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1.
Hell J Nucl Med ; 22(2): 135-139, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31273356

RESUMO

SUBJECT AND METHODS: A total of 40 patients (M:F::26:14; age range: 37-84yrs; mean: 64.1yrs) with known chronic obstructive pulmonary disease (COPD) (ranging from mild to severe), referred for a stress myocardial perfusion study, were included in this study over a period of one year. All patients underwent adenosine stress in a titrated protocol and pre-infusion of short acting bronchodilator salbutamol 2 puffs few minutes prior to start adenosine infusion. In a fraction of 26 patients, pulmonary function tests (PFT) were performed and used in addition to clinical examination to classify the severity of pulmonary obstruction. On the basis of forced expiratory volume in one second (FEV1) on PFT, 4 patients had a mild disease (FEV1 60%-80%), 17 had a moderate obstructive disease (FEV1 41%-59%) and 4 had severe COPD/asthma (FEV1 <40%) while 2 patients had normal >95% FEV1. Post-stress questionnaire to assess subjective tolerance and symptoms were undertaken for all patients. RESULTS: The results demonstrated an excellent tolerance to adenosine infusion in this group of patients, with adequate stress achieved in all. None had complaints of severe dyspnoea or respiratory distress requiring medical intervention. Thirteen patients had mild to moderate degree dyspnoea during infusion. The study included a significant number of 23 elderly patients (>65 years), who showed better tolerance than the younger patients. CONCLUSION: In this pilot study in patients with COPD who referred for myocardial perfusion scintigraphy, the feasibility and safety of adenosine in a graded protocol along with a good pre-stress assessment and a short acting bronchodilator treatment was documented.


Assuntos
Adenosina/farmacologia , Asma/diagnóstico por imagem , Imagem de Perfusão do Miocárdio/efeitos adversos , Imagem de Perfusão do Miocárdio/métodos , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Segurança , Estresse Fisiológico/efeitos dos fármacos , Adenosina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/fisiopatologia , Estudos de Viabilidade , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Tomografia Computadorizada de Emissão de Fóton Único
2.
Int Immunopharmacol ; 72: 479-486, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31051404

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative method for blood cancers and other blood disorders, but is limited by the development of graft-versus-host disease (GVHD). GVHD results in inflammatory damage to the host liver, gastrointestinal tract and skin, resulting in high rates of morbidity and mortality in HSCT recipients. Activation of the A2A receptor has been previously demonstrated to reduce disease in allogeneic mouse models of GVHD. This study aimed to investigate the effect of A2A activation on disease development in a humanised mouse model of GVHD. Immunodeficient non-obese diabetic-severe combined immunodeficiency-interleukin (IL)-2 receptor γnull (NSG) mice injected with human (h) peripheral blood mononuclear cells (hPBMCs), were treated with either the A2A agonist CGS 21680 or control vehicle. Contrary to the beneficial effect of A2A activation in allogeneic mouse models, CGS 21680 increased weight loss, and failed to reduce the clinical score or increase survival in this humanised mouse model of GVHD. Moreover, CGS 21680 reduced T regulatory cells and increased serum human IL-6 concentrations. Conversely, CGS 21680 reduced serum human tumour necrosis factor (TNF)-α concentrations and leukocyte infiltration into the liver, indicating that A2A activation can, in part, reduce molecular and histological GVHD in this model. Notably, CGS 21680 also prevented healthy weight gain in NSG mice not engrafted with hPBMCs suggesting that this compound may be suppressing appetite or metabolism. Therefore, the potential benefits of A2A activation in reducing GVHD in HSCT recipients may be limited and confounded by adverse impacts on weight, decreased T regulatory cell frequency and increased IL-6 production.


Assuntos
Agonistas do Receptor A2 de Adenosina/uso terapêutico , Adenosina/análogos & derivados , Doença Enxerto-Hospedeiro/tratamento farmacológico , Fenetilaminas/uso terapêutico , Adenosina/efeitos adversos , Adenosina/uso terapêutico , Agonistas do Receptor A2 de Adenosina/efeitos adversos , Animais , Peso Corporal/efeitos dos fármacos , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Doença Enxerto-Hospedeiro/imunologia , Humanos , Camundongos , Fenetilaminas/efeitos adversos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
3.
Pain Manag ; 9(3): 233-237, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31140915

RESUMO

Background: The effects of adenosine in acute chronic pain are not clear. Literature supports both a pronociceptive/inflammatory role of the A2aR/A2bR and antihyperalgesia/allodynia with A1Rs/A3Rs. Adenosine could participate in the reactivation of chronic regional pain syndrome (CRPS) through inflammatory pathways and via A2Rs. Plastic changes in the brain CRPS-related overlap with those seen in systemic inflammation and persist even after symptoms of CRPS resolve. Aim: To illustrate the hypothesis that intravenous adenosine can reactivate dormant CRPS. Case report: An individual with successfully treated CRPS developed supraventricular tachycardia, he was treated with intravenous adenosine. Shortly after a second dose, he developed severe pain at a lower limb from relapsed CRPS. Treatment included lumbar sympathetic block, physical therapy and pharmacological agents. Conclusion: Intravenous adenosine can reactivate dormant CRPS. Its potential pronociceptive role in CRPS calls for further studies to better elucidate the underlying mechanisms.


Assuntos
Adenosina/efeitos adversos , Antiarrítmicos/efeitos adversos , Síndromes da Dor Regional Complexa/induzido quimicamente , Analgésicos/uso terapêutico , Analgésicos Opioides/uso terapêutico , Síndromes da Dor Regional Complexa/tratamento farmacológico , Gabapentina , Humanos , Masculino , Pessoa de Meia-Idade , Bloqueio Nervoso/métodos , Recidiva , Tapentadol/uso terapêutico
4.
J Surg Res ; 242: 157-165, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31078900

RESUMO

BACKGROUND: Limited data exist that compare the predominant cardiac preservation solutions (CPSs). MATERIALS AND METHODS: The United Network for Organ Sharing database was retrospectively reviewed from January 1, 2004 to March 31, 2018, for donor hearts. Of 34,614 potential donors, 21,908 remained after applying the exclusion criteria. The CPS analyzed included saline, the University of Wisconsin (UW), cardioplegia, Celsior, and Custodiol. The primary endpoints were recipient survival and posttransplant rejection. Logistic and Cox models were used to quantify survival endpoints. RESULTS: Saline was used as the CPS in 2549 patients (12%), UW in 10,549 (48%), cardioplegia in 1307 (6%), Celsior in 5081 (23%), and Custodiol in 2422 (11%). Donor age ranged from 15 to 68 y (mean = 32.0 y, median = 30.0 y), and 71% were male. Adjusted survival probabilities of recipients whose donor hearts were procured with saline was 96% 30 d, 90% 1 y, UW: 97% 30 d, 92% 1 y, cardioplegia: 95% 30 d, 87% 1 y, Celsior: 96% 30 d, 90% 1 y, and Custodiol: 97% 30 d, 92% 1 y. When these comparisons were adjusted for donor age, sex, ethnicity, ischemic time, recipient age, sex, ethnicity, creatinine, ventricular assist device (VAD), length of stay, region and days on waiting list, cardioplegia solution was demonstrated to have a higher risk of death (30 d, 1 y, overall) and posttransplant rejection versus UW (odds ratio 1.70, P = 0.001; odds ratio 1.63, P < 0.001; hazard ratio 1.22, P < 0.001; hazard ratio 1.21, P < 0.001, respectively). CONCLUSIONS: Cardioplegia solutions for cardiac preservation are associated with a higher mortality in heart transplant recipients.


Assuntos
Soluções Cardioplégicas/efeitos adversos , Rejeição de Enxerto/epidemiologia , Insuficiência Cardíaca/cirurgia , Soluções para Preservação de Órgãos/efeitos adversos , Preservação de Órgãos/efeitos adversos , Adenosina/efeitos adversos , Adolescente , Adulto , Idoso , Aloenxertos/efeitos dos fármacos , Alopurinol/efeitos adversos , Dissacarídeos/efeitos adversos , Eletrólitos/efeitos adversos , Feminino , Seguimentos , Glucose/efeitos adversos , Glutamatos/efeitos adversos , Glutationa/efeitos adversos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Coração/efeitos dos fármacos , Insuficiência Cardíaca/mortalidade , Transplante de Coração/efeitos adversos , Histidina/efeitos adversos , Humanos , Insulina/efeitos adversos , Masculino , Manitol/efeitos adversos , Pessoa de Meia-Idade , Preservação de Órgãos/métodos , Cloreto de Potássio/efeitos adversos , Procaína/efeitos adversos , Rafinose/efeitos adversos , Estudos Retrospectivos , Solução Salina/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
5.
J Cosmet Dermatol ; 18(4): 1083-1091, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30375189

RESUMO

BACKGROUND: Dissolving microneedles (DMNs), microscale needles with a biodegradable polymer matrix, have been widely investigated for transdermal drug delivery. However, the restricted drug loading space of DMNs limited the delivery of the desired quantity of active compounds. In this study, we developed novel combinatorial therapies involving sequential application of adenosine-loaded DMN (Ad-DMN) patches and a topical adenosine-loaded cream (Ad-cream). The application of DMNs created skin channels, which delivered encapsulated drugs from both the DMNs and cream. The use of combinatorial therapies can maximize drug delivery. METHODS: To compare the efficacy of combinatorial therapies and Ad-cream application, a double-blind clinical test was conducted over 10 weeks on 21 females with wrinkles around their eyes, and the skin parameters such as wrinkles, dermal density, elasticity, and hydration were analyzed. The skin irritation test was assessed by expert interviewers to elucidate undesirable side effects. RESULTS: The combinatorial therapies showed statistically significant efficacy for the improvement of average depth of wrinkles, dermal density, elasticity, and hydration after an 8-week application (P < 0.001). Adverse effects on the skin were not observed in any subject during the test period. CONCLUSION: The efficacy and safety results showed that the combinatorial therapies were a safe and outstanding innovation for the optimization of transdermal therapy.


Assuntos
Adenosina/administração & dosagem , Técnicas Cosméticas/efeitos adversos , Sistemas de Liberação de Medicamentos/métodos , Envelhecimento da Pele/efeitos dos fármacos , Adenosina/efeitos adversos , Administração Cutânea , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Método Duplo-Cego , Sistemas de Liberação de Medicamentos/efeitos adversos , Elasticidade/efeitos dos fármacos , Face , Feminino , Humanos , Ácido Hialurônico , Pessoa de Meia-Idade , Pele/química , Pele/efeitos dos fármacos , Creme para a Pele/administração & dosagem , Creme para a Pele/efeitos adversos , Adesivo Transdérmico/efeitos adversos , Resultado do Tratamento
6.
Perfusion ; 34(1): 67-75, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30058944

RESUMO

INTRODUCTION: This experimental study compares myocardial function after prolonged arrest by St. Thomas' Hospital polarizing cardioplegic solution (esmolol, adenosine, Mg2+) with depolarizing (hyperkalaemic) St. Thomas' Hospital No 2, both administered as cold oxygenated blood cardioplegia. METHODS: Twenty anaesthetized pigs on tepid (34°C) cardiopulmonary bypass (CPB) were randomised to cardioplegic arrest for 120 min with antegrade, repeated, cold, oxygenated, polarizing (STH-POL) or depolarizing (STH-2) blood cardioplegia every 20 min. Cardiac function was evaluated at Baseline and 60, 150 and 240 min after weaning from CPB, using a pressure-conductance catheter and epicardial echocardiography. Regional tissue blood flow, cleaved caspase-3 activity and levels of malondialdehyde were evaluated in myocardial tissue samples. RESULTS: Preload recruitable stroke work (PRSW) was increased after polarizing compared to depolarizing cardioplegia 150 min after declamping (73.0±3.2 vs. 64.3±2.4 mmHg, p=0.047). Myocardial tissue blood flow rate was high in both groups compared to the Baseline levels and decreased significantly in the STH-POL group only, from 60 min to 150 min after declamping (p<0.005). Blood flow was significantly reduced in the STH-POL compared to the STH-2 group 240 min after declamping (p<0.05). Left ventricular mechanical efficiency, the ratio between total pressure-volume area and blood flow rate, gradually decreased after STH-2 cardioplegia and was significantly reduced compared to STH-POL cardioplegia after 150 and 240 min (p<0.05 for both). CONCLUSION: Myocardial protection for two hours of polarizing cardioplegic arrest with STH-POL in oxygenated blood is non-inferior compared to STH-2 blood cardioplegia. STH-POL cardioplegia alleviates the mismatch between myocardial function and perfusion after weaning from CPB.


Assuntos
Soluções Cardioplégicas/uso terapêutico , Ponte Cardiopulmonar/métodos , Parada Cardíaca Induzida/métodos , Disfunção Ventricular Esquerda/etiologia , Adenosina/efeitos adversos , Adenosina/uso terapêutico , Animais , Soluções Cardioplégicas/efeitos adversos , Ponte Cardiopulmonar/efeitos adversos , Modelos Animais de Doenças , Parada Cardíaca Induzida/efeitos adversos , Magnésio/efeitos adversos , Magnésio/uso terapêutico , Potássio/efeitos adversos , Potássio/uso terapêutico , Propanolaminas/efeitos adversos , Propanolaminas/uso terapêutico , Suínos , Disfunção Ventricular Esquerda/fisiopatologia
7.
J Cosmet Dermatol ; 18(3): 936-943, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30160014

RESUMO

BACKGROUND: Dissolving microneedles (DMNs) have been used for skin restoration and wrinkle improvement. Although lipophilic compounds, for example, natural oils or ceramides, enrich the skin barrier, their delivery via DMNs is challenging because of DMN fabrication difficulties. OBJECTIVES: In the present study, we combined a topical formulation and a DMN patch to perform two-phase delivery comprising a lipophilic formulation and hydrophilic compound-loaded DMNs to improve skin barrier status and the efficacy of drug delivery. METHODS: Horse oil-spread and adenosine-loaded DMN arrays were developed in a single patch (HOS-Ad-DMN patch). In vitro analysis was conducted to confirm the successful delivery of the compositions. Clinical assessments were conducted on the lateral canthus of 20 women to compare the efficacy of HOS-Ad-DMN patches with that of adenosine-loaded DMN patches (Ad-DMN patches). RESULTS: Adenosine was delivered via the DMNs after skin penetration and horse oil was delivered successfully into the skin through the microchannels created by the Ad-DMNs. Compared with Ad-DMN patches, HOS-Ad-DMN patches significantly improved skin elasticity, hydration, dermal density, and wrinkles. No adverse events were observed. CONCLUSION: HOS-Ad-DMN patches are a safe and efficient system for skin restoration and wrinkle improvement.


Assuntos
Adenosina/administração & dosagem , Produtos Biológicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Óleos/administração & dosagem , Envelhecimento da Pele/efeitos dos fármacos , Adenosina/efeitos adversos , Adenosina/farmacocinética , Administração Cutânea , Adulto , Animais , Produtos Biológicos/efeitos adversos , Sistemas de Liberação de Medicamentos/instrumentação , Elasticidade , Cavalos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Pessoa de Meia-Idade , Agulhas , Óleos/efeitos adversos , Pele/efeitos dos fármacos , Pele/metabolismo , Distribuição Tecidual , Adesivo Transdérmico , Perda Insensível de Água
8.
Transplantation ; 102(11): 1870-1877, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30130321

RESUMO

BACKGROUND: Both University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate (HTK) solutions are currently used in the Eurotransplant region for preservation of liver allografts. Previous studies on their effect have led to a lot of discussion. This study aims to compare the effect of HTK and UW on graft survival. METHODS: First liver transplantations in recipients 18 years or older from January 1, 2007, until December 31, 2016, were included. Graft survival was compared for livers preserved with HTK and UW at 30 days, 1, 3, and 5 years. Multivariable analysis of risk factors was performed and outcome was adjusted for important confounders. RESULTS: Of all 10 628 first liver transplantations, 8176 (77%) and 2452 (23%) were performed with livers preserved with HTK and UW, respectively. Kaplan-Meier curves showed significant differences in graft survival between HTK and UW at 30 days (89% vs 93%, P=<0.001), 1 year (75% vs 82%, P=<0.001), 3 years (67% vs 72%, P<0.001), and at 5 years (60% vs 67%, P<0.001). No significant differences in outcome were observed in separate analyses of Germany or non-German countries. In multivariable analysis, UW was associated with a decreased risk of graft loss at 30 days (HR 0.772, P=0.002) and at 1 year (0.847 (0.757-0.947). When adjusted for risk factors, no differences in long term outcome could be detected. CONCLUSIONS: Because the use of preservation fluids is clustered geographically, differences in outcome by preservation fluids are strongly affected by regional differences in donor and recipient characteristics. When adjusted for risk factors, no differences in graft survival exist between transplantations performed with livers preserved with either HTK or UW.


Assuntos
Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Fígado/métodos , Soluções para Preservação de Órgãos/uso terapêutico , Preservação de Órgãos/métodos , Adenosina/efeitos adversos , Adenosina/uso terapêutico , Adulto , Idoso , Alopurinol/efeitos adversos , Alopurinol/uso terapêutico , Europa (Continente) , Feminino , Glucose/efeitos adversos , Glucose/uso terapêutico , Glutationa/efeitos adversos , Glutationa/uso terapêutico , Disparidades em Assistência à Saúde , Humanos , Insulina/efeitos adversos , Insulina/uso terapêutico , Transplante de Fígado/efeitos adversos , Masculino , Manitol/efeitos adversos , Manitol/uso terapêutico , Pessoa de Meia-Idade , Preservação de Órgãos/efeitos adversos , Soluções para Preservação de Órgãos/efeitos adversos , Cloreto de Potássio/efeitos adversos , Cloreto de Potássio/uso terapêutico , Procaína/efeitos adversos , Procaína/uso terapêutico , Rafinose/efeitos adversos , Rafinose/uso terapêutico , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
9.
Rev. Soc. Cardiol. Estado de Säo Paulo ; 28(3)jul.-ago. 2018. tab, ilus, graf
Artigo em Português | LILACS | ID: biblio-916531

RESUMO

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


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Arritmias Cardíacas/diagnóstico , Emergências , Taquicardia Supraventricular/diagnóstico por imagem , Terapêutica , Adenosina/efeitos adversos , Adenosina/uso terapêutico , Amiodarona/uso terapêutico , Fibrilação Atrial , Bloqueio de Ramo/diagnóstico , Diagnóstico por Imagem/métodos , Cardioversão Elétrica/métodos , Eletrocardiografia/métodos , Heparina/efeitos adversos , Heparina/uso terapêutico , Prevalência , Propafenona/efeitos adversos , Propafenona/uso terapêutico , Verapamil/efeitos adversos , Verapamil/uso terapêutico
10.
Medicine (Baltimore) ; 97(26): e11206, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29952973

RESUMO

RATIONALE: Ticagrelor, a new type of P2Y12 receptor antagonist, has been highly recommended to be used in acute coronary syndrome by the latest guideline, but its side effects are not well-known. We seek to illustrate a potential fatal condition, thrombotic thrombocytopenic purpura (TTP), caused by ticagrelor. PATIENT CONCERNS: An 87-year-old man who had been prescribed with ticagrelor for 2 months after ST-elevation myocardial infarction (STEMI), presented with severe thrombocytopenia, anemia, renal and liver dysfunction, heart failure and fever. DIAGNOSES: Peripheral blood smear showed schistocytosis, and a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) activity is low, with normal initial coagulation tests, which were compatible with a diagnosis of TTP. INTERVENTIONS: After cessation of ticagrelor and initiation of therapeutic plasma exchange, our patient recovered. OUTCOMES: Re-administration of ticagrelor aggravated TTP and led the patient to death. LESSONS: Clinicians should be aware of the possibility of ticagrelor-induced TTP in patients with a history of recent myocardial infarction; It is of crucial significance to discontinue and never reuse ticagrelor as long as it is suspected to be implicated in TTP.


Assuntos
Adenosina/análogos & derivados , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Púrpura Trombocitopênica Trombótica/induzido quimicamente , Proteína ADAMTS13/metabolismo , Adenosina/efeitos adversos , Idoso de 80 Anos ou mais , Evolução Fatal , Humanos , Masculino , Troca Plasmática/métodos , Púrpura Trombocitopênica Trombótica/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Ticagrelor , Suspensão de Tratamento
11.
Int J Clin Pharmacol Ther ; 56(8): 372-380, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29932414

RESUMO

OBJECTIVES: The manuscript was mainly aimed to evaluate effects of food and gender on the pharmacokinetics of ticagrelor and its main active metabolite AR-C124910XX in healthy Chinese subjects observed in the bioequivalence studies of the two formulations of ticagrelor tablets. MATERIALS AND METHODS: The single-dose, two-sequence, two-period and crossover studies were respectively conducted under fasting and fed conditions. Plasma samples were analyzed by an HPLC-MS/MS method. Log-transformed pharmacokinetic parameters of ticagrelor and AR-C124910XX obtained from the trials were compared by the mean of two one-sided t-test. RESULTS: Pharmacokinetic parameters of the two formulations were evaluated. The mean ticagrelor tmax value was delayed by 0.28 - 0.53 hours owing to meals. A 21.6 - 24.0% (p < 0.05) increase in the mean ticagrelor AUC* (body weight-normalized AUC) value was measured (fed vs. fasting). For AR-C124910XX, the mean T1/2 value was delayed by 0.84 - 1.33 hours (p < 0.05) due to meals. A 52.0 - 55.8% (p < 0.05) decrease in the mean Cmax* (body weight-normalized Cmax) value and a 15.6 - 16.9% (p < 0.05) decrease in the mean AUC* value were observed (fed vs. fasting). The female subjects exhibited higher exposures to ticagrelor and AR-C124910XX than the male subjects. Compared with other populations, the Chinese subjects in this study experienced a greater decrease in Cmax of AR-C124910XX due to meals. 21 adverse events of mild intensity occurred over the study periods. CONCLUSION: The studies showed food effects on the absorption of ticagrelor and the formation of AR-C124910XX, and gender effects on exposures to the drug after single oral-dose administration.
.


Assuntos
Adenosina/análogos & derivados , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Adenosina/efeitos adversos , Adenosina/sangue , Adenosina/farmacocinética , Adulto , Grupo com Ancestrais do Continente Asiático , Estudos Cross-Over , Composição de Medicamentos , Jejum , Feminino , Interações Alimento-Droga , Voluntários Saudáveis , Humanos , Absorção Intestinal , Masculino , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Segurança , Caracteres Sexuais , Equivalência Terapêutica , Ticagrelor , Adulto Jovem
12.
Expert Opin Pharmacother ; 19(9): 1013-1019, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29893152

RESUMO

INTRODUCTION: Cardiovascular disease (CVD) is the main cause of death in the world. Coronary artery disease (CAD) is the most common form of CVD presentation, but the prevalence of peripheral artery disease (PAD) is increasing. Patients with polyvascular disease comprise a very high-risk population that has been infrequently studied. Areas covered: The authors review the current evidence of the efficacy and safety of ticagrelor in the setting of acute coronary syndrome and stable patients post-MI with and without PAD and summarize its pharmacokinetics, pharmacodynamics, and regulatory issues. Expert opinion: Randomized studies showed that ticagrelor is superior to clopidogrel in patients with acute coronary syndromes, and is superior to placebo in the chronic phase (>1 year) post-myocardial infarction. Sub-analyses of these studies suggest that patients with myocardial infarction and PAD, compared to patients without these characteristics, may have greater benefit with ticagrelor. Nonetheless, the global evidence about the role of ticagrelor in patients with myocardial infarction and PAD remains relatively sparse, and a prospective randomized trial testing this hypothesis would be necessary to provide more definite data regarding the efficacy and safety of ticagrelor in this very high-risk population.


Assuntos
Síndrome Coronariana Aguda/prevenção & controle , Adenosina/análogos & derivados , Infarto do Miocárdio/prevenção & controle , Doença Arterial Periférica/prevenção & controle , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Síndrome Coronariana Aguda/patologia , Adenosina/efeitos adversos , Adenosina/farmacocinética , Adenosina/uso terapêutico , Regulamentação Governamental , Meia-Vida , Hemorragia/etiologia , Humanos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/patologia , Doença Arterial Periférica/complicações , Doença Arterial Periférica/patologia , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Ticagrelor , Resultado do Tratamento
13.
JAMA ; 319(16): 1677-1686, 2018 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-29710164

RESUMO

Importance: The effect of ticagrelor with or without aspirin on saphenous vein graft patency in patients undergoing coronary artery bypass grafting (CABG) is unknown. Objective: To compare the effect of ticagrelor + aspirin or ticagrelor alone vs aspirin alone on saphenous vein graft patency 1 year after CABG. Design, Setting, and Participants: Randomized, multicenter, open-label, clinical trial among 6 tertiary hospitals in China. Eligible patients were aged 18 to 80 years with indications for elective CABG. Patients requiring urgent revascularization, concomitant cardiac surgery, dual antiplatelet or vitamin K antagonist therapy post-CABG, and who were at risk of serious bleeding were excluded. From July 2014 until November 2015, 1256 patients were identified and 500 were enrolled. Follow-up was completed in January 2017. Interventions: Patients were randomized (1:1:1) to start ticagrelor (90 mg twice daily) + aspirin (100 mg once daily) (n = 168), ticagrelor (90 mg twice daily) (n = 166), or aspirin (100 mg once daily) (n = 166) within 24 hours post-CABG. Neither patients nor treating physicians were blinded to allocation. Main Outcomes and Measures: Primary outcome was saphenous vein graft patency 1 year after CABG (FitzGibbon grade A) adjudicated independently by a committee blinded to allocation. Saphenous vein graft patency was assessed by multislice computed tomographic angiography or coronary angiography. Results: Among 500 randomized patients (mean age, 63.6 years; women, 91 [18.2%]), 461 (92.2%) completed the trial. Saphenous vein graft patency rates 1 year post-CABG were 88.7% (432 of 487 vein grafts) with ticagrelor + aspirin; 82.8% (404 of 488 vein grafts) with ticagrelor alone; and 76.5% (371 of 485 vein grafts) with aspirin alone. The difference between ticagrelor + aspirin vs aspirin alone was statistically significant (12.2% [95% CI, 5.2% to 19.2%]; P < .001), whereas the difference between ticagrelor alone vs aspirin alone was not statistically significant (6.3% [95% CI, -1.1% to 13.7%]; P = .10). Five major bleeding episodes occurred during 1 year of follow-up (3 with ticagrelor + aspirin; 2 with ticagrelor alone). Conclusions and Relevance: Among patients undergoing elective CABG with saphenous vein grafting, ticagrelor + aspirin significantly increased graft patency after 1 year vs aspirin alone; there was no significant difference between ticagrelor alone and aspirin alone. Further research with more patients is needed to assess comparative bleeding risks. Trial Registration: clinicaltrials.gov Identifier: NCT02201771.


Assuntos
Adenosina/análogos & derivados , Aspirina/administração & dosagem , Ponte de Artéria Coronária , Inibidores da Agregação de Plaquetas/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Veia Safena/transplante , Grau de Desobstrução Vascular/efeitos dos fármacos , Adenosina/administração & dosagem , Adenosina/efeitos adversos , Adulto , Idoso , Aspirina/efeitos adversos , Ponte de Artéria Coronária/efeitos adversos , Reestenose Coronária/prevenção & controle , Quimioterapia Combinada , Procedimentos Cirúrgicos Eletivos , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Ticagrelor
14.
J Pharmacol Exp Ther ; 366(1): 29-36, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29739826

RESUMO

Intestinal preservation injury (IPI) and the resulting mucosa injury raise several serious challenges early after intestinal transplantation. The current clinical approach using only vascular perfusion allows the shortest preservation period among the abdominal organs. The experimental addition of luminal polyethylene glycol (PEG) solutions has been repeatedly suggested to alleviate preservation injury, improve graft quality, and prolong the preservation time. We investigated whether the molecular mass of PEG in solution influences the development of intestinal preservation injury. Small intestines of Sprague-Dawley rats were perfused with University of Wisconsin solution. Group 1 underwent vascular perfusion only (clinical control), group 2 received additional luminal PEG3350 Da, group 3 received luminal PEG10000 Da, and group 4 received luminal PEG20000 Da (n = 8/group). Tissue samples were obtained after 4, 8, and 14 hours. We studied the tissue damage (Chiu/Park score, Goblet cells, apoptosis, tight junctions), activation of c-Jun NH2-terminal kinase (JNK), and p38-mitogen-activated protein kinase (MAPK), and we performed Ussing chamber assessments. Mucosal morphologic and electrophysiologic parameters were significantly improved in the groups receiving luminal PEG. There was significantly less apoptotic activity in groups 2, 3, and 4. Both MAPKs revealed an activation peak after 4 hours with group 3 showing lesser p38-MAPK activation. PEG 20 kDa interfered with protein immunodetection. The results indicate that luminal solutions of PEG of medium and large molecular mass significantly delay the onset and development of IPI, providing further evidence that luminal interventions may allow for longer cold storage intervals of intestinal grafts.


Assuntos
Intestino Delgado/efeitos dos fármacos , Intestino Delgado/lesões , Soluções para Preservação de Órgãos/efeitos adversos , Polietilenoglicóis/farmacologia , Adenosina/efeitos adversos , Alopurinol/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Glutationa/efeitos adversos , Insulina/efeitos adversos , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Peso Molecular , Permeabilidade/efeitos dos fármacos , Polietilenoglicóis/química , Rafinose/efeitos adversos , Ratos , Ratos Sprague-Dawley , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Transplant Proc ; 50(2): 539-542, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29579846

RESUMO

INTRODUCTION: Ischemia reperfusion injury (IRI) is the main cause of early allograft dysfunction (EAD) and subsequent primary allograft failure (PAF). OBJECTIVES: The purpose of this study is to compare IRI, EAD, and PAF in liver transplantation in a cohort of patients perfused with histidine-tryptophan-ketoglutarate (HTK) solution and University of Wisconsin (UW) solution versus HTK alone. METHODS: A randomized trial was performed to compare outcomes in liver recipients who underwent transplantation surgery in the University Regional Hospital of Malaga, Spain. Forty patients were randomized to two groups. Primary endpoints included IRI, EAD, PAF, re-intervention, acute cellular rejection, retransplantation, arterial complications, and biliary complications at postoperative day 90. RESULTS: Postoperative glutamic oxaloacetic transaminase (1869.15 ± 1559.75 UI/L vs. 953.15 ± 777.27 UI/L; P = .004) and glutamic pyruvic transaminase (1333.60 ± 1115.49 U/L vs. 721.70 ± 725.02 U/L; P = .023) were significantly higher in patients perfused with HTK alone. A clear tendency was observed in recipients perfused with HTK alone to present moderate to severe IRI (7 patients in the HTK + UW solution group vs. 15 patients in the HTK-alone solution group; P = .06), EAD (0 patients in the HTK + UW solution group vs. 0 patients in the HTK-alone solution group; P = .76), and PAF (3 patients in the HTK + UW solution group vs. 8 patients in the HTK-alone solution group; P = .15). CONCLUSIONS: Initial perfusion with HTK solution followed by UW solution in liver transplantation improves early liver function as compared to perfusion with HTK alone.


Assuntos
Transplante de Fígado/métodos , Soluções para Preservação de Órgãos/administração & dosagem , Perfusão/métodos , Adenosina/administração & dosagem , Adenosina/efeitos adversos , Adulto , Alanina Transaminase/sangue , Alopurinol/administração & dosagem , Alopurinol/efeitos adversos , Aspartato Aminotransferases/sangue , Estudos de Coortes , Quimioterapia Combinada , Feminino , Glucose/administração & dosagem , Glucose/efeitos adversos , Glutationa/administração & dosagem , Glutationa/efeitos adversos , Rejeição de Enxerto/induzido quimicamente , Humanos , Insulina/administração & dosagem , Insulina/efeitos adversos , Fígado , Masculino , Manitol/administração & dosagem , Manitol/efeitos adversos , Pessoa de Meia-Idade , Soluções para Preservação de Órgãos/efeitos adversos , Perfusão/efeitos adversos , Período Pós-Operatório , Cloreto de Potássio/administração & dosagem , Cloreto de Potássio/efeitos adversos , Procaína/administração & dosagem , Procaína/efeitos adversos , Rafinose/administração & dosagem , Rafinose/efeitos adversos , Reoperação , Traumatismo por Reperfusão/induzido quimicamente , Espanha , Resultado do Tratamento
16.
Pediatr Cardiol ; 39(2): 275-282, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29063953

RESUMO

The purpose of this study was to assess the safety and indications for cardiac magnetic resonance (CMR) with myocardial perfusion imaging (MPI) in a cohort of children and young adults. A retrospective review of 178 children and young adults who underwent CMR with MPI was performed. Studies were categorized based on study protocols as MPI with resting perfusion only, adenosine stress MPI, exercise-induced stress MPI, and MPI for cardiac mass diagnosis. Relevant clinical history, exam indications, and adverse reactions following gadolinium-based contrast agent and adenosine administration were recorded. Studies were reviewed for the presence of myocardial perfusion defects, wall motion abnormalities, and delayed myocardial enhancement. The most common indications from MPI were congenital heart disease (CHD), Kawasaki disease, anomalous coronary artery, or myocardial mass characterization. Of these, 51% were protocoled with adenosine stress, 23% without stress, 6% with exercise stress, and 20% for cardiac mass evaluation. Excluding patients for myocardial mass evaluation, MPI defects were present in 16% (14 with adenosine stress, 1 with exercise stress, 8 on resting studies only). For cardiac mass evaluation, a mass was confirmed in 58%. No adverse reactions occurred with intravenous administration of a gadolinium-based contrast agent. Three self-limited adverse reactions, 2 patients with chest pain, and 1 patient with bradycardia, occurred following adenosine administration. MPI is a safe modality for the evaluation of pediatric and young adults with minimal adverse events. The most common indications for MPI were for the evaluation of CHD, Kawasaki disease, anomalous coronary artery, or myocardial mass characterization.


Assuntos
Teste de Esforço/métodos , Cardiopatias/diagnóstico , Imagem Cinética por Ressonância Magnética/métodos , Imagem de Perfusão do Miocárdio/métodos , Adenosina/administração & dosagem , Adenosina/efeitos adversos , Adolescente , Criança , Pré-Escolar , Meios de Contraste/administração & dosagem , Meios de Contraste/efeitos adversos , Feminino , Humanos , Lactente , Imagem Cinética por Ressonância Magnética/efeitos adversos , Masculino , Imagem de Perfusão do Miocárdio/efeitos adversos , Estudos Retrospectivos , Adulto Jovem
18.
Rev Esp Cardiol (Engl Ed) ; 71(7): 538-544, 2018 Jul.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-29146484

RESUMO

INTRODUCTION AND OBJECTIVES: Acute coronary syndrome (ACS) guidelines recommend the use of newer P2Y12 inhibitors (prasugrel and ticagrelor) over clopidogrel in patients with moderate-to-high ischemic risk, unless they have an increased bleeding risk. The aim of our study was to assess the GRACE risk score and the CRUSADE bleeding risk score relative to prescription of newer P2Y12 inhibitors at discharge in ACS patients. METHODS: Retrospective analysis of a multicenter ACS registry; 3515 consecutive patients were included. The association between risk scores and prescription of newer P2Y12 inhibitors was assessed by binary logistic regression analysis. RESULTS: A total of 1021 patients (29%) were treated with prasugrel or ticagrelor. On multivariate analyses, both GRACE (OR per 10 points, 0.89; 95%CI, 0.86-0.92; P < .001) and CRUSADE (OR per 10 points, 0.96; 95%CI, 0.94-0.98; P < .001) risk scores were inversely associated with the use of newer P2Y12 inhibitors. Moreover, other factors not included in these scores (revascularization approach, in-hospital stent thrombosis, major bleeding, and concomitant indication for anticoagulation therapy) also predicted the use of newer P2Y12 inhibitors. CONCLUSIONS: New P2Y12 inhibitors were more frequently prescribed among ACS patients with lower CRUSADE bleeding risk. However, an ischemic risk paradox was found, with higher use of these agents in patients with lower ischemic risk based on GRACE risk score estimates. These results underscore the importance of risk stratification to safely deliver optimal therapies.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Adenosina/análogos & derivados , Hemorragia/induzido quimicamente , Cloridrato de Prasugrel/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Adenosina/efeitos adversos , Idoso , Prescrições de Medicamentos/estatística & dados numéricos , Feminino , Hospitalização , Humanos , Masculino , Isquemia Miocárdica/prevenção & controle , Alta do Paciente/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Ticagrelor
19.
Cardiol Rev ; 26(2): 107-111, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29215418

RESUMO

Ticagrelor and prasugrel are newer antiplatelet drugs which, like clopidogrel, block the P2Y12 platelet receptor to inhibit platelet aggregation. Compared with clopidogrel, both ticagrelor and prasugrel have greater clinical efficacy but also have a higher risk of bleeding and are much more costly. Therefore, some institutions and providers switch patients from ticagrelor or prasugrel to clopidogrel in an effort to lower bleeding risk, stem costs, or otherwise ensure that patients can safely adhere to long-term P2Y12 inhibitor therapy. From a pharmacodynamic perspective, switching patients from ticagrelor or prasugrel to clopidogrel comes at a cost of less antiplatelet efficacy. However, it is unclear if antiplatelet efficacy is diminished enough to affect clinical outcomes. This is because clinical trial data investigating such a switch is scant, leaving the clinician unsure as to the acceptability of this practice. Current clinical trial data have thus far not shown any clinical detriment from switching from ticagrelor or prasugrel to clopidogrel, but there are many limitations to these investigations. So although a large-scale switch of patients from ticagrelor or prasugrel to clopidogrel is not recommended, if the patient is unable to adhere to long-term ticagrelor or prasugrel therapy, switching him/her to clopidogrel seems to be a reasonable practice to maintain chronic suppression of platelet aggregation and minimize the risk of ischemic events.


Assuntos
Inibidores da Agregação de Plaquetas/uso terapêutico , Ticlopidina/análogos & derivados , Adenosina/efeitos adversos , Adenosina/análogos & derivados , Adenosina/uso terapêutico , Clopidogrel , Humanos , Segurança do Paciente , Cloridrato de Prasugrel/efeitos adversos , Cloridrato de Prasugrel/uso terapêutico , Ticagrelor , Ticlopidina/efeitos adversos , Ticlopidina/uso terapêutico , Resultado do Tratamento
20.
J Nucl Med Technol ; 46(2): 114-122, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29273695

RESUMO

This study investigated differences in cardiac displacement during adenosine stress versus regadenoson stress in 13N-ammonia (13NH3) MP PET/CT scans. Methods: In total, 61 myocardial perfusion PET/CT scans were acquired using either adenosine (n = 30) or regadenoson (n = 31) as a stressor. For both groups, cardiac displacement during rest and stress was measured 3-dimensionally, relative to either a fixed reference frame or the previous frame, in each 1-min frame of a list-mode PET acquisition of 25 min. All stress scans were additionally evaluated for the presence of motion artifacts. Also, the tolerability of the agents and the occurrence of side effects were compared between groups. Results: Significantly larger cardiac displacement during stress was detected in the adenosine group than in the regadenoson group, reflected by both maximal cardiac displacement (P = 0.022) and mean cardiac displacement (P = 0.001). The duration of the movement was typically shorter in the regadenoson group. Frames with cardiac displacement of at least 5 mm were observed nearly twice as frequently when adenosine was used instead of regadenoson. Conclusion: The displacement during regadenoson stress is of lower amplitude and shorter duration than that during adenosine stress and may therefore contribute to a lower incidence of motion artifacts on PET/CT scans.


Assuntos
Adenosina/farmacologia , Amônia , Coração/diagnóstico por imagem , Imagem de Perfusão do Miocárdio/métodos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Purinas/farmacologia , Pirazóis/farmacologia , Estresse Fisiológico/efeitos dos fármacos , Adenosina/efeitos adversos , Adulto , Artefatos , Feminino , Coração/efeitos dos fármacos , Coração/fisiologia , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Radioisótopos de Nitrogênio , Purinas/efeitos adversos , Pirazóis/efeitos adversos , Segurança
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