RESUMEN
INTRODUCTION AND OBJECTIVES: Glecaprevir/pibrentasvir is a highly effective and well tolerated treatment for hepatitis C infection. Brazilian patients were not included in the original development studies for glecaprevir/pibrentasvir. This study aimed to assess safety and efficacy of glecaprevir/pibrentasvir in treatment-naïve Brazilian adults without cirrhosis or with compensated cirrhosis. PATIENTS AND METHODS: EXPEDITION-3 was a Phase 3, open-label, multicenter study in treatment-naïve Brazilian adults with hepatitis C infection genotype 1-6. Patients without cirrhosis (F2 or F3) or with compensated cirrhosis (F4) received 8 or 12 weeks of glecaprevir/pibrentasvir, respectively. The primary efficacy endpoint was the rate of sustained virologic response at post-treatment Week 12. Secondary endpoints were on-treatment virologic failure and relapse rates. Baseline polymorphisms were assessed in NS3 and NS5A. Adverse events and laboratory abnormalities were monitored. RESULTS: 100 patients were enrolled, 75 received 8 weeks of treatment and 25 received 12 weeks; all patients completed treatment. Overall sustained virologic response at post-treatment Week 12 rate was high (98.0%; 98/100; 95% confidence interval: 93.0-99.4) and remained high regardless of baseline viral or host factors, including demographics, hepatitis C virus RNA levels, polymorphisms in NS3 and/or NS5A, genotype, and relevant comorbidities. 55% of patients reported ≥1 adverse event, the most common being headache (18.0%). Four patients reported serious adverse events; none were considered drug related or led to study drug discontinuation. No hepatic decompensations were observed. CONCLUSIONS: Glecaprevir/pibrentasvir was effective and well tolerated in treatment-naïve Brazilian patients with hepatitis C infection without cirrhosis and with compensated cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT03219216.
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Bencimidazoles/uso terapéutico , Hepacivirus , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Pirrolidinas/uso terapéutico , Quinoxalinas/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Anciano , Esquema de Medicación , Combinación de Medicamentos , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Respuesta Virológica Sostenida , Resultado del TratamientoRESUMEN
Transcatheter arterial chemoembolization is a technique for provoking ischemia and cytotoxic activity by selectively injecting microspheres containing chemotherapy drugs into vessels supplying a tumor. An 87-year-old female patient on palliative treatment for hepatocellular carcinoma and with indications for chemoembolization underwent preparatory angiography, which revealed celiac trunk occlusion. The treatment option chosen was selective catheterization of the hepatic artery proper to release the chemotherapy agent via an alternative route through the superior mesenteric artery with communication using the pancreaticoduodenal arcade. Studies have reported evidence showing increased survival after chemoembolization and also reduced tumor growth rate. However, difficulties with accessing and catheterizing the artery feeding the tumor via the alternative access make the procedure a challenge, because of the tortuosity of the pancreaticoduodenal arcade.
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To ascertain the mechanism of interaction between angiotensins (AI and AII) and the liver, an angiotensin-converting enzyme inhibitor (captopril) and a receptor antagonist (losartan) were used. Monovascular or bivascular liver perfusion was used to assess both hemodynamic (portal and arterial hypertensive responses) and metabolic (glucose production and oxygen consumption) effects. Microphysiometry was used for isolated liver cell assays to assess AII or losartan membrane receptor-mediated interaction. Captopril abolishes portal hypertensive response (PHR) to AI but not the AII effect. AII infused via the portal pathway promotes calcium-dependent PHR but not a hypertensive response in the arterial pathway (AHR); when infused into the arterial pathway AII promotes calcium-dependent PHR and AHR. Losartan infused into the portal vein abolishes PHR to AII but not the metabolic response; when infused via both pathways it abolishes the hypertensive responses and inhibits the metabolic effects. Isolated liver cells specifically respond to AII. Sinusoidal cells, but not hepatocytes, respond to 10 nM losartan. We conclude that AI has to be converted to AII to produce PHR. Quiescent stellate cells interacts in vitro with AII and losartan. Hemodynamic responses to AII are losartan-dependent but metabolic responses are partially losartan-independent. AII hemodynamic actions are mainly presinusoidal.
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Angiotensina II/farmacología , Hemodinámica/efectos de los fármacos , Circulación Hepática/efectos de los fármacos , Hígado/metabolismo , Angiotensina II/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Antihipertensivos/farmacología , Glucemia/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Captopril/farmacología , Relación Dosis-Respuesta a Droga , Hepatocitos/efectos de los fármacos , Cinética , Macrófagos del Hígado/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/fisiología , Losartán/farmacología , Masculino , Consumo de Oxígeno/efectos de los fármacos , Perfusión , Ratas , Ratas WistarRESUMEN
It has been proposed that key enzymes of ureagenesis and the alanine aminotransferase activity predominate in periportal hepatocytes. However, ureagenesis from alanine, when measured in the perfused liver, did not show periportal predominance and even the release of the direct products of alanine transformation, lactate and pyruvate, was higher in perivenous cells. An alternative way of analyzing the functional distributions of alanine aminotransferase and the urea cycle along the hepatic acini would be to measure alanine and urea production from precursors such as lactate or pyruvate plus ammonia. In the present work these aspects were investigated in the bivascularly perfused rat liver. The results of the present study confirm that gluconeogenesis and the associated oxygen uptake tend to predominate in the periportal region. Alanine synthesis from lactate and pyruvate plus ammonia, however, predominated in the perivenous region. Furthermore, no predominance of ureagenesis in the periportal region was found, except for conditions of high ammonia concentrations plus oxidizing conditions induced by pyruvate. These observations corroborate the view that data on enzyme activity or expression alone cannot be extrapolated unconditionally to the living cell. The current view of the hepatic ammonia-detoxifying system proposes that the small perivenous fraction of glutamine synthesizing perivenous cells removes a minor fraction of ammonia that escapes from ureagenesis in periportal cells. However, since urea synthesis occurs at high rates in all hepatocytes with the possible exclusion of those cells not possessing carbamoyl-phosphate synthase, it is probable that ureagenesis is equally important as an ammonia-detoxifying mechanism in the perivenous region.
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Amoníaco/farmacología , Carbono/metabolismo , Lactatos/metabolismo , Hígado/fisiología , Nitrógeno/metabolismo , Ácido Pirúvico/metabolismo , Alanina/metabolismo , Amoníaco/administración & dosificación , Animales , Ácido Glutámico/metabolismo , Técnicas In Vitro , Hígado/irrigación sanguínea , Masculino , Microcirculación/efectos de los fármacos , Perfusión/métodos , Ratas , Ratas Wistar , Urea/metabolismoRESUMEN
BACKGROUND AND AIM: Angiotensin I (AI) and angiotensin II (AII) induce a portal hypertensive response (PHR) and the liver is able to convert AI into AII to trough the action of the angiotensin-converting enzyme (ACE). Our purpose was to characterize angiotensin I liver conversion. METHODS: AI, AII or angiotensin (1-7) were used in monovascular or bivascular perfusions. RESULTS: The maximum gain in portal pressure induced by AII took place significantly earlier (P = 0.031) than that occurring after an equimolar AI infusion. The AI-induced PHR was abolished both by captopril or losartan, whereas the AII-induced PHR was not affected by captopril, but was abolished by losartan. Angiotensin (1-7) has no hemodynamic effect in the perfused liver. After partial hepatectomy, the AII-PHR pattern changes from a rapid return to baseline values to a pattern where there was no return to baseline values (3-7 days ex-surgery). In the bivascular perfusion system when AII was infused in the arterial branch in the retrograde mode of perfusion (peptide available only to the periportal zone), the PHR was at least 50% of that obtained when the prograde mode was used (peptide available to the periportal and perivenous zones). CONCLUSION: AI does not induce PHR; this effect is a result of its mandatory conversion into AII by the ACE and the sequential action of AII on the AII receptor type 1 located in the hepatic periportal zone. AII induced PHR pattern changes during liver regeneration.
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Angiotensina II/farmacología , Angiotensina I/metabolismo , Hipertensión Portal/metabolismo , Regeneración Hepática/fisiología , Hígado/fisiología , Animales , Antihipertensivos/farmacología , Modelos Animales de Enfermedad , Cinética , Hígado/efectos de los fármacos , Hígado/fisiopatología , Circulación Hepática , Ratas , Ratas WistarRESUMEN
AIMS/BACKGROUND: Zonation of alanine metabolism was investigated in the bivascularly perfused rat liver, a technique in which a selective area of the periportal region can be reached via the hepatic artery. METHODS: Bivascular liver perfusion was done in both the antegrade and retrograde modes. Predominance of a given metabolic parameter in the periportal or perivenous area was deduced from comparisons of the changes caused by alanine infusion into the hepatic artery in antegrade and retrograde perfusion. RESULTS: Confirming previous notions, glutamine synthesis predominated in the perivenous area, however, the contribution of the periportal area was significant. Gluconeogenesis and the associated extra oxygen consumption were more pronounced in the periportal region. The capacity of urea synthesis in the periportal region was relatively small as indicated by the ratios of urea to glucose production, which were lower in this region. Ammonia in the periportal region was considerably above the mean ammonia production of whole the liver parenchyma. The overflows of pyruvate and lactate were considerably smaller in the periportal region. CONCLUSION: The distribution of alanine metabolism seems to reflect mainly zonation of the fates of the carbon skeleton (mainly gluconeogenesis). The production of glutamine in the periportal area is in agreement with recent reports about the presence of glutamine synthetase in Kupffer and endothelial cells.
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Alanina/metabolismo , Quimioterapia del Cáncer por Perfusión Regional/métodos , Hígado/anatomía & histología , Hígado/metabolismo , Animales , Gluconeogénesis/fisiología , Glucosa/metabolismo , Arteria Hepática , Masculino , Consumo de Oxígeno , Ratas , Ratas WistarRESUMEN
BACKGROUND AND AIM: Bradykinin (BK) infused into the portal vein elicits a hypertensive response via the B2 receptor (B2R) and is efficiently hydrolyzed by the liver. Our purpose was to characterize the mechanism of interaction between BK and the liver. METHOD: BK, HOE-140 (a B2R antagonist), des-R(9)-BK (a B1R agonist) and enzyme inhibitors were used in monovascular or bivascular perfusions and in isolated liver cell assays. RESULTS: Des-R(9)-BK did not elicit a portal hypertensive response (PHR); BK infused into the hepatic artery elicited a calcium-dependent PHR and a calcium-independent arterial hypertensive response (HAHR), with the latter being almost abolished by naproxen. BK has a predominant distribution in the extracellular space and an average hepatic extraction of 8% in the steady state. Hydrolysis products of infused BK (R(1)-F(5) and R(1)-P(7)) did not elicit PHR. Angiotensin converting enzyme (ACE) is concentrated in the perivenous region and B2R in the periportal region. Microphysiometry showed that BK (and not a B1 agonist) interacts with stellate cells and the endothelial sinusoidal/Kupffer cell fraction. This effect was inhibited by the B2R antagonist. CONCLUSIONS: Events can be summarized as: the hypertensive action of BK on sinusoidal cells of the periportal region is followed by its hydrolysis by ACE which is primarily present in the perivenous region; there is no functional B1R in the normal liver; BK induces HAHR via eicosanoid release and PHR by a distinct pathway on the B2R. Our data suggest that BK may participate in the modulation of sinusoidal microvasculature tonus both in the portal and the arterial routes.
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Bradiquinina/análogos & derivados , Bradiquinina/farmacocinética , Hígado/metabolismo , Antagonistas Adrenérgicos beta/farmacología , Animales , Bradiquinina/administración & dosificación , Bradiquinina/farmacología , Antagonistas del Receptor de Bradiquinina B2 , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Espacio Extracelular/metabolismo , Técnica del Anticuerpo Fluorescente , Arteria Hepática , Hidrólisis/efectos de los fármacos , Hipertensión Portal/tratamiento farmacológico , Hipertensión Portal/metabolismo , Hipertensión Portal/fisiopatología , Infusiones Intraarteriales , Infusiones Intravenosas , Macrófagos del Hígado/citología , Macrófagos del Hígado/efectos de los fármacos , Macrófagos del Hígado/metabolismo , Hígado/citología , Hígado/efectos de los fármacos , Circulación Hepática/efectos de los fármacos , Circulación Hepática/fisiología , Masculino , Espectrometría de Masas , Peptidil-Dipeptidasa A/metabolismo , Presión Portal/efectos de los fármacos , Presión Portal/fisiología , Vena Porta , Ratas , Ratas Wistar , Receptor de Bradiquinina B2/metabolismoRESUMEN
O efeito metabólico e hemodinâmico de dois peptídeos vasoativos, bradicinina (BK) e angiotensina 11 (Al1), foram estudados por meio da técnica de perfusão bivascular do figado de rato, a qual consistiu em perfundir o órgão através da veia porta e da artéria hepática, com monitoramento das pressões nas duas vias. A direção do fluxo foi no modo anterógrado, que consistiu em administrar o líquido de perfusão na direção da veia porta para a veia hepática, ou retrógrado, da veia hepática para a veia porta. Desta forma, a administração de uma só substância envolveu 4 protocolos experimentais: (1 administração pela veia porta, modo anterógrado, (2) administração pela artéria hepática, modo anterógrado, (3) administração pela veia hepática, modo retrógrado, e (4) administração pela, artéria hepática, modo retrógrado. Os seguintes resultados foram obtidos:' Em relação a A11: (1) promoveu aumento de pressão na veia porta, seja administrada na veia porta ou na artéria hepática; quando administrada na veia porta, ocorreu pequeno aumento de pressão na artéria hepática; (2) promoveu aumento na produção de glicose e do consumo de oxigênio; os efeitos foram mais pronunciados quando All foi infundida na veia porta; (3) na perfusão retrógrada, seja na artéria ou veia hepática, ocorreu menor aumento de pressão venosa que na administração anterógrada; (4) a administração prévia de losartan 10 pM bloqueou o aumento de pressão na veia porta e artéria hepática, porém não foi capaz de bloquear por completo a resposta metabólica; (5) os efeitos hemodinâmicos e metabólicos foram Ca2+dependentes; (6) o efeito metabólico e hemodinâmico, após administração aguda de CC4, não foram modificados. Em relação à BK: (1) a administração na artéria hepática, seja no modo anterógrado ou, retrógrado promoveu aumento de pressão na artéria hepática e no sistema venoso (portal, na perfusão anterógrada e da veia hepática, na perfiisão retrógrada); (2) a ausência dos íons Ca2+ promoveu inibição parcial no aumento de pressão na veia porta, porém, não inibiu o aumento de pressão na artéria hepática; (3) naproxeno e o inibidor da óxido nítrico sintetase, NNLA,...(au)