs, a common medication for rheumatoid arthritis (RA) and osteoarthritis (OA) reported with serious cardiovascular side effects. AIM OF THE STUDY: Based on an innovative drug screening platform, this study aimed to discover safe, effective COX-2 selective inhibitors from SL. MATERIALS AND METHODS: An enzyme-anchored nanomagnetic fishing assay was developed to separate COX-2 ligands from SL. Cell and animal models of cardiomyocytes, lipopolysaccharide-stimulated macrophages, rat adjuvant-induced arthritis, and anterior cruciate ligament transection-induced OA rats, were adopted to screen the single/combined ligands regarding toxicity and bioactivity levels. Molecular docking was employed to unravel binding mechanisms of the ligands towards COX-1 and COX-2. RESULTS: Four COX-2 selective compounds were separated from SL using optimized COX-2-functionalized magnetic nanoparticles. All the four ligands were proved with evidently lower cardiotoxicity both in vitro and in vivo than celecoxib, a known COX-2 selective inhibitor. Two ligands, scopoletin and syringin, exhibited potent anti-arthritic activities in rat models of RA and OA by alleviating clinical statuses, immune responses, and joint pathological features; their optimum combination ratio was discovered with stronger remedial effects on rat OA than single administrations. The COX-1/2 binding modes of the two phytochemicals contributed to explain their cardiac safety and therapeutic performances. CONCLUSIONS: The screened chemicals are promising to be developed as COX-2 selective inhibitors as part of treating RA and OA. The hybrid strategy for discovering therapeutic agents from SL is shown here to be efficient; it should be equally valuable for finding other active chemicals in other natural sources.
Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Descoberta de Drogas/métodos , Medicamentos de Ervas Chinesas/farmacologia , Nanopartículas Magnéticas de Óxido de Ferro/química , Nanoconjugados/química , Saussurea/química , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Celecoxib/efeitos adversos , Linhagem Celular , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/química , Glucosídeos/efeitos adversos , Glucosídeos/farmacologia , Articulações/diagnóstico por imagem , Articulações/patologia , Ligantes , Simulação de Acoplamento Molecular , Células Musculares/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Osteoartrite/etiologia , Fenilpropionatos/efeitos adversos , Fenilpropionatos/farmacologia , Componentes Aéreos da Planta/química , Ratos Sprague-Dawley , Escopoletina/efeitos adversos , Escopoletina/farmacologia , Remodelação Ventricular/efeitos dos fármacosRESUMO
The inflammatory response to and the subsequent development of Adult Respiratory Distress Syndrome (ARDS) is considered to underpin COVID-19 pathogenesis. With a developing world catastrophe, we need to examine our known therapeutic stocks, to assess suitability for prevention and/or treatment of this pro-inflammatory virus. Analyzing commonly available and inexpensive immunomodulatory and anti-inflammatory medications to assess their possible effectiveness in improving the host response to COVID-19, this paper recommends the following: (1) optimize current health-cease (reduce) smoking, ensure adequate hypertension and diabetes control, continue exercising; (2) start on an HMG CoA reductase inhibitor "statin" for its immunomodulatory and anti-inflammatory properties, which may reduce the mortality associated with ARDS; and (3) consider using Diclofenac (or other COX-2 inhibition medications) for its anti-inflammatory and virus toxicity properties. For purposes of effectiveness, this needs to be in the early course of the disease (post infection and/or symptom presentation) and given in a high dose. The downsides to these recommended interventions are considered manageable at this stage of the pandemic.
Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Síndrome do Desconforto Respiratório/complicações , Síndrome do Desconforto Respiratório/tratamento farmacológico , Corticosteroides/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Antivirais/efeitos adversos , Antivirais/uso terapêutico , COVID-19 , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Diclofenaco/efeitos adversos , Diclofenaco/uso terapêutico , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório/prevenção & controle , Síndrome do Desconforto Respiratório/virologia , SARS-CoV-2 , Internalização do Vírus/efeitos dos fármacos , Tratamento Farmacológico da COVID-19RESUMO
There are many new treatment options available for migraine and more are coming. Three calcitonin gene-related peptide (CGRP) antagonist monoclonal antibodies have been approved and a 4th is due in early 2020. Small molecule CGRP receptor-blocking oral compounds, both for acute care and prevention, are also coming. Four neurostimulators are available, with others on the way. New acute treatments coming soon include the 5HT1F agonist lasmiditan, a zolmitriptan intradermal micro-needle patch, and a nasal mist sumatriptan with a permeability enhancer. Farther out, three novel dihydroergotamine delivery systems, and a liquid-filled capsule of celecoxib show early promise. A new, safer form of methysergide is in the works, as is a longer-duration onabotulinumtoxinA. As always with new products, questions regarding safety, tolerability, cost, and insurance coverage will need to be addressed. Despite these concerns and uncertainties, a robust headache treatment pipeline is good for patients who are not satisfied with the results of their treatment and/or cannot tolerate existing treatments.
Assuntos
Analgésicos não Narcóticos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Terapia por Estimulação Elétrica , Transtornos de Enxaqueca/terapia , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Estimulação Magnética Transcraniana , Vasoconstritores/uso terapêutico , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/efeitos adversos , Analgésicos não Narcóticos/economia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/economia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/administração & dosagem , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/economia , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/economia , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/efeitos adversos , Agonistas do Receptor 5-HT1 de Serotonina/economia , Vasoconstritores/administração & dosagem , Vasoconstritores/efeitos adversos , Vasoconstritores/economiaRESUMO
The risk of coronary events with non-steroidal anti-inflammatory drugs has been the subject of much debate since the original trial of rofecoxib raised the issue. Since then, over almost 20 years, such risks have been shown in clinical trials of long-term high-dose users, and in observational studies comparing users with non-users. The roles of cyclooxygenase (COX)-2/COX-1 selectivity and COX-2 inhibitory potency have been proposed to explain this increased risk of myocardial infarction (MI). Among NSAIDs, diclofenac appeared to be associated with a relatively higher risk of MI, similar to that of rofecoxib, compatible with the drug's high COX-2 inhibitory potency. Recent studies have resulted in further information being available. A study in the Danish healthcare system using active comparators found a slightly increased risk of MI in healthy persons. However, risk decreased with increasing baseline cardiovascular risk, to the point that in patients at high cardiovascular risk, there was no additional risk associated with diclofenac compared with paracetamol or other NSAIDs. The other major study, from the SOS project, studied several million persons in four countries in Europe, comparing the use of many NSAIDs with non-use. That study found a slightly increased risk with diclofenac compared with non-use, but this was not different from other NSAIDs. Comparing risks with selectivity or potency found no effect of either. These studies refute the main hypotheses to explain the coronary risk of NSAIDs. Finding risk in healthy low-risk patients only questions the reality of a link between the use of the drugs and the occurrence of MI in these conditions. Biases or confounding may be the major reason for small increases in cardiovascular risks in healthy users of NSAIDs in real life.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Diclofenaco/efeitos adversos , Cardiotoxicidade , Doenças Cardiovasculares/epidemiologia , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Humanos , Lactonas/efeitos adversos , Metanálise como Assunto , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/epidemiologia , Fatores de Risco , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/epidemiologia , Sulfonas/efeitos adversosRESUMO
NSAIDs are widely used to treat pain and rheumatic conditions, but they induce adverse events in different body systems, although the major, most frequent events occur in the upper and lower gastrointestinal (GI) tracts. Areas covered: This review is focused on damage caused by NSAIDs in the upper and lower GI tracts, the different mechanisms of damage and the GI-sparing NSAIDs designed to minimize adverse events based on understanding of these mechanisms. Expert commentary: Among the new NSAIDs, COX-2 selective inhibitors have been extensively investigated, and some were approved for human use. Celecoxib demonstrated its safety for the entire GI tract, compared to traditional NSAIDs. However, coxibs, like traditional NSAIDs, are toxic to the cardiovascular (CV) system. Other GI-sparing agents include nitric oxide-NSAIDs and phosphatidylcholine-associated NSAIDs. Testing in animal models and humans they showed GI advantages over the parent NSAID compounds, but none obtained regulatory approval or were further investigated. Hydrogen sulfide-releasing NSAIDs are currently under clinical development, and more data are needed before clinical use. Alternative therapies, such as modulating gut microbiota, are being explored. Currently, clinicians must continue prescribing traditional NSAIDs or coxibs, associated with/without proton pump inhibitor therapy, based on the presence of GI/CV risk factors.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Desenho de Fármacos , Gastroenteropatias/prevenção & controle , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Aprovação de Drogas , Gastroenteropatias/induzido quimicamente , Humanos , Inibidores da Bomba de Prótons/uso terapêutico , Fatores de RiscoRESUMO
BACKGROUND: Colorectal cancer is a common and often fatal malignancy. Currently, the modifications that alter disease outcome include early symptom recognition, population screening as well as improved surgical and adjuvant treatments. Preventative strategies have been limited with little evidence that lifestyle changes significantly alter risk. There is however a growing awareness of a potential role for chemoprevention in some patient groups. This study aimed to review the literature associated with chemoprevention in colorectal cancer. METHODS: An electronic literature search of MEDLINE and Embase databases was performed on PubMed for studies detailing the use of chemoprevention agents in colon and rectal cancer. The search was limited to clinical trials on adult humans (>16 years of age) published in English since 1990. RESULTS: The strongest evidence is for non-steroidal anti-inflammatory drugs slowing polyp progression, notably Sulindac and aspirin in patients with familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, respectively. There is also increasing evidence that continuing use of low-dose aspirin reduces long-term incidence of colorectal cancers. Cyclooxygenase 2 inhibitors also have a potential role but cardiac toxicity currently limits their use. Folic acid, statins, antioxidants, calcium and 5-aminosalicylic acid lack evidence to support their use at present. CONCLUSIONS: Currently, there is not enough evidence to support the implementation of a chemopreventative agent for general use. However, there appears to be a role for aspirin in selected subgroups.
Assuntos
Polipose Adenomatosa do Colo/prevenção & controle , Quimioprevenção/efeitos adversos , Quimioprevenção/métodos , Neoplasias Colorretais Hereditárias sem Polipose/prevenção & controle , Neoplasias Colorretais/prevenção & controle , Polipose Adenomatosa do Colo/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Cardiotoxicidade/complicações , Quimioprevenção/economia , Ensaios Clínicos como Assunto , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Progressão da Doença , Humanos , Incidência , Metanálise como Assunto , Pessoa de Meia-Idade , Sulindaco/uso terapêutico , Adulto JovemRESUMO
The consumption of low-dose aspirin (LDA) to prevent cardiovascular disease continues to increase worldwide. Consequently, the number of chronic LDA users seeking dental procedures that require complementary acute anti-inflammatory medication has also grown. Considering the lack of literature evaluating this interaction, we analyzed the gastric and renal effects caused by a selective COX-2 inhibitor (etoricoxib) and a non-selective COX-2 inhibitor (ibuprofen) nonsteroidal anti-inflammatory drug (NSAID) in rats receiving chronic LDA therapy. Male Wistar rats were divided into six experimental groups (carboxymethylcellulose (CMC) - vehicle; LDA; LDA + ibuprofen; ibuprofen; LDA + etoricoxib; and etoricoxib) and submitted to long-term LDA therapy with a subsequent NSAID administration for three days by gavage. After the experimental period, we analyzed gastric and renal tissues and quantified serum creatinine levels. The concomitant use of LDA with either NSAID induced the highest levels of gastric damage when compared to the CMC group (F = 20.26, p < 0.05). Treatment with either LDA or etoricoxib alone was not associated with gastric damage. No significant damage was observed on kidney morphology and function (F = 0.5418, p > 0.05). These results suggest that even the acute use of an NSAID (regardless of COX-2 selectivity) can induce gastric damage when combined with the long-term use of low-dose aspirin in an animal model. Additional studies, including clinical assessments, are thus needed to clarify this interaction, and clinicians should be careful of prescribing NSAIDs to patients using LDA.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Mucosa Gástrica/efeitos dos fármacos , Rim/efeitos dos fármacos , Inibidores da Agregação Plaquetária/administração & dosagem , Animais , Doenças Cardiovasculares/prevenção & controle , Creatinina/sangue , Etoricoxib , Ibuprofeno/efeitos adversos , Nefropatias/induzido quimicamente , Masculino , Piridinas/efeitos adversos , Distribuição Aleatória , Ratos Wistar , Fatores de Risco , Gastropatias/induzido quimicamente , Sulfonas/efeitos adversos , Fatores de Tempo , Resultado do TratamentoAssuntos
Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite/tratamento farmacológico , Artrite/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Celecoxib/efeitos adversos , Celecoxib/farmacocinética , Ensaios Clínicos como Assunto/métodos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Hemorragia/induzido quimicamente , Humanos , Trombose/induzido quimicamenteRESUMO
Nonsteroidal anti-inflammatory drugs (NSAIDs) used as analgesics expose patients to cardiovascular risks that can be predicted from their pharmacological properties. As of mid-2015, what is known about the cardiovascular harms of the NSAIDs of choice, ibuprofen and naproxen? Most of the data from comparative trials of NSAIDs concern cox-2 inhibitors, diclofenac, ibuprofen and naproxen. Few studies have addressed the serious cardiovascular effects of other NSAIDs. In 2013, a U.K. team published a large meta-analysis of hundreds of randomised trials comparing NSAIDs with placebo or one NSAID with another NSAID. Compared with placebo, a statistically significant increase in the risk of serious cardiovascular adverse effects was demonstrated with cox-2 inhibitors and with diclofenac (about +40%). This risk is mainly due to an increase in myocardial infarctions and vascular deaths. Another meta-analysis found similar results in terms of cardiovascular deaths. The results of epidemiological studies are consistent with those of randomised clinical trials. According to meta-analyses of randomised trials, high-dose ibuprofen increases cardiovascular risks to the same degree as diclofenac or cox-2 inhibitors. The risk seems to mainly apply to daily doses of 2400 mg, a finding borne out by epidemiological studies that showed no increased risk with ibuprofen 1200 mg. Two meta-analyses of clinical trials showed that all NSAIDs roughly double the risk of heart failure. One meta-analysis showed a small, statistically significant increase in the risk of atrial fibrillation. In practice, from a cardiovascular perspective, the NSAIDs of choice are ibuprofen, on condition that the dose does not exceed 1200 mg per day, and naproxen. In contrast, it would appear from the study data that cox-2 inhibitors, diclofenac and high-dose ibuprofen (2400 mg per day) are best avoided. As for other NSAIDs, the clinical data are too sparse to allow a meaningful comparison with the better studied NSAIDs. It is advisable to avoid using these other drugs.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Diclofenaco/efeitos adversos , Humanos , Ibuprofeno/efeitos adversos , Naproxeno/efeitos adversosRESUMO
OBJECTIVE: To assess the cost-effectiveness of celecoxib and non-selective non-steroidal anti-inflammatory drugs for the treatment of osteoarthritis in clinical practice in Spain. METHODS: A decision-tree model using distribution, doses, treatment duration and incidence of GI and CV events observed in the pragmatic PROBE-designed «GI-Reasons¼ trial was used for cost-effectiveness. Effectiveness was expressed in terms of event averted and quality-adjusted life-years (QALY) gained. QALY were calculated based on utility decrement in case of any adverse events reported in GI-Reasons trial. The National Health System perspective in Spain was applied; cost calculations included current prices of drugs plus cost of adverse events occurred. The analysis was expressed as an incremental cost-effectiveness ratio per QALY gained and per event averted. One-way and probabilistic analyses were performed. RESULTS: Compared with non-selective non-steroidal anti-inflammatory drugs, at current prices, celecoxib treatment had higher overall treatment costs 201 and 157, respectively. However, celecoxib was associated with a slight increase in QALY gain and significantly lower incidence of gastrointestinal events (p<.001), with mean incremental cost-effectiveness ratio of 13,286 per QALY gained and 4,471 per event averted. Sensitivity analyses were robust, and confirmed the results of the base case. CONCLUSION: Celecoxib at current price may be considered as a cost-effective alternative vs. non-selective non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis in daily practice in the Spanish NHS.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Osteoartrite/tratamento farmacológico , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/economia , Doenças Cardiovasculares/economia , Doenças Cardiovasculares/epidemiologia , Celecoxib/efeitos adversos , Celecoxib/economia , Análise Custo-Benefício , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/economia , Árvores de Decisões , Custos de Medicamentos , Gastroenteropatias/economia , Gastroenteropatias/epidemiologia , Humanos , Incidência , Programas Nacionais de Saúde/economia , Osteoartrite/economia , Anos de Vida Ajustados por Qualidade de Vida , Estudos Retrospectivos , EspanhaRESUMO
Abstract The consumption of low-dose aspirin (LDA) to prevent cardiovascular disease continues to increase worldwide. Consequently, the number of chronic LDA users seeking dental procedures that require complementary acute anti-inflammatory medication has also grown. Considering the lack of literature evaluating this interaction, we analyzed the gastric and renal effects caused by a selective COX-2 inhibitor (etoricoxib) and a non-selective COX-2 inhibitor (ibuprofen) nonsteroidal anti-inflammatory drug (NSAID) in rats receiving chronic LDA therapy. Male Wistar rats were divided into six experimental groups (carboxymethylcellulose (CMC) - vehicle; LDA; LDA + ibuprofen; ibuprofen; LDA + etoricoxib; and etoricoxib) and submitted to long-term LDA therapy with a subsequent NSAID administration for three days by gavage. After the experimental period, we analyzed gastric and renal tissues and quantified serum creatinine levels. The concomitant use of LDA with either NSAID induced the highest levels of gastric damage when compared to the CMC group (F = 20.26, p < 0.05). Treatment with either LDA or etoricoxib alone was not associated with gastric damage. No significant damage was observed on kidney morphology and function (F = 0.5418, p > 0.05). These results suggest that even the acute use of an NSAID (regardless of COX-2 selectivity) can induce gastric damage when combined with the long-term use of low-dose aspirin in an animal model. Additional studies, including clinical assessments, are thus needed to clarify this interaction, and clinicians should be careful of prescribing NSAIDs to patients using LDA.
Assuntos
Animais , Masculino , Inibidores da Agregação Plaquetária/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Mucosa Gástrica/efeitos dos fármacos , Rim/efeitos dos fármacos , Piridinas/efeitos adversos , Gastropatias/induzido quimicamente , Sulfonas/efeitos adversos , Fatores de Tempo , Doenças Cardiovasculares/prevenção & controle , Distribuição Aleatória , Ibuprofeno/efeitos adversos , Fatores de Risco , Resultado do Tratamento , Ratos Wistar , Creatinina/sangue , Etoricoxib , Nefropatias/induzido quimicamenteRESUMO
The objectives of the study are to demonstrate the non-inferiority of PG201 (Layla(®)) 600 mg in comparison with celecoxib 200 mg for the treatment of symptomatic knee osteoarthritis (OA). In total, 309 patients were randomly assigned to receive either the test drug, PG201 600 mg (n = 154) or celecoxib 200 mg (n = 155). The primary efficacy variable was improvement in mean 100-mm pain VAS score from baseline to the final visit (week 8), and this value was compared between the 2 treatment groups. Secondary outcome variables included changes from baseline in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain VAS score and subscale score, patient's global assessment of disease status quality of life (short form-36) and responder index at weeks 4 and 8. For safety assessment, adverse events were recorded at each clinical visit. At weeks 8, the 100-mm pain VAS scores were significantly decreased in patients receiving both PG201 600 mg (p < 0.0001) and celecoxib 200 mg (p < 0.0001) as compared to the baseline scores; however, no statistically significant differences in these values were noted between the groups (p = 0.312). These results met pre-specified criteria for non-inferiority for both the intent-to-treat and per-protocol populations. PG201 600 mg and celecoxib 200 mg were both well tolerated and no statistically significant differences in the tolerability profile between the groups. PG201 600 mg was as effective and safe as celecoxib 200 mg in the treatment of symptomatic knee OA and might be a useful new medication for the treatment of symptomatic knee OA.
Assuntos
Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Osteoartrite do Joelho/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Celecoxib , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Extratos Vegetais/efeitos adversos , Pirazóis/efeitos adversos , Qualidade de Vida , Sulfonamidas/efeitos adversos , Resultado do TratamentoRESUMO
The new generation cyclooxygenase (COX-2) inhibitor could reduce the gastrointestinal side effect of NSAID drugs, but eventually increase the cardiovascular risk, because its selective inhibition of COX-2 induces the imbalance between PGI2 and TXA2 and the reduction of vasodilatory NO. Under pathological conditions, active oxygen species (O2-*2, etc) were used to induce endo- thelial dysfunction, activate NF-κB to induce expressions of pro-inflammatory cytokines IL-1ß and TNF-α, increase ET-1, TXA2 with vasoconstrictor effect, reduce PGI2 and NO with vasodilatory effect, generate further oxidative damage together with NO, and reduce the bioavailability of NO. NO-NSAIDs and NO-Coxibs drugs raised the level of NO by introducing NO-donor (ONO2). NSAIDs drugs enhanced the anti-inflammatory activity of COX-2 and reduced gastrointestinal side effects by inhibiting selectively COX-2. If antioxidant structures with active ingredients of traditional Chinese medicines were introduced to improve the antioxidant activity of NSAIDs, they could scavenge the active oxygen species to protect the normal function of vascular endothelia and enhance the bioavailability of NO, which is conducive to enhance the cardiovascular safety of cyclooxygenase (COX-2) inhibitor.
Assuntos
Anti-Inflamatórios/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Biomarcadores Farmacológicos , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/imunologia , Ciclo-Oxigenase 2/imunologia , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Humanos , NF-kappa B/imunologia , Espécies Reativas de Oxigênio/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
OBJECTIVE: We investigated the effects of celecoxib, diclofenac, and ibuprofen on the disease-specific quality of life, synovial fluid cytokines and signal transduction pathways in symptomatic knee osteoarthritis (OA). DESIGN: Ninety patients scheduled for a total knee arthroplasty (TKA) were randomized to six groups that were treated with low and high dosages of celecoxib, diclofenac or ibuprofen. At the time of the first admission (T0) and at surgery (T1 = 14 days after beginning of the nonsteroidal anti-inflammatory drugs (NSAIDs)), samples of knee synovial fluid were obtained from each patient for analysis. During the surgery the synovial tissue was harvested from the knee of patients. The Western Ontario and McMaster universities (WOMAC) score was used to evaluate the patient disease-specific quality of life at T0 and T1. Microarray tests performed at T0 and T1 were used to evaluate the effects of NSAIDs on Tumor necrosis factor (TNF)-alpha, Interleukin-6 (IL-6), IL8 and Vascular endothelial growth factor (VEGF) concentration in the synovial fluid. Western blot assays evaluated the effects of NSAIDs on MAP kinase (MAPK) signal transduction pathway in the synovial membrane. RESULTS: NSAID treatment induced a statistically significant improvement in the WOMAC score and a statistically significant decrease in the IL-6, VEGF and TNF-alpha concentration in the synovial fluid. Higher dosages of NSAIDs provided a greater improvement in the disease-specific quality of life of patients and lower concentrations of pro-inflammatory cytokines in the synovial fluid. Inhibition of MAPKs was noted after NSAID treatment. CONCLUSION: Short-term NSAID treatment improves the patient disease-specific quality of life with a parallel decrease in pro-inflammatory synovial fluid cytokine levels in knee OA. Signal transduction pathways may be involved in regulating the anti-inflammatory effects of NSAIDs. ClinicalTrial.gov: NCT01860833.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Diclofenaco/administração & dosagem , Ibuprofeno/administração & dosagem , Osteoartrite do Joelho/tratamento farmacológico , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/efeitos adversos , Celecoxib , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Citocinas/metabolismo , Diclofenaco/efeitos adversos , Feminino , Humanos , Ibuprofeno/efeitos adversos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/metabolismo , Pirazóis/efeitos adversos , Qualidade de Vida , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Sulfonamidas/efeitos adversos , Líquido Sinovial/efeitos dos fármacos , Líquido Sinovial/metabolismo , Resultado do TratamentoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: This prospective, randomized, double-blind, multicenter study compared the efficacy and safety of Celecoxib and GCSB-5, a new product from extracts of six herbs, for the treatment of knee osteoarthritis. MATERIALS AND METHODS: A total of 198 eligible patients were randomly assigned to the Celecoxib group (n=99 patients) or the GCSB-5 group (n=99 patients) for the 12-week study. The amount of change and percentage of the change in Western Ontario and McMaster Universities (WOMAC) Arthritis Index from the baseline, the change in pain on walking by visual analogue scale (VAS), physician's global assessment on response to therapy (PGART) by five point Likert scale, and the amount of rescue medicine taken were used as parameters for efficacy. Adverse drug reactions (ADRs) were carefully investigated. RESULTS: The WOMAC score improved in both the Celecoxib group and GCSB-5 group by 20.5 and 21.3 (P=0.79). The percentage of the change in WOMAC score were -42.0% and -38.9% (P=0.54). The pain VAS score decreased by 29.9 and 27.9 (P=0.58). The responders by PGART were 95.3% and 93.8% (P= 0.66), and the median amount of rescue medicine taken were 2.0 and 6.5 tablets (P=0.06). The incidence of ADRs were 31.3% and 21.2% (P=0.11). The most common ADRs were gastrointestinal system related; 17.2% in GCSB-5 group and 22.2% in Celecoxib group. Any severe ADR was not observed in either group. CONCLUSIONS: The result of this study supports that GCSB-5 is comparable to Celecoxib in terms of the efficacy and safety for the treatment of osteoarthritis of knee joint.
Assuntos
Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Osteoartrite do Joelho/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Celecoxib , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Extratos Vegetais/administração & dosagem , Extratos Vegetais/efeitos adversos , Estudos Prospectivos , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Índice de Gravidade de Doença , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Inquéritos e Questionários , Resultado do Tratamento , CaminhadaRESUMO
BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Gastroenteropatias/induzido quimicamente , Doenças Vasculares/induzido quimicamente , Vasos Sanguíneos/efeitos dos fármacos , Doença das Coronárias/induzido quimicamente , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Diclofenaco/efeitos adversos , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Ibuprofeno/efeitos adversos , Infarto do Miocárdio/induzido quimicamente , Naproxeno/efeitos adversos , Acidente Vascular Cerebral/induzido quimicamenteRESUMO
Osteoarthritis (OA) is a joint disease of high prevalence and affects > 90 % of the population, depending on several risk factors. Symptomatic OA is less frequent, but requires an individually tailored therapeutic regimen consisting of non-pharmacological and pharmacological treatment modalities. Pharmacologic therapy, however, is mainly limited to analgetic and anti-inflammatory agents; structure modifying remedies do not exist. The therapeutic approach to hand-, knee- and hip-OA is basically similar and differs only at some minor points. Generally, topical agents or paracetamol are recommended as first-line agents. If unsuccessful oral non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2-selctive inhibitors should be introduced. Tramadol is an option in the case patients will not respond satisfactorily to NSAIDs. Glucosamine and chondroitine sulphate are no longer recommended in knee and hip OA, but chondroitine might be efficient in treating hand OA. Oral NSAIDs should be prescribed with caution due to potential side effects. Opioids are not recommended as their benefits are outweighed by an increased risk for serious adverse events.
Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Articulação da Mão , Osteoartrite do Quadril/tratamento farmacológico , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Acetaminofen/efeitos adversos , Acetaminofen/uso terapêutico , Administração Oral , Administração Tópica , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Analgésicos/efeitos adversos , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Capsaicina/efeitos adversos , Capsaicina/uso terapêutico , Condroitina/efeitos adversos , Condroitina/uso terapêutico , Terapia Combinada , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Glucosamina/efeitos adversos , Glucosamina/uso terapêutico , Humanos , Tramadol/efeitos adversos , Tramadol/uso terapêuticoRESUMO
OBJECTIVES: To evaluate the changes in types of medications prescribed for pain before and after withdrawal of certain selective cyclooxygenase 2 (COX-2) inhibitors in 2004 and to determine whether there was an association with fall events in elderly adults with a diagnosis of osteoarthritis (OA). DESIGN: A nested case-control design using electronic medical records compiled between 2001 and 2009. SETTING: Electronic medical records for care provided in an integrated health system in rural Pennsylvania over a 9-year period (2001-09), the midpoint of which rofecoxib and valdecoxib were pulled from the market. PARTICIPANTS: Thirteen thousand three hundred fifty-four individuals aged 65 to 89 with a diagnosis of OA. MEASUREMENTS: The incidence of falls and fractures was examined in relation to analgesics prescribed: narcotics, COX-2 inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs). The comparison sample of individuals who did not fall was matched 3:1 with those who fell according to age, sex, and comorbidity. RESULTS: Narcotic analgesic prescriptions were associated with a significantly greater risk of falls and fractures. The likelihood of experiencing a fall/fracture was higher in participants prescribed narcotic analgesics than those prescribed a COX-2 inhibitor (odds ratio (OR) = 3.3, 95% confidence interval (CI) = 2.5-4.3) or NSAID (OR = 4.1, 95% CI = 3.7-4.5). CONCLUSION: Use of narcotic analgesics is associated with risk of falls and fractures in elderly adults with OA, an observation that suggests that the current guidelines for the treatment of pain, which include first-line prescription of narcotics, should be reevaluated.