Eficácia e segurança da tripla terapia com Selexipague comparada à dupla terapia para tratamento de hipertensão arterial pulmonar: revisão rápida de evidências / Effectiveness and safety of triple therapy with Selexipag compared dual therapy for treatment of pulmonary arterial hypertension: rapid response review of evidence

Selexipague e outros medicamentos de controle da Hipertensão Arterial Pulmonar grupo 1. Indicação: Tratamento de Hipertensão Arterial Pulmonar grupo 1. Pergunta: Há superioridade em eficácia e segurança da tripla terapia com selexipague, comparado a dupla terapia, disponível no SUS, no tratamento de Hipertensão Arterial Pulmonar grupo 1? Métodos: Revisão rápida de evidências (overview) de ensaios clínicos randomizados e revisões sistemáticas, com levantamento bibliográfico realizado na base de dados PUBMED, utilizando estratégia estruturada de busca. A qualidade metodológica das revisões sistemáticas foi avaliada pela ferramenta risco de viés da Cochrane. Resultados: Foi selecionado um ensaio clínico randomizado, especificamente um artigo contendo análise de subgrupo de dados desse estudo. Conclusão: As evidências demonstraram redução do número de hospitalizações relacionadas à HAP e de eventos de progressão da doença no tratamento de selexipague em tripla terapia em pacientes na classe funcional II, quando comparada à dupla terapia sem selexipague. A tripla terapia é tão segura quanto a dupla terapia, pois tem riscos similares de eventos adversos e eventos adversos sérios. A tripla terapia não é diferente da dupla terapia no risco da mortalidade geral

Selexipag and other drugs for the control of Pulmonary Arterial Hypertension group 1. Indication: Treatment of Pulmonary Arterial Hypertension group 1. Question: Is there superiority in efficacy and safety of triple therapy with selexipag, compared to dual therapy, available in the SUS, in the treatment of ulmonary Arterial Hypertension group 1? Methods: Rapid review of evidence (overview) of randomized clinical trials and systematic reviews, with a bibliographic survey carried out in the PUBMED database, using a structured search strategy. Results: A randomized clinical trial was selected, specifically an article showing a subgroup analysis of data from this study. Conclusion: Evidence showed a reduction in the number of Pulmonary Arterial Hypertension related hospitalizations and disease progression events in the treatment of selexipag in triple therapy in patients in functional class II, when compared to dual therapy without selexipag. Triple therapy is as safe as dual therapy, as it has similar risks of adverse events and serious adverse events. Triple therapy is no different from dual therapy in the risk of overall mortality

The Effect of Bortezomib on Expression of Inflammatory Cytokines and Survival in a Murine Sepsis Model Induced by Cecal Ligation and Puncture

PURPOSE: Although the proteasome inhibitor known as bortezomib can modulate the inflammatory process through the nuclear factor-kappa B signaling pathway, the immunomodulatory effect of pre-incubated bortezomib has not been fully evaluated for inflammation by infectious agents. Therefore, we evaluated the effect of bortezomib on the expression of inflammatory cytokines and mediators in macrophage cell lines and on survival in a murine peritonitis sepsis model. MATERIALS AND METHODS: Bortezomib was applied 1 hr before lipopolysaccharide (LPS) stimulation in RAW 264.7 cells. The cecal ligation and puncture (CLP) experiments were performed in C57BL/6J mice. RESULTS: Pre-incubation with bortezomib (25 nM or 50 nM) prior to LPS (50 ng/mL or 100 ng/mL) stimulation significantly recovered the number of viable RAW 264.7 cells compared to those samples without pre-incubation. Bortezomib decreased various inflammatory cytokines as well as nitric oxide production in LPS-stimulated cells. The 7-day survival rate in mice that had received bortezomib at 0.01 mg/kg concentration 1 hr prior to CLP was significantly higher than in the mice that had only received a normal saline solution of 1 mL 1 hr prior to CLP. In addition, the administration of bortezomib at 0.01 mg/kg concentration 1 hr before CLP resulted in a significant decrease in inflammation of the lung parenchyma. Collectively, pretreatment with bortezomib showed an increase in the survival rate and changes in the levels of inflammatory mediators. CONCLUSION: These results support the possibility of pretreatment with bortezomib as a new therapeutic target for the treatment of overwhelming inflammation, which is a characteristic of severe sepsis.

The Effect of Bortezomib on Antibody-Mediated Rejection after Kidney Transplantation

PURPOSE: Recently, bortezomib has been used to treat antibody-mediated rejection (AMR) refractory to conventional treatment such as plasmapheresis, intravenous immunoglobulin, and rituximab. The authors aimed to describe their experiences when bortezomib was used to treat refractory AMR. MATERIALS AND METHODS: Eleven refractory AMR episodes treated with bortezomib were included in this study. The patients received one or two cycles of bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11. RESULTS: Bortezomib effectively reduced antibodies against various targets, including human leukocyte antigen (HLA) class I and II, ABO blood group antigen, and angiotensin II type 1 receptor. Antibodies were depleted or reduced significantly in eight AMR episodes. Overall, there was a significant improvement in the mean estimated glomerular filtration rate (eGFR) at 3 months after therapy (36.91+/-22.15 mL/min/1.73 m2) versus eGFR at time of AMR diagnosis (17.00+/-9.25 mL/min/1.73 m2; p=0.007). All six early-onset AMR episodes (within 6 months post-transplantation) showed full recovery of allograft function. Additionally, three of the five late-onset AMR episodes (>6 months post-transplantation) showed improved allograft function. CONCLUSION: Anti-humoral treatment based on bortezomib might be an effective strategy against refractory AMR caused by various types of antibodies. Notably, this treatment could be more effective in early-onset AMR than in late-onset AMR.

A Pilot Study of Bortezomib in Korean Patients with Relapsed or Refractory Myeloma

Recent clinical trials showed that bortezomib, a novel proteasome inhibitor, had therapeutic activity in multiple myeloma. However, there was no data about the feasibility of bortezomib in Korean patients. We performed a pilot study of bortezomib in patients with relapsed or refractory myeloma (1.3 mg/m2 twice weekly for 2 week in a 3-week cycle). Seven patients were enrolled. The median age of patients was 59 yr. All patients previously received VAD (vincristine, doxorubicin and dexamethasone) and thalidomide chemotherapy. Three patients previously received alkylator-containing chemotherapy and 4 patients, autologous stem cell transplantation. Bortezomib monotherapy resulted in 3 partial remissions (43%), 3 no changes (43%) and 1 progressive disease (14%). One patient who had no response to bortezomib monotherapy experienced partial remission after addition of dexamethasone to bortezomib. The most common serious toxicity was thrombocytopenia (grade 3/4, 10 of 20 cycles (50%)) and grade 3 peripheral neuropathy was developed in 2 of 20 cycles (10%). Drug-related adverse event led to discontinuation of bortezomib in 1 patient. There was no treatment related mortality. Overall, bortezomib seems to be effective and feasible. Conduction of larger clinical studies on Korean patients is necessary to characterize clinical efficacy and safety of bortezomib more precisely.

Central serotonergic modulation of drinking behavior induced by water deprivation: effect of a serotonergic agonist (MK-212) administered intracerebroventricularly

The present study was carried out to evaluate the participation of the serotonergic system (5-HT) in the modulation of the drinking response induced by water deprivation. Male Wistar rats implanted with a cannula in the 3rd ventricle were injected with the 5-HT1C/5-HT2 agonist 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) at doses of 0.5, 5, 25, 50 and 125 nmol/2 µl. MK-212 induced a significant reduction (p < ou = 0.05) in water intake over a period of 300 min. This result indicates that the central 5-HT system plays an important role, probably at the level of the periventricular hypothalamus, in the modulation of drinking behavior induced by water deprivation

Central serotonergic modulation of drinking behavior induced by angiotensin II and carbachol in normally hydrated rats: effect of intracerebroventricular injection of MK-212

The objective of the present study was to evaluate the role of the central erotonergic (5-HT) system in the modulation of drinking behavior induced angiotensin II (Ang II) and carbachol. Male Wistar rats implanted with a delay cannula in the 3 rd ventricle were injected with the 5-HT1C/5-HT2 agonist 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) (50 nmol/2 µl) before receiving an intracerebro-ventricular (icv) injection of Ang II or carbachol (100 ng/2 µl). MK-212 induced a significant reduction in the drinking response evoked by Ang II or carbachol which was more marked in the case of the cholinergic agonist. The results obtained suggest that thirst and water intake produced by angiotensinergic or cholinergic activation are modulated by the action of 5-HT, possibly at the level of the periventricular hypothalamus

Estudio de la eficacia y seguridad de un tratamiento a largo plazo con acipimox en hiperlipogroteinemia / Efficacy and security of a long-term treatment with acipimox in hyperlipoproteinemia

Diseño experimental: Abierto, no controlado. Número de pacientes: 117 pacientes externos (64 varones, 53 mujeres) con hiperlipoproteinemia tipo 2a, (35), 2b (38) y 4 (44). Horario de tratamiento: Los pacientes fueron instruidos para que tomaran una cápsula de 250 mg. o 400 mg. t. i. d. por un período de 6 - 24 meses. Evaluación: Mensualmente los primeros dos meses y de allí en adelante bi-mensualmente: peso corporal, ritmo cardíaco, presión sanguínea sistólica y diastólica, lípidos plasmáticos, (colesterol) total y triglicéridos). Con el mismo horario mencionado para el primer año y luego por lo menos una vez cada seis meses hemograma y bioquímica sanguínea (glicemia, uricemia, BUN, creatinina, proteínas totales, bilirrubina total, SGOT, SGPT, fosfatasa alcalina, RBC, hemoglobina, hematocrito, WBC total y diferencial, trombocitos, tiempo de protrombina), urianálisis. La electroforesis lipoproteína se hizo sólo en el momento de admisión y en algunos controles durante el estudio. Resultados: 15 pacientes interrumpieron el tratamiento: 10 debido a motivos adversos, 1 debido a enfermedad intercurrente, 1 por mejoramiento definitivo, 1 debido a empeoramiento de enfermedad concomitante y 2 se perdieron en el seguimiento. De los pacientes restantes 45, 18 y 39 completaron 6, 12 y 24 meses de tratamiento, respectivamente. Durante la prueba el peso corporal de los pacientes no cambió significativamente. a) Eficacia. Los niveles medios de triglicéridos bajaron alrededor de 57% en pacientes hiperlipoproteinémicos del tipo 4 y casi 39% en pacientes del tipo 2b con diferencias muy significativas en comparación con los valores básicos. En los pacientes del tipo 2a. la trigliceridemia bajó alrededor de 13%. Los niveles medios de colesterol total bajaron 17% en pacientes de tipo 2a y 2b y 16% en pacientes de tipo 4 con diferencias muy significativas en comparación con los valores básicos...