Economic Evaluation of Ticagrelor for Secondary Prevention Following Acute Coronary Syndromes

INTRODUCTION AND OBJECTIVES: To estimate the cost-effectiveness and cost-utility of ticagrelor in the treatment of patients with acute coronary syndromes (unstable angina or myocardial infarction with or without ST-segment elevation), including patients treated medically and those undergoing percutaneous coronary intervention or coronary artery bypass grafting. METHODS: A short-term decision tree and a long-term Markov model were used to simulate the evolution of patients' life-cycles. Clinical effectiveness data were collected from the PLATO trial and resource use data were obtained from the Hospital de Santa Marta database, disease-related group legislation and the literature. RESULTS: Ticagrelor provides increases of 0.1276 life years and 0.1106 quality-adjusted life years (QALYs) per patient. From a societal perspective these clinical gains entail an increase in expenditure of €610. Thus the incremental cost per life year saved is €4780 and the incremental cost per QALY is €5517. CONCLUSIONS: The simulation results show that ticagrelor reduces events compared to clopidogrel. The costs of ticagrelor are partially offset by lower costs arising from events prevented. The use of ticagrelor in clinical practice is therefore cost-effective compared to generic clopidogrel.

Intraocular Pressure in Eyes Receiving Intravitreal Antivascular Endothelial Growth Factor Injections

PURPOSE: The aim of the this study was to determine the effect of intravitreal antivascular endothelial growth factor injections on intraocular pressure (IOP) and identify possible risk factors for the development of increased IOP. MATERIALS AND METHODS: This prospective study included a total of 106 eyes receiving intravitreal injection of bevacizumab as treatment for macular edema or active choroidal neovascularization. IOP was measured by Goldmann applanation tonometry immediately before the intravitreal injection and 5 min, 1 h and 15 days after the procedure. The records of the study patients were reviewed for age, gender, history of glaucoma, diabetes mellitus, phakic status, systemic and topical medication and number of previous injections. Subconjunctival reflux was registered. IOP elevation was defined as IOP ≥21 mm Hg and/or a change from baseline of ≥5 mm Hg recorded at least on two or more measurements on the same visit. RESULTS: Mean preoperative IOP was 15.31 ± 3.90 mm Hg and postoperative IOP values were 27.27 ± 11.87 mm Hg (after 5 min), 17.59 ± 6.24 mm Hg (after 1 h) and 16.86 ± 3.62 mm Hg (after 15 days). The IOP variation was statistically significant between pre- and postoperative measurements (p < 0.05). Subconjunctival reflux was recorded in 11.3%, and in this subgroup the IOP at 5 min and at 1 h was lower than preoperative IOP (p < 0.05). CONCLUSIONS: More than one third of the eyes achieved IOPs >30 mm Hg 5 min after injection. Subconjunctival reflux contributed to a lower mean postoperative IOP (p < 0.05). Considerations for the management include prophylactic IOP lowering with medical therapy and/or preinjection ocular decompression for patients with a history of glaucoma or ocular hypertension and switching to an as-needed injection protocol in patients suffering a marked IOP rise in previous injections. © 2015 S. Karger AG, Basel.

Homogneous time resolved fluorescence: a new technique for detection and quantifications of infliximab in autoimmune patients

RESUMO:As terapias biológicas revolucionaram o tratamento das doenças autoimunes nos últimos anos. Tipicamente têm como alvos mediadores importantes no mecanismo das doenças. Os antagonistas do fator de necrose tumoral-α (TNF-α) são um grupo de agentes biológicos muito prescrito, pois estão indicados no tratamento de doenças imuno-mediadas comuns, tais como artrite reumatoide, artrite idiopática juvenil, artrite psoriática, espondilite anquilosante, doença de Crohn e colite ulcerosa. Com o uso frequente de inibidores do TNF-α, tem-se tornado evidente que estes agentes têm um potencial imunogénico importante, que pode comprometer o prognóstico a longo prazo dos doentes cronicamente tratados. A produção de anticorpos anti-fármaco parece causar falência terapêutica secundária em muitos doentes. Um dos efeitos dos anticorpos anti-fármaco é o aumento da eliminação do fármaco. A eliminação do fármaco, por sua vez, varia entre indivíduos, refletindo diferentes perfis farmacocinéticos. A determinação dos níveis séricos mínimos do agente anti-TNF-α é assim muito informativa e pode auxiliar nas decisões terapêuticas. Contudo, os testes imunológicos para determinar as concentrações séricas do fármaco não estão facilmente disponíveis na prática clínica. De forma a investigar uma nova técnica potencialmente fidedigna e prática para a deteção e quantificação dos agentes biológicos anti-TNF-α, foi testada a técnica por HTRF (homogeneous time-resolved fluorescence resonance energy transfer) para a determinação de concentrações séricas de infliximab. Apesar de apresentar algumas limitações relacionadas com as condições de leitura da fluorescência, esta técnica provou obter resultados próximos das concentrações obtidas por ELISA (enzyme-linked immunosorbent assay) bridging. Adicionalmente, tem a vantagem de ser de execução muito mais fácil e rápida. Deste modo, a técnica por HTRF poderá ser otimizada e tornar-se uma valiosa ferramenta laboratorial para orientar as decisões terapêuticas em doentes autoimunes com falência da terapêutica anti-TNF-α.--------- ABSTRACT: Biologic therapies revolutionized the treatment of autoimmune diseases in the last years. Typically, they target important disease mediators. Tumor necrosis factor-alpha (TNF-α) antagonists constitute a very prescribed group of biologic agents as they are indicated for the treatment of common immune-mediated diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease and ulcerative colitis. With the increasing use of TNF-α inhibitors it has been noticed that they have an important immunogenic potential that can compromise long-term outcomes in chronically treated patients. The production of anti-drug antibodies seems to cause secondary therapeutic failure in many patients. One of the effects of anti-drug antibodies is the enhancement of drug clearance. Drug clearance, in turn, varies among individuals, reflecting different pharmacokinetic profiles. Determination of serum anti-TNF-α drug trough levels is though very informative and could support treatment decisions. However, immunologic assays to determine drug serum concentrations are not readily available in clinical practice. In order to investigate a potentially reliable and practical new technique for detection and quantification of anti-TNF-α biologic agents, homogeneous time-resolved fluorescence resonance energy transfer (HTRF) technique was tested for determination of serum infliximab concentrations. Although presenting some limitations related with fluorescence reading conditions, this technique proved to give results close to the concentrations obtained by the widely used bridging enzyme-linked immunosorbent assay (ELISA). In addition, it has the advantage of being much easier and faster to perform. Thus, HTRF technique can be optimized and become a valuable laboratorial tool to guide treatment decisions in autoimmune patients with anti-TNF-α therapy failure.

Post-Treated Prostate Cancer: Normal Findings and Signs of Local Relapse on Multiparametric Magnetic Resonance Imaging

The use of multiparametric magnetic resonance imaging (mp-MRI) for prostate cancer has increased over recent years, mainly for detection, staging, and active surveillance. However, suspicion of recurrence in the set of biochemical failure is becoming a significant reason for clinicians to request mp-MRI. Radiologists should be able to recognize the normal post-treatment MRI findings. Fibrosis and atrophic remnant seminal vesicles after prostatectomy are often found and must be differentiated from local relapse. Moreover, brachytherapy, external beam radiotherapy, cryosurgery, and hormonal therapy tend to diffusely decrease the signal intensity of the peripheral zone on T2-weighted images (T2WI) due to the loss of water content, consequently mimicking tumor and hemorrhage. The combination of T2WI and functional studies like diffusion-weighted imaging and dynamic contrast-enhanced improves the identification of local relapse. Tumor recurrence tends to restrict on diffusion images and avidly enhances after contrast administration either within or outside the gland. The authors provide a pictorial review of the normal findings and the signs of local tumor relapse after radical prostatectomy, external beam radiotherapy, brachytherapy, cryosurgery, and hormonal therapy.

Baseline Susceptibility of Primary HIV-2 to Entry Inhibitors

BACKGROUND: The baseline susceptibility of primary HIV-2 to maraviroc (MVC) and other entry inhibitors is currently unknown. METHODS: The susceptibility of 19 HIV-2 isolates obtained from asymptomatic and AIDS patients and seven HIV-1 clinical isolates to the fusion inhibitors enfuvirtide (ENF) and T-1249, and to the coreceptor antagonists AMD3100, TAK-779 and MVC, was measured using a TZM-bl cell-based assay. The 50% inhibitory concentration (IC(50)), 90% inhibitory concentration (IC(90)) and dose-response curve slopes were determined for each drug. RESULTS: ENF and T-1249 were significantly less active on HIV-2 than on HIV-1 (211- and 2-fold, respectively). AMD3100 and TAK-779 inhibited HIV-2 and HIV-1 CXCR4 tropic (X4) and CCR5 tropic (R5) variants with similar IC(50) and IC(90) values. MVC, however, inhibited the replication of R5 HIV-2 variants with significantly higher IC(90) values (42.7 versus 9.7 nM; P<0.0001) and lower slope values (0.7 versus 1.3; P<0.0001) than HIV-1. HIV-2 R5 variants derived from AIDS patients were significantly less sensitive to MVC than variants from asymptomatic patients, this being inversely correlated with the absolute number of CD4(+) T-cells. CONCLUSIONS: T-1249 is a potent inhibitor of HIV-2 replication indicating that new fusion inhibitors might be useful to treat HIV-2 infection. Coreceptor antagonists TAK-779 and AMD3100 are also potent inhibitors of HIV-2 replication. The reduced sensitivity of R5 variants to MVC, especially in severely immunodeficient patients, indicates that the treatment of HIV-2-infected patients with MVC might require higher dosages than those used in HIV-1 patients, and should be adjusted to the disease stage.

Adult B-Cell Acute Lymphoblastic Leukemia Cells Display Decreased PTEN Activity and Constitutive Hyperactivation of PI3K/Akt Pathway Despite High PTEN Protein Levels

Adult B-cell acute lymphoblastic leukemia remains a major therapeutic challenge, requiring a better characterization of the molecular determinants underlying disease progression and resistance to treatment. Here, using a phospho-flow cytometry approach we show that adult diagnostic B-cell acute lymphoblastic leukemia specimens display PI3K/Akt pathway hyperactivation, irrespective of their BCR-ABL status and despite paradoxically high basal expression of PTEN, the major negative regulator of the pathway. Protein kinase CK2 is known to phosphorylate PTEN thereby driving PTEN protein stabilization and concomitant PTEN functional inactivation. In agreement, we found that adult B-cell acute lymphoblastic leukemia samples show significantly higher CK2 kinase activity and lower PTEN lipid phosphatase activity than healthy controls. Moreover, the clinical-grade CK2 inhibitor CX-4945 (Silmitasertib) reversed PTEN levels in leukemia cells to those observed in healthy controls, and promoted leukemia cell death without significantly affecting normal bone marrow cells. Our studies indicate that CK2-mediated PTEN posttranslational inactivation, associated with PI3K/Akt pathway hyperactivation, are a common event in adult B-cell acute lymphoblastic leukemia and suggest that CK2 inhibition may constitute a valid, novel therapeutic tool in this malignancy.

Migration and differentiation of neuronal precursors in the postnatal brain: insights from the subventricular zone and cerebellum

Fundação para a Ciência e a Tecnologia - SFRH/BD/42848/2008, através do Programa MIT_Portugal em Sistemas de Bioengenharia; projectos PTDC/SAUNEU/104415/2008 e Projecto ref. 96542 da Fundação Caloust Gulbenkian

Adesão terapêutica e hipertensão arterial : o uso de fontes administrativas de dados de prescrição e levantamento de medicação na estimação da adesão à terapêutica com antagonistas dos recetores da angiotensina

RESUMO - Objetivos: São objetivos do presente estudo caraterizar a adesão terapêutica, primária e secundária, na Região de Saúde do Alentejo em utentes que seguiram tratamento para Hipertensão Arterial com Antagonistas dos Receptores da Angiotensina e constatar se a adopção de diferentes medidas produz diferentes resultados de adesão terapêutica. Metodologia: Este estudo é uma análise retrospetiva da prescrição e levantamento de ARA nos anos de 2010 e 2011 na Região de Saúde do Alentejo. Foram considerados 22.450 utentes e cinco diferentes medidas de adesão terapêutica: Rácio de Adesão Primária, Medication Possession Ratio, Compliance Rate, Refill Compliance Rate, Continuous Measure of Medication Gaps. Resultados: Constatou-se que a adesão terapêutica primária para os 22.450 utentes considerados na amostra foi de 0,612 (DP 0,325), a adesão terapêutica medida pelo indicador MPR foi de 0,557 (DP 0,380), pelo indicador CR foi de 0,697 (DP 0,517), pelo indicador RCR foi de 0,695 (DP 0,518) e pelo indicador CMG foi de 0,648 (DP 0,351). Independentemente do indicador considerado, a adesão terapêutica foi mais elevada no sexo feminino do que no sexo masculino, os utentes do sexo feminino apresentaram níveis de sobre-aquisição de medicação mais elevados e a prevalência de utentes que no período não chegaram a levantar nenhuma embalagem de medicação, não obstante a necessidade clínica ter sido identificada em pelo menos 2 momentos no período, foi mais elevada no sexo masculino. As faixas etárias acima dos 70 anos apresentaram níveis médios de adesão terapêutica significativamente superiores aos verificados nas faixas etárias que compreendem os utentes em idade ativa. Constatou-se que os concelhos que apresentaram resultados de adesão terapêutica inferiores à média amostral por um determinado indicador, em regra, viram confirmada essa tendência pelos restantes indicadores. Não obstante, verificou-se que os rankings de desempenho obtidos pelos cinco indicadores apresentaram concordância estatística fraca. Conclusões: Concluiu-se que, não obstante a existência de um conjunto de limitações e condicionalismos metodológicos, os dados atualmente recolhidos ao nível da prescrição e conferência de receituário permitem a mensuração dos comportamentos de adesão terapêutica. A inexistência de consenso científico terminológico tem conduzido à proliferação de indicadores com o fito de medir a adesão terapêutica que, sendo conceptualmente distintos na sua construção, conduzem a diferentes resultados de adesão terapêutica. Os resultados obtidos pelo presente estudo permitiram confirmar este aspecto pelo que não se recomenda a utilização de apenas um indicador para análise dos comportamentos de adesão terapêutica dos utentes.

Neuroendocrine factors regulate retinoic acid receptors in normal and hypoplastic lung development

Congenital diaphragmatic hernia (CDH) is characterised by a spectrum of lung hypoplasia and consequent pulmonary hypertension, leading to high morbidity and mortality rates. Moreover, CDH has been associated with an increase in the levels of pulmonary neuroendocrine factors, such as bombesin and ghrelin, and a decrease in the action of retinoic acid (RA). The present study aimed to elucidate the interaction between neuroendocrine factors and RA. In vitro analyses were performed on Sprague-Dawley rat embryos. Normal lung explants were treated with bombesin, ghrelin, a bombesin antagonist, a ghrelin antagonist, dimethylsulfoxide (DMSO), RA dissolved in DMSO, bombesin plus RA and ghrelin plus RA. Hypoplastic lung explants (nitrofen model) were cultured with bombesin, ghrelin, bombesin antagonist or ghrelin antagonist. The lung explants were analysed morphometrically, and retinoic acid receptor (RAR) α, β and γ expression levels were assessed via Western blotting. Immunohistochemistry analysis of RAR was performed in normal and hypoplastic lungs 17.5 days post-conception (dpc). Compared with the controls, hypoplastic lungs exhibited significantly higher RARα/γ expression levels. Furthermore considering hypoplastic lungs, bombesin and ghrelin antagonists decreased RARα/γ expression. Normal lung explants (13.5 dpc) treated with RA, bombesin plus RA, ghrelin plus RA, bombesin or ghrelin exhibited increased lung growth. Moreover, bombesin and ghrelin increased RARα/γ expression levels, whereas the bombesin and ghrelin antagonists decreased RARα/γ expression. This study demonstrates for the first time that neuroendocrine factors function as lung growth regulators, sensitising the lung to the action of RA through up-regulation of RARα and RARγ.

Influence of caffeine on blood pressure and platelet aggregation

OBJECTIVE: Studies have demonstrated that methylxanthines, such as caffeine, are A1 and A2 adenosine receptor antagonists found in the brain, heart, lungs, peripheral vessels, and platelets. Considering the high consumption of products with caffeine in their composition, in Brazil and throughout the rest of the world, the authors proposed to observe the effects of this substance on blood pressure and platelet aggregation. METHODS: Thirteen young adults, ranging from 21 to 27 years of age, participated in this study. Each individual took 750mg/day of caffeine (250mg tid), over a period of seven days. The effects on blood pressure were analyzed through the pressor test with handgrip, and platelet aggregation was analyzed using adenosine diphosphate, collagen, and adrenaline. RESULTS: Diastolic pressure showed a significant increase 24 hours after the first intake (p<0.05). This effect, however, disappeared in the subsequent days. The platelet aggregation tests did not reveal statistically significant alterations, at any time during the study. CONCLUSION: The data suggest that caffeine increases diastolic blood pressure at the beginning of caffeine intake. This hypertensive effect disappears with chronic use. The absence of alterations in platelet aggregation indicates the need for larger randomized studies.

Response of blood pressure to maximum exercise in hypertensive patients under different therapeutic programs

OBJECTIVE: To evaluate the behavior of blood pressure during exercise in patients with hypertension controlled by frontline antihypertension drugs. METHODS: From 979ergometric tests we retrospectively selected 49 hipertensive patients (19 males). The age was 53±12 years old and normal range rest arterial pressure (<=140/90 mmHg) all on pharmacological monotherapy. There were 12 on beta blockers; 14 on calcium antagonists, 13 on diuretics and 10 on angiotensin converting enzyme inhibitor. Abnormal exercise behhavior of blood pressure was diagnosed if anyone of the following criteria was detected: peak systolic pressure above 220 mmHg, raising of systolic pressure > or = 10 mmHg/MET; or increase of diastolic pressure greater than 15 mmHg. RESULTS: Physiologic response of arterial blood pressure occurred in 50% of patients on beta blockers, the best one (p<0.05), in 36% and 31% on calcium antagonists and on diuretics, respectively, and in 20% on angiotensin converting enzyme inhibitor, the later the leastr one (p<0.05). CONCLUSION: Beta-blockers were more effective than calcium antagonists, diuretics and angiotensin-converting enzyme inhibitors in controlling blood pressure during exercise, and angiotensin converting enzyme inhibitors the least effective drugs.

Do cardiologists at a university hospital adopt the guidelines for the treatment of heart failure?

OBJECTIVE: To verify whether the guidelines for the treatment of heart failure have been adopted at a university hospital. The guidelines recommend the following: use of angiotensin-converting enzyme inhibitors for all patients with systolic ventricular dysfunction, use of digitalis and diuretics for symptomatic patients, use of beta-blockers for patients in functional classes II or III, use of spironolactone for patients in functional classes III or IV. METHODS: We analyzed the prescriptions of 199 patients. All these patients had ejection fraction (EF) <=0.50, their ages ranged from 25 to 86 years, and 142 were males. Cardiomyopathy was the most frequent diagnosis: 67 (33.6%) patients had dilated cardiomyopathy, 65 (32.6%) had ischemic cardiomyopathy. RESULTS: Angiotensin-converting enzyme inhibitors were prescribed for 93% of the patients. 71.8% also had a prescription for digitalis, 86.9% for diuretics, 27.6% for spironolactone, 12% for beta-blockers, 37.2% for acetylsalicylic acid, 6.5% for calcium channel antagonists, and 12.5% for anticoagulants. In regard to vasodilators, 71% of the patients were using captopril (85.2mg/day), 20% enalapril (21.4mg/day), 3% hydralazine and nitrates. In 71.8% of the cases, the dosages prescribed were in accordance with those recommended in the large studies. CONCLUSION: Most patients were prescribed the same doses as those recommended in the large studies. Brazilian patients tolerate well the doses recommended in the studies, and that not using these doses may be a consequence of the physician's fear of prescribing them and not of the patient's intolerance.

Pharmacological Therapy for Myocardial Infarction in the Elderly: An 8-year Analysis

OBJECTIVE:To assess the changes in the medicamentous treatment of elderly patients hospitalized with acute myocardial infarction occurring over an 8-year period. METHODS:We retrospectively analyzed 379 patients above the age of 65 years with acute myocardial infarction who were admitted to the coronary unit of a university-affiliated hospital from 1990 to 1997. The patients were divided into 2 groups, according to the period of time of hospital admission as follows: group 1 - from 1990 to 1993; and group 2 - from 1994 to 1997. RESULTS:The use of beta-blockers (40.8%chi 75.2%, p<0.0001) and angiotensin-converting enzyme inhibitors (42% chi59.5%, p=0.001) was significantly greater in group 2, while the use of calcium antagonists (42% chi 18.5%, p<0.0001) and general antiarrhythmic drugs (19.1% chi 10.8%, p=0.03) was significantly lower. No significant difference was observed in regard to the use of acetylsalicylic acid, thrombolytic agents, nitrate, and digitalis in the period studied. The length of hospitalization was shorter in group 2 (13.4±8.9 days chi 10.5±7.5 days, p<0.001). The in-hospital mortality was 35.7% in group 1 and 26.6% in group 2 (p=0.07). CONCLUSION: Significant changes were observed in the treatment of elderly patients with acute myocardial infarction, with a greater use of beta-blockers and angiotensin-converting enzyme inhibitors and a lower use of calcium antagonists and antiarrhythmic drugs in group 2. The length of hospitalization and the mortality rate were also lower in group 2, even though the reduction in mortality was not statistically significant.

Influence of angiotensin II receptor subtypes of the paraventricular nucleus on the physiological responses induced by angiotensin II injection into the medial septal area

OBJECTIVE: We determined the effects of losartan and PD 123319 (antagonists of the AT1 and AT2 angiotensin receptors, respectively), and [Sar¹, Ala8] ANG II (a relatively peptide antagonist of angiotensin receptors) injected into the paraventricular nucleus (PVN) on water and 3% NaCl intake, and the diuretic, natriuretic, and pressor effects induced by administration of angiotensin II (ANG II) into the medial septal area (MSA) of conscious rats. METHODS: Holtzman rats were used . Animals were anesthetized with tribromoethanol (20 mg) per 100 grams of body weight, ip. A stainless steel guide cannula was implanted into the MSA and PVN. All drugs were injected in 0.5-mul volumes for 10-15 seconds. Seven days after brain surgery, water and 3% NaCl intake, urine and sodium excretion, and arterial blood pressure were measured. RESULTS: Losartan (40 nmol) and [Sar¹, Ala8] ANG II (40 nmol) completely eliminated whereas PD 123319 (40 nmol) partially blocked the increase in water and sodium intake and the increase in arterial blood pressure induced by ANG II (10 nmol) injected into the MSA. The PVN administration of PD 123319 and [Sar¹, Ala8] ANG II blocked whereas losartan attenuated the diuresis and natriuresis induced by MSA administration of ANG II. CONCLUSION: MSA involvement with PVN on water and sodium homeostasis and arterial pressure modulation utilizing ANGII receptors is suggested.

Presença de substâncias fisològicamente ativas em culturas de E. Coli isolados das fezes de pacientes alérgicos pela técnica de Heist-Cohen

Four patients with several allergic symptoms have been studied. Heist-Cohen pathogen selective method was positive in feces of all these patients for E. coli. Other causes that could be responsible for the allergic symptoms were discarded. Samplets after seeding in a medium physiologically inactive have been tested in guinea pig illea following Cohnheim-Magnus technique. It was demonstrated that all samples isolated by the Heist-Cohen technique were physiologically active.(Fig.1). Ten other strains of E. coli taken at random from the collection of I.O.C. and tried according similar technique, brought evidence that only three samples possessed such activity. This confirms the works of KOESSLER-HANKE (1922). In order to obtain a quick relief from allergic symptoms, one of us had employed in some others, identical cases an antibiotic (Teramycin, Chas Pfeizer) before the specific disesitization was done (Figs. 2, 3, 4, 5). Such method were choice since LABORDE, PARROT, and URQUIA (1953) have demonstrated the importance of production of histamine, from components of the bowel's flora in the production of allergic symptoms.