Blocking Adenosine/A2AR Pathway for Cancer Therapy / 中国肺癌杂志

Adenosine is a metabolite produced abundantly in the tumor microenvironment, dampening immune response in inflamed tissues via adenosine A2A receptor (A2AR) which is widely expressed on immune cells, inhibiting anti-tumor immune response accordingly. Therefore, blocking adenosine signaling pathway is of potential to promote anti-tumor immunity. This review briefly introduces adenosine signaling pathway, describes its role in regulating tumor immunity and highlights A2AR blockade in cancer therapy. Prospective anti-tumor activity of adenosine/A2AR inhibition has been revealed by preclinical data, and a number of clinical trials of A2AR antagonists are under way. Primary results from clinical trials suggest that A2AR antagonists are well tolerated in cancer patients and are effective both as monotherapy and in combination with other therapies. In the future, finding predictive biomarkers are critical to identify patients most likely to benefit from adenosine pathway blockade, and further researches are needed to rationally combine A2AR antagonists with other anti-tumor therapies.
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The variation of serum uric acid levels among patients with myocardial infarction treated with ticagrelor and the association between serum uric acid and platelet reactivity / 中华心血管病杂志

Objectives: To compare the impact of ticagrelor or clopidogrel on serum uric acid levels among patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI) and further evaluate the effects of variation of serum uric acid levels on platelet reactivity. Methods: STEMI patients who admitted to Fuwai Hospital from April 2017 to January 2020, and underwent primary PCI and discharged alive with aspirin and ticagrelor or clopidogrel were included in this study. Patients were divided into ticagrelor group and clopidogrel group. The baseline clinical data were collected. Serum uric acid and creatinine levels at baseline and 30 days post-PCI were measured. Light transmittance aggregometry was used to assess maximum aggregation rate induced by adenosine diphosphate and arachidonic acid. The changes of serum uric acid and creatinine were compared between the two groups. Multivariate logistic regression was performed to evaluate independent related factors for rise in the uric acid levels, and the effect of variation of serum uric acid level on platelet reactivity was analyzed. Results: A total of 967 patients were included, the age was (59.4±12.1) years, and 163 case were female. There were 550 cases in ticagrelor group (56.9%) and 417 cases in clopidogrel group (43.1%). Baseline serum uric acid and creatinine levels were similar between the 2 groups. At 30 days, the serum uric acid level [(347.2±96.5) mmol/L vs. (341.2±105.3) mmol/L, P=0.009] and absolute [46.4 (-2.4, 88.1) mmol/L vs. 25.0 (-21.9, 73.0) mmol/L, P=0.001] and percentage [13.2 (-0.01, 29.0) % vs. 7.9 (-5.7, 25.0) %, P=0.007] increase in the serum uric acid levels were significantly higher in ticagrelor group than in clopidogrel group. The level of serum creatinine at 30 days was significantly lower in ticagrelor group than in clopidogrel group [(89.7±21.3) μmol/L vs. (94.4±43.9) μmol/L, P<0.05], whereas there were no differences in absolute [8.0 (-1.4, 16.6) μmol/L vs. 7.8 (-2.0, 16.6) μmol/L] and percentage [10.5 (-1.7%, 22.6%) vs. 9.8 (-2.4%, 22.1%)] change in the serum creatinine between the 2 groups (all P>0.05). Logistic regression analysis showed that, after adjusting for confounding factors, ticagrelor therapy was an independent related factor of serum uric acid elevation (OR=1.582, 95% CI:1.023-2.447, P=0.039). The variation of the serum uric acid levels did not affect platelet aggregation and the percentage of high platelet reactivity in both groups. Conclusions: Ticagrelor use is related to a significant increase in the serum uric acid levels at 30 days post-PCI in this patient cohort. The variations in the uric acid levels do not increase the percentage of high platelet reactivity in STEMI patients treated with ticagrelor or clopidogrel.

Evaluation of platelet activity by multiple electrode impedance aggregometry in acute coronary syndromes: pilot study in a Brazilian tertiary-care public hospital

There is no definite recommendation for testing platelet aggregation (PA) in acute coronary syndromes (ACS) due to inconclusive evidence on the usefulness of platelet function tests to guide therapy and improve clinical outcomes. The evaluation of PA with multiple electrode impedance platelet aggregometry (MEA) may be useful to manage antiplatelet therapy and possibly influence patient outcome. The primary aim of this study was to measure PA with MEA in Brazilian patients with ACS and evaluate the association between PA and adverse clinical outcomes. Forty-seven consecutive patients admitted with ACS to a Brazilian tertiary-care public hospital were studied and PA was evaluated using MEA. Patients were followed for six months for the occurrence of all-cause death, acute myocardial infarction, or stroke. Suboptimal inhibition of PA was found in 7 patients (14.9%); 5 (10.6%) in response to ASA (acetylsalicylic acid), 2 (5.0%) to clopidogrel, and none to ticagrelor. Inadequate PA inhibition in response to ASA was significantly associated with the composite end point, but there was no significant association for insufficient PA inhibition in response to clopidogrel. This study suggested that the evaluation of PA in ACS using MEA may identify non-responders to ASA. Larger studies are necessary to define, in a public health scenario, the value of MEA in the management of ACS.

Therapeutic effect of adenosine on experimentally induced acute ulcerative colitis model in rats

Abstract Purpose To examine the therapeutic effect of external adenosine on an acetic acid-induced acute ulcerative colitis model in rats. Methods Thirty male mature rats were divided into three groups as control, acute colitis (AC) and AC+adenosine group (AC+AD). AC was induced by rectal administration of 4% acetic acid (AA). 5mg/kg/day adenosine was performed i.p for 4 weeks to AC+AD group. Rectum and colon were excised for microscopic and histopathological histopathologic evaluations, and immunohistochemical analysis of nuclear factor kappa B (NF-kB). Blood samples were collected for biochemical detection of TNF-α, Pentraxin-3 and malondialdehyde (MDA) levels. Results AC group had generalized hyperemia and hemorrhage with increased macroscopic and histopathological scores compared with control (P <0.0001) while adenosine treatment decreased these scores significantly (P <0.001), with reduced distribution of disrupted epithelium, leukocyte infiltrates, and focal hemorrhage. AC group showed significantly increased immunoexpression of NF-kB in rectum, plasma and tissue levels of TNF-α, plasma Pentraxin-3 and MDA levels (P <0.0001) while adenosine reduced these levels (P < 0.05). Conclusion Adenosine appears to promote healing of colon and rectum exposed to AA-induced AC, suggesting a boosting effect of adenosine on the intestinal immune system to cure ulcerative colitis.

Arritmias na sala de emergência e UTI. Taquicardias de QRS estreito: fundamentos para a abordagem / Arrythmias in the emergency room and ICU Narrow QRS rachycardias: bases for clinical approach

As taquicardias de QRS estreito apresentam origem supraventricular. O histórico clínico, exame físico e eletrocardiograma na sala de emergência constituem-se nas principais ferramentas para o tratamento do quadro. As taquicardias que apresentam instabilidade hemodinâmica devem ser, imediatamente, revertidas através de cardioversão elétrica sincronizada. Aquelas que se apresentam como estáveis hemodinamicamente podem, se regulares, ser tratadas através de manobras vagais ou através do uso de fármacos endovenosos. Se irregulares, podem caracterizar fibrilação e flutter atrial, sendo, então, avaliados a duração do episódio e o risco de tromboembolismo para determinar não apenas a necessidade de anticoagulação, mas também a estratégia para tratamento do quadro, seja através do controle da frequência cardíaca ou do controle do ritmo, este último podendo ser alcançado através do uso de fármacos (propafenona oral ou amiodarona endovenosa) ou da cardioversão elétrica sincronizada. Dessa forma, o papel do clínico na sala de emergência é fundamental para garantir a condução adequada dos episódios de taquicardia supraventricular, especialmente, na prevenção ou pronta intervenção em caso de deterioração hemodinâmica relacionada ao quadro

Narrow QRS tachycardias are supraventricular in origin. The clinical history, physical exam, and electrocardiogram in the emergency room are the main tools used to manage this condition. Tachycardias that present haemodynamic instability must be promptly reverted through synchronized electrical cardioversion. Those that present haemodynamic stability may be treated with vagal maneuvers or intravenous drugs. If irregular, they may take the form of atrial fibrillation or atrial flutter, and in this case, the duration of the episode and the thromboembolic risk are evaluated to determine not only the need for anticoagulation, but also the treatment strategy, whether through heart rate or rhythm control. The latter may be achieved through the use of drugs (oral propafenone or intravenous amiodarone) or synchronized electrical cardioversion. The role of the clinician in the emergency room is therefore fundamental in ensuring adequate conduct of episodes of supraventricular tachycardia, especially in prevention or prompt intervention in case of haemodynamic deterioration related to the condition

Taquicardia supraventricular paroxística durante el trabajo de parto / Paroxysmal supraventricular tachycardia during labor

Afortunadamente, las arritmias malignas en un embarazo de curso normal son raras y la mayoría de las quejas por palpitaciones se deben a arritmias benignas. Dentro de ellas las taquicardias supraventriculares paroxísticas (TSP) se describen en la literatura con relativa frecuencia y pueden ocurrir sólo, o incluso exacerbarse, durante el embarazo, debido a un efecto pro-arritmogénico de la gestación. Así en pacientes gestantes la carga hemodinámica y los cambios del tono autonómico facilitan la aparición de arritmias, más frecuentemente en mujeres con limitada reserva cardíaca y pueden llegar a comprometer la supervivencia del feto y de la madre debido a las consecuencias hemodinámicas o los efectos adversos de los tratamientos farmacológicos y no farmacológicos. Presentamos el caso de una gestante a término que durante el trabajo de parto, posterior a la administración de analgesia epidural con ropivacaína y fentanilo, sufre un cuadro de hipotensión materna y bradicardia materna/fetal mantenida que requiere ser medicada con efedrina y atropina intravenosa. Inmediatamente presenta palpitaciones y dolor torácico sostenido, diagnosticándosele TSP que cede con la administración de adenosina intravenosa, no repitiendo nuevos episodios durante el trabajo de parto ni puerperio. En nuestro caso la arritmia ocurrió como efecto adverso de la efedrina y administradas para recuperar el cuadro de hipotensión causada por la analgesia epidural.

Ischemic preconditioning vs adenosine vs prostaglandin E1 for protection against liver ischemia/reperfusion injury

Ischemia/reperfusion injury is still a major cause of morbidity and mortality during liver surgery and transplantation. A variety of surgical and pharmacological therapeutic strategies have been investigated to minimize the effects of ischemia/reperfusion. The aim of our study was to analyze and compare preventive influences of ischemic preconditioning, adenosine and prostaglandin E1 in the experimental model of hepatic ischemia/reperfusion injury. Adult chinchilla rabbits were divided into four groups: 10 rabbits subjected to liver ischemic preconditioning (3-min period of inflow occlusion followed by a 5-min period of reperfusion) followed by 45 min of Pringle maneuver; 10 rabbits subjected to pre-treatment with intraportal injection of adenosine followed by 45 min of Pringle maneuver; 10 rabbits subjected to pre-treatment with intraportal injection of prostaglandin E1 followed by 45 min of Pringle maneuver; and control group of 10 rabbits subjected to 45 min of inflow liver ischemia without any preconditioning. On the second postoperative day, blood samples were obtained and biochemical parameters of liver function were measured and compared. Liver tissue samples were also obtained and histopathological changes were compared. Based on biochemical and histopathological parameters, it was demonstrated that ischemic preconditioning provided the best protection against hepatic ischemia/reperfusion injury. This was probably due to a wider range of mechanisms of action of this method oriented to reduce oxidative stress and inflammation, and restore liver microcirculation and hepatocyte energy compared to the examined pharmacological strategies.

Cost-effectiveness analysis of ticagrelor compared to clopidogrel for the treatment of patients with acute coronary syndrome in Colombia / Análisis de costo-efectividad del ticagrelor en comparación con el clopidogrel para el tratamiento de pacientes con síndrome coronario agudo en Colombia

Introduction: Acute coronary syndrome is one of the most frequent medical emergencies in developing countries. Objective: To determine, from the perspective of the Colombian health system, the cost-effectiveness of ticagrelor compared to clopidogrel for the treatment of patients with acute coronary syndrome. Materials and methods: We conducted a cost-effectiveness analysis from the perspective of the Colombian health system comparing ticagrelor and clopidogrel for the treatment of patients with acute coronary syndrome. To estimate the expected costs and outcomes, a Markov model was constructed in which patients could remain stable without experiencing new cardiovascular events, suffer from a new event, or die. For the baseline case, a 10-year time horizon and a discount ratio of 3% for costs and benefits were adopted. The transition probabilities were extracted from the PLATO (Platelet Inhibition and Patient Outcomes) clinical trial. Vital statistics were drawn from the Departmento Administrativo Nacional de Estadística (DANE) and additional information from Colombian patients included in the Access registry. To identify and measure resource use, a standard case was built by consulting guidelines and protocols. Unit costs were obtained from Colombian rate lists. A probabilistic sensitivity analysis was conducted in which costs were represented by a triangular distribution, and the effectiveness through a beta distribution. Results: In the base case, the additional cost per quality-adjusted life-year gained with ticagrelor was COP$ 28,411,503. The results were sensitive to changes in the time horizon and the unit cost of clopidogrel. For a willingness-to-pay equivalent to three times the Colombian per capita gross domestic product, the probability of ticagrelor being cost-effective was 75%. Conclusions: Ticagrelor is a cost-effective strategy for the treatment of patients with acute coronary syndrome in Colombia.

Introducción. El síndrome coronario agudo es una de las emergencias médicas más frecuentes en los países en desarrollo. Objetivo. Determinar, desde la perspectiva del sistema de salud colombiano, la relación de costo-efectividad del ticagrelor comparado con el clopidogrel para el tratamiento de pacientes con síndrome coronario agudo. Materiales y métodos. Se hizo un análisis de costo-efectividad desde la perspectiva del sistema de salud colombiano, comparando el ticagrelor y el clopidogrel para el tratamiento de pacientes con síndrome coronario agudo. Para estimar los costos y resultados esperados de las dos alternativas, se construyó un modelo de Markov en el cual los pacientes podían permanecer estables sin experimentar nuevos eventos cardiovasculares, sufrir de un nuevo evento coronario o morir. Para el caso de base, se adoptó un horizonte temporal de 10 años y una tasa de descuento de 3 % para los costos y beneficios. Las probabilidades de transición se extrajeron del estudio Platelet Inhibition and Patient Outcomes , PLATO. Las estadísticas vitales se consultaron en informes del Departamento Administrativo Nacional de Estadística (DANE) y los parámetros adicionales del modelo se basaron en la información de los pacientes colombianos incluidos en el registro en Access. Para identificar y medir el uso de recursos, se construyó un caso estándar a partir de guías y protocolos. Los costos unitarios se obtuvieron de manuales tarifarios colombianos. Se hizo un análisis de sensibilidad probabilístico en el que los costos se representaron por una distribución triangular y, las probabilidades de transición, mediante una distribución beta. Resultados. En el caso de base, el costo adicional por años de vida ajustados por calidad ganados con el ticagrelor fue de COP$ 28´411.503. Los resultados fueron sensibles a los cambios en el horizonte temporal y al costo unitario del clopidogrel. Para un umbral de costo-efectividad equivalente a tres veces el producto interno bruto per cápita de Colombia, la probabilidad de que el ticagrelor fuera costo-efectivo fue de 75 %. Conclusiones. El ticagrelor es una estrategia costo-efectiva para el tratamiento de los pacientes con síndrome coronario agudo en Colombia.

Ticagrelor en el síndrome coronario agudo. Explicando lo inexplicable / [Ticagrelor in acute coronary syndrome. Explaining the inexplicable]

The PLATO study evaluated the efficacy of adding ticagrelor, instead of clopidogrel, to aspirin in patients with acute coronary syndrome, which showed surprisingly positive results making the drug acceptable to regulatory agencies and specialty societies worldwide. Notwithstanding the aforementioned success, contradictory information supplied by critical analysis was submitted by the sponsor. The controversial findings revealed several aspects that are difficult to explain, threatening the veracity of the study’s conclusions. Mortality rate pattern, excessive benefit not comparable to prior studies, unexplained loss of follow-up development and inconsistency in findings in accordance with the country, the type of events arbitrator and monitoring committee are some of the most questionable issues. Dubious reaction to this trial is based on the fact that the information could not be found in published articles. This complex situation poses a challenge to the critical analysis of the text and raises questions as to how far the conflicts of financial interest influenced the development of the study, the communication of its results and probably, acceptance of the drug for commercial use.

P2Y12 inhibitors in acute coronary syndromes: Which and when.

Acute coronary syndromes (ACS) are the commonest acute manifestation of coronary artery disease and a major cause of hospitalization and death. Plaque rupture and subsequent platelet activation are the key factors in its pathogenesis. Platelet inhibitors are crucial in the management of ACS. Aspirin remains the standard antiplatelet but use of dual antiplatelet drugs is beneficial in ACS. Platelet P2Y12 receptor inhibitors are an important group of antiplatelet compounds that can be combined with aspirin in the management of ACS. P2Y12 inhibitors may belong to the thienopyridine or nonthienopyridine group of compounds. The former (clopidogrel, prasugrel) combine irreversibly with the receptor and therefore have a prolonged duration of action. On the other hand, the non-thienopyridine compounds (ticagrelor, elinogrel) have a reversible action and hence a shorter duration of action. Several new compounds in this group have become or are likely to become available. The newer agents have a more uniform and complete antiplatelet effect and are much less likely to be affected by genetic variability of CYP2C19 enzyme activity compared with that of clopidogrel. Large phase 3 trials have shown that ticagrelor and prasugrel reduce major cardiovascular events in ACS compared to clopidogrel when given in addition to aspirin. This is accompanied by some increase in bleeding. This review discusses the properties, clinical profile and possible place of P2Y12 receptor inhibitors in clinical practice.

Ventricular tachycardia in structurally normal hearts: recognition and management.

Idiopathic ventricular tachycardia is a defined set of tachycardias when structural or pathological cause has been ruled out for the same. This paper tries to define and classify these arrhythmias to organize a logical therapeutic approach to deal with them. 60-80% of the idiopathic tachycardias originate from the right ventricular outflow tract (RVOT) and in 10% from the left ventricular outflow tract (LVOT). Outflow tract tachycardias have either LBBB or RBBB morphology with early R wave transition in chest leads. Adenosine, beta blockers and calcium channel blockers is the common medical treatment. Radiofrequency ablation is however the treatment of choice. Verapamil sensitive left ventricular tachycardia (ILVT) and propranolol sensitive left ventricular tachycardia (IPVT) are the other two forms recognized. RF ablation seems ideal for long-term management of ILVT and implantable cardioverter defibrillator (ICD) for IPVT. Inherited channelopathies include catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome and long QT syndrome where there is an inherited disorder in the ion-exchange channels of the cell-membrane leading to tachycardia. Prognosis in these is variable; CPVT, in particular, has a malignant course when untreated. RF ablation and placement of an ICD are important in the overall management of specific arrhythmia.

Refractory adenosine-sensitive congenital His bundle tachycardia: response to calcium-channel blockers.

The congenital form of His bundle tachycardia is an uncommon pediatric arrhythmia. We report the case of a 7-year-old child with tachycardiomyopathy. The incessant arrhythmia, detected in infancy, was resistant to amiodarone and beta-blockers. During electrophysiologic study, the tachycardia converted to sinus rhythm with intravenous adenosine and diltiazem. Subsequently, the child is maintaining sinus rhythm on oral verapamil. Calcium-channel blockers should be considered for the treatment of this arrhythmia, which is often resistant to multiple antiarrhythmic drugs.

Treatment of recurrent attacks of supraventricular tachycardia during pregnancy causing complications in both mother and fetus.

Cardiac arrhythmias including supraventricular tachycardia are commonly encountered during pregnancy. The case of a young Indian woman with recurrent attacks of supraventricular tachycardia during pregnancy which was managed with adenosine and verapamil is reported. The possible mechanisms of maternal and fetal complications are discussed.

Taquiarritmias supraventriculares no feto. Experiência de uma unidade de referência em cardiologia fetal / Fetal supraventricular Tachyarrhythmias. Experience of a fetal cardiology reference center

OBJETIVO: Avaliar a forma de apresentaçäo, diagnóstico e tratamento das taquiarritmias supraventriculares fetais, através do relato de uma série de casos acompanhados em um centro terciário de cardiologia fetal. MÉTODOS: Säo descritos 25 casos de taquiarritmia supraventricular diagnosticados intra-útero, no período de janeiro/89 a outubro/97, em uma populaçäo compreendendo 3117 gestantes. RESULTADOS: Foram diagnosticados 17 casos taquiarritmia supraventricular e 8 casos de flutter atrial fetal. As idades gestacionais variam de 26 a 40 semanas. Doze fetos apresentavam hidropisia no momento do diagnóstico (6 com taquicardia supraventricular (TSV) e 6 com flutter atrial). Quatro fetos com TSV apresentavam cardiopatias estruturais (dois casos de anomalia de Ebstein e dois com comunicaçäo interventricular). Todos os fetos foram internados na Unidade de Cardiologia Fetal para monitorizaçäo e tratamento. Entre os 17 fetos com TSV, 12 apresentaram reversäo da arritmia após administraçäo de digoxina, mas esta medida näo foi eficaz em nenhum paciente com flutter. Dois pacientes com TSV e seis com necessitaram interrupçäo da gestaçäo para cardioversäo elétrica pós-natal. A mortalidade foi de 3/17 no grupo da TSV (incluindo dois pacientes com anomalia de Ebstein) e de 0/8 no grupo com flutter. CONCLUSÄO: As taquiarritmias supraventriculares fetais säo enventos raros na populaçäo geral. Entretanto, podem provocar insuficiência cardíaca e óbito intrauterino. Como a resposta ao tratamento é satisfatória, tornam-se de extrema importância o diagnóstico precoce e o tratamento adequado.

Tratamiento de la taquicardia supraventricular en pediatría / Treatment of supraventricular tachycardia in pediatrics

Las arritmias sintomáticas en la edad pediátrica son excepcionales, siendo la más común la taquicardia supraventricular (TSV). Se trata de una alteración del ritmo originada proximal a la bifurcación del haz de His, y puede deberse al aumento de automatismo, o a un mecanismo de reentrada. El diagnóstico preciso de la arritmia puede obtenerse mediante el análisis cuidadoso del electrocardiograma durante y después de la crisis. Aunque es bien tolerada en las primeras horas, puede causar un deterioro serio del estado hemodinámico del niño y comprometer su vida si se prolonga demasiado o se asocia a cardiopatía. El tratamiento de la TSV en su fase aguda depende del estado clínico del paciente y comprende medidas accesibles en todo nivel de atención médica. Los métodos diagnósticos actuales, incluyendo la etapa prenatal, y la terapéutica definitiva de las arritmias en constante avance, son recursos recientes cuya aplicación debe considerarse en los niños afectados por estos problemas

Experiência clínica com o uso de adenosina em pacientes pediátricos / Clinical experience with use of adenosine in pediatric patients

Descrevemos nossa experiência com o uso de adenosina no diagnóstico e tratamento de quatro pacientes pediátricos com taquicardia supraventricular. Brevemente, revisamos o reconhecimento e manejo das taquidisritmias supraventriculares em crianças, bem como a farmacocinética, indicaçoes e efeitos colaterais associados ao uso de adenosina. Concluímos que a adenosina é uma nova droga antiarrítmica segura e eficaz no tratamento e diagnóstico das taquidisritmias com complexo QRS estreito em pediatria, inclusive no período neonatal. Com adequada monitorizaçao eletrocardiográfica, sua utilizaçao torna-se importante subsídio para o diagnóstico de diversos outros ritmos supraventriculares.