Manejo de hemorragia asociada a anticoagulantes orales directos: estado actual de las estrategias de reversión / Management of bleeding associated with direct oral anticoagulants: update on reversal strategies

Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban have at least comparable efficacy as vitamin K antagonists along with a better safety profile, reflected by a lower incidence of intracranial hemorrhage. Specific reversal agents have been developed in recent years. Namely, idarucizumab, a specific antidote for dabigatran, is currently approved in most countries. Andexanet, which reverses factor Xa inhibitors, has been recently approved by the FDA, and ciraparantag, a universal antidote targeted to reverse all DOACs, is still under investigation. In this review we provide an update on the pharmacology of DOACs, the risk of hemorrhagic complications associated with their use, the measurement of their anticoagulant effect and the reversal strategies in case of DOAC-associated bleeding.

Reduced Food Intake is the Major Contributor to the Protective Effect of Rimonabant on Islet in Established Obesity-Associated Type 2 Diabetes

PURPOSE: Although the presence of cannabinoid type 1 (CB1) receptor in islets has been reported, the major contributor to the protective effect of rimonabant on islet morphology is unknown. We determined whether the protective effect of rimonabant on pancreatic islet morphology is valid in established diabetes and also whether any effect was independent of decreased food intake. MATERIALS AND METHODS: After diabetes was confirmed, Otsuka Long-Evans Tokushima Fatty rats, aged 32 weeks, were treated with rimonabant (30 mg/kg/d, rimonabant group) for 6 weeks. Metabolic profiles and islet morphology of rats treated with rimonabant were compared with those of controls without treatment (control group), a pair-fed control group, and rats treated with rosiglitazone (4 mg/kg/d, rosiglitazone group). RESULTS: Compared to the control group, rats treated with rimonabant exhibited reduced glycated albumin levels (p<0.001), islet fibrosis (p<0.01), and improved glucose tolerance (p<0.05), with no differences from the pair-fed control group. The retroperitoneal adipose tissue mass was lower in the rimonabant group than those of the pair-fed control and rosiglitazone groups (p<0.05). Rimonabant, pair-fed control, and rosiglitazone groups showed decreased insulin resistance and increased adiponectin, with no differences between the rimonabant and pair-fed control groups. CONCLUSION: Rimonabant had a protective effect on islet morphology in vivo even in established diabetes. However, the protective effect was also reproduced by pair-feeding. Thus, the results of this study did not support the significance of islet CB1 receptors in islet protection with rimonabant in established obesity-associated type 2 diabetes.

The psychiatric side-effects of rimonabant / Os efeitos-colaterais psiquiátricos do rimonabanto

OBJECTIVE: Experimental evidence has suggested that drugs that enhance cannabinoid type-1 (CB1) receptor activity may induce anxiolytic and antidepressant effects, whilst the opposite has been reported with antagonists. Thus, the objective of the present review is to discuss the potential psychiatric side-effects of CB1 receptor antagonists, such as rimonabant, which has been recently marketed in several countries for the treatment of smoking cessation, obesity and associated metabolic disorders. METHOD: Literature searches were performed in PubMed and SciELO databases up to February 2009. The terms searched were "obesity", "rimonabant", "cannabinoids", "unwanted effects", "diabetes", "smoking cessation" and "side-effects". RESULTS: Clinical trials have revealed that rimonabant may promote weight loss in obese patients, although it may also induce symptoms of anxiety and depression. DISCUSSION: Patients taking CB1 receptor antagonists should be carefully investigated for psychiatric side-effects. These drugs should not be prescribed for those already suffering from mental disorders. Nevertheless, the development of new compounds targeting the endocannabinoid system for the treatment of several conditions would be necessary and opportune.

OBJETIVO: Evidência experimental sugere que drogas que aumentam a atividade dos receptores canabinóides tipo 1 (CB1) podem induzir efeitos ansiolíticos ou antidepressivos, enquanto que o oposto tem sido relatado com antagonistas. Assim, o objetivo da presente revisão é discutir os potenciais efeitos-colaterais psiquiátricos de antagonistas do receptor CB1, como o rimonabanto, que foi recentemente liberado para comercialização em diversos países para o tratamento do tabagismo, obesidade e de desordens metabólicas associadas. MÉTODO: Foi realizada uma busca na literatura no PubMed e Scielo até fevereiro de 2009, com os termos "obesity", "rimonabant", "cannabinoids", "unwanted effects", "diabetes" , "smoking cessation" e "side effects". RESULTADOS: Ensaios clínicos revelaram que o rimonabanto pode produzir perda de peso em pacientes obesos, embora também possa induzir sintomas de ansiedade e depressão. DISCUSSÃO: Pacientes tomando antagonistas do receptor CB1 devem ser cuidadosamente examinados quanto aos efeitos-colaterais psiquiátricos. Estas drogas não devem ser prescritas a indivíduos que já sofrem de transtornos mentais. Entretanto, o desenvolvimento de novos compostos que atuem no sistema endocanabinóide para o tratamento das mais diversas condições parece necessário e oportuno.

Cardio-renal effects of celecoxib versus ibuprofen in patients with arthritis

Arthritis is a common condition that co-exists in the elderly population. This condition leads to frequent administration of co-morbid Non Steroidal Anti-inflammatory drugs [NSAIDs]. To study cardio-renal toxicity of celecoxib versus ibuprofen in arthritic patients. Seven hundred ninety two arthritic patients were enrolled in the study for 6 months. Three hundred ninty six patients administered celecoxib, 400 mg twice a day; 396 patients administered ibuprofen 300 mg three times a day Effects measured included: investigator reported hypertension, edema, or congestive heart failure, and increases in serum creatinine or reduction in serum creatinine clearance, and changes in serum electrolytes. Celecoxib was associated with significant [P<0.05] lower incidence of hypertension and edema in comparison with ibuprofen. Systolic hypertension occurred significantly less [P<0.05] with celecoxib compared with ibuprofen. Serum creatinine was significantly increased [P<0.05] in patients treated with ibuprofen in comparison with celecoxib. Creatinine clearance was significantly lower [P<0.05] in cases treated with ibuprofen in comparison to celecoxib. Non significant changes in serum body electrolytes. The most important finding of this study was the lowering incidence of cardiorenal complications of celecoxib in comparison with ibuprofen

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) Syndrome Induced by Celecoxib and Anti-tuberculosis Drugs

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome reflects a serious hypersensitivity reaction to drugs, characterized by skin rash, fever, lymph node enlargement, and internal organ involvement. So far, numerous drugs such as sulfonamides, phenobarbital, sulfasalazine, carbamazepine, and phenytoin have been reported to cause the DRESS syndrome. We report a case in a 29-yr-old female patient who had been on celecoxib and anti-tuberculosis drugs for one month to treat knee joint pain and pulmonary tuberculosis. Our patient's clinical manifestations included fever, lymphadenopathy, rash, hypereosinophilia, and visceral involvement (hepatitis and pneumonitis). During the corticosteroid administration for DRESS syndrome, swallowing difficulty with profound muscle weakness had developed. Our patient was diagnosed as DRESS syndrome with eosinophilic polymyositis by a histopathologic study. After complete resolution of all symptoms, patch tests were positive for both celecoxib and ethambutol. Although further investigations might be needed to confirm the causality, celecoxib and ethambutol can be added to the list of drugs as having the possibility of DRESS syndrome.

Omeprazole and misoprostol for preventing gastric mucosa effects caused by indomethacin and celecoxib in rats

OBJETIVO: Avaliar e comparar macro e microscopicamente as lesões agudas da mucosa gástrica de ratos provocadas pelos AINEs celecoxib e indometacina e a citoproteção gástrica com omeprazol e misoprostol. MÉTODOS: A amostragem consistiu 150 ratos machos da raça Wistar, com peso médio de 200g, divididos em quatro grupos, a saber: grupo A, subdividido em grupos A1 e A2 – pré-tratamento com omeprazol (20 mg/rato) durante sete dias, e no oitavo dia receberam o AINEs, sendo A1 (20 ratos) receberam celecoxib (1mg/rato) e A2 (20 ratos) receberam indometacina (12,5mg/rato). O grupo B, subdividido em grupo B1 e B2 – pré-tratamento com misoprostol (20ìg/rato) durante sete dias e no oitavo dia receberam AINEs, sendo B1 (20 ratos) receberam celecoxib (1mg/rato) e B2 (20 ratos) receberam indometacina (12,5mg/rato). O grupo C não recebeu citoproteção durante sete dias e no oitavo dia recebeu AINEs, sendo C1 (20 ratos) receberam celecoxib (1mg/rato) , C2 (20ratos) receberam indometacina (12,5mg/rato), C3 (20 ratos) receberam celecoxib e grupo D – grupo controle, no qual dez ratos foram observados recebendo ração e água ad libitum. A seguir, no 9º dia (de todos os grupos), os estômagos eram removidos e avaliados macro e microscopicamente para a identificação das lesões gástricas. RESULTADOS: Na análise macroscópica, os grupos A2, B2 e C2 apresentaram número de lesões por cm2/animal significativamente elevados, sendo respectivamente 18,55 lesões por cm2/animal, 16,25 lesões por cm2/animal e 13,55 lesões por cm2/animal. Na análise microscópica, a porcentagem da mucosa com lesão mostrou diferença significativa entre os grupos A1, B1, C1 quando comparados com os grupos A2, B2 e C2 (p<0,0001). Os resultados da média da extensão/lesão e da média da profundidade das lesões não mostraram diferenças estatísticas significativas entre os grupos A2, B2 e C2. A média do edema mostrou diferença estatística significativa entre os grupos A2 e D; B2 e C2 e entre C2 e D (p<0,05)...

Estudo de efeitos antibacterianos do derivado pirazolonico: 3-Metil-IH, 6H-Pirano[2,3-C] Pirazol-6-Ona / Effect of study antibacterial activities of the pyrazolonic derivative: 3 Metyl-1H, 6H-Pyrano[2,3-C]-Pyrasol-6-One

Objetivo principal foi de identificar e caracterizar atividades antibacterianas no derivado pirazolônico (DP) - 3-metil-1H, 6H-piranozol-6-ona, sintetizado no Laboratório de Sintese Orgânica do Instituto de Química da Universidade Federal Fluminense - UFF. O DP mostrou atividade contra as seguintes bactérias clínicas (1cepa de cada): Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus faecalis e outro Streptococccus do grupo D. Os resultados mostraram que o derivado pirazolônico (DP) sintetizado no Instituto de Química - UFF e bactericida contra diferentes especies clínicas, embora esta atividade seja baixa em relaçäo aquelas exibidas pelos antibióticos de uso clínico contra as mesmas bactérias testados em nossas experiências. Isto näo invalida a possibilidade de que o DP possa vir a ser uma droga efetiva para a antibioticoterapia, na medida em que tenhamos sucesso nas próximas etapas do Projeto: aumento da solubilizaçäo da droga, massificaçäo e diversificaçäo dos testes contra bactérias clínicas e demonstraçäo de sua atoxidade e de sua eficácia terapêutica in vivo