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1.
Intern Med ; 59(22): 2945-2949, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32963155

RESUMO

Treatment with tocilizumab (TCZ) to block interleukin-6 (IL-6) signalling is predicted to mitigate cytokine release syndrome (CRS) caused by coronavirus disease 2019 (COVID-19). However, the adverse effects of TCZ on patients with COVID-19 remain unclear. We herein report a patient with COVID-19 treated with TCZ who developed acute hypertriglyceridaemia. Despite favipiravir treatment, acute respiratory distress syndrome developed in a 45-year-old patient with COVID-19; thus, TCZ was initiated. The triglyceride levels greatly increased after TCZ administration. Physicians should consider the negative impact of TCZ on the lipid profile in patients with COVID-19, although COVID-19-induced CRS itself may be an aggravating factor.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Hipertrigliceridemia/induzido quimicamente , Pneumonia Viral/tratamento farmacológico , Doença Aguda , Anticorpos Monoclonais Humanizados/uso terapêutico , Infecções por Coronavirus/sangue , Infecções por Coronavirus/epidemiologia , Humanos , Hipertrigliceridemia/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/epidemiologia , Estudos Retrospectivos , Triglicerídeos/sangue
2.
An. sist. sanit. Navar ; 43(1): 103-106, ene.-abr. 2020.
Artigo em Espanhol | IBECS | ID: ibc-193684

RESUMO

Everolimus es un inhibidor de mTOR, empleado en oncología y como inmunosupresor en el trasplante de órgano sólido. Sus efectos adversos a nivel metabólico son muy frecuentes, especialmente los más severos. Puede ocasionar hiperglucemia, hipercolesterolemia e hipertrigliceridemia, por lo que la monitorización de los parámetros metabólicos en las sucesivas visitas es vital para detectar e iniciar tratamientos que puedan prevenir las complicaciones. Se presenta el caso de una mujer con diagnóstico de tumor neuroendocrino intestinal que desarrolló dos pancreatitis agudas secundarias a hipertrigliceridemia severa por everolimus. Tras inicio de tratamiento con fibratos y omega-3, se normalizó la cifra de triglicéridos sin presentar nuevas complicaciones metabólicas ni digestivas secundarias al fármaco. La recomendación en pacientes con cáncer en tratamiento activo con everolimus es mantener los triglicéridos por debajo de 500 o 300 mg/dL, dependiendo de si la esperanza de vida es inferior o superior a un año, respectivamente


Everolimus is an mTOR inhibitor, approved as a treatment for cancer and as an immunosuppressant agent in solid organ transplantation; it frequently produces toxic metabolic effects, particularly of the most severe kind. Its use can cause hyperglycemia, hypercholesterolemia and hypertriglyceridemia; thus, metabolic values should be monitored regularly to prevent these adverse events. We present the case of a woman with an intestinal neuroendocrine tumor who developed two episodes of acute pancreatitis, secondary to severe hypertriglyceridemia caused by everolimus. After treatment with fibrates and omega-3, triglyceride levels returned to baseline, without developing new metabolic or digestive complications. Targeted levels of triglyceride for cancer patients treated with everolimus, should be below 500 or 300 mg/dL, depending on whether life expectancy is less or longer than one year, respectively


Assuntos
Humanos , Feminino , Adulto , Hipolipemiantes/administração & dosagem , Pancreatite Necrosante Aguda/tratamento farmacológico , Hipertrigliceridemia/induzido quimicamente , Everolimo/administração & dosagem , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/tratamento farmacológico , Imunossupressores/administração & dosagem , Everolimo/efeitos adversos , Tomografia Computadorizada de Emissão , Íleo/diagnóstico por imagem , Proteína Regulatória Associada a mTOR/antagonistas & inibidores
4.
Ann Hematol ; 99(4): 737-741, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32030447

RESUMO

For patients with pure red cell aplasia (PRCA), cyclosporine (CsA) is the first line therapy. Occasionally, some patients who suffer from renal insufficiency cannot tolerate CsA. To explore the efficacy and tolerance of sirolimus treatment for those patients, twelve PRCA patients with renal insufficiency from May 2014 to May 2018 in Peking Union Medical College Hospital were enrolled, treated with sirolimus, and followed up at the median time of 16 (10-50) months. Eleven patients (91.7%) responded to sirolimus, with 58.3% complete response (CR) and 41.7% partial response (PR). The median time to achieve the optimum effect was 4 (1-7) months. The serum creatinine level remained stable or even reduced during the treatment period for eleven patients. Seven patients (58.3%) reported adverse events during sirolimus therapy, including increased blood glucose, infection, skin rash, elevated triglyceride or total cholesterol, and elevated serum creatinine compared with baseline. No treatment-related death was noticed during the follow-up time. Three patients relapsed with an overall response rate of 75.0% at 1 year. These results suggested that sirolimus was effective and tolerable for patients with PRCA complicated with renal insufficiency.


Assuntos
Imunossupressores/uso terapêutico , Aplasia Pura de Série Vermelha/tratamento farmacológico , Insuficiência Renal/etiologia , Sirolimo/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Creatinina/sangue , Ciclosporina/efeitos adversos , Ciclosporina/uso terapêutico , Erupção por Droga/etiologia , Avaliação de Medicamentos , Substituição de Medicamentos , Feminino , Humanos , Hiperglicemia/induzido quimicamente , Hipertrigliceridemia/induzido quimicamente , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva , Aplasia Pura de Série Vermelha/complicações , Indução de Remissão , Insuficiência Renal/sangue , Estudos Retrospectivos , Sirolimo/efeitos adversos , Resultado do Tratamento
5.
J Oncol Pharm Pract ; 26(6): 1533-1537, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32054410

RESUMO

INTRODUCTION: Actionable mutations are tested as standard of care for all new metastatic non-small cell lung cancers. Tumors harboring an anaplastic lymphoma kinase mutation respond to tyrosine kinase inhibitors targeting anaplastic lymphoma kinase pathway. Patients are monitored for common adverse effects, although we occasionally encounter unexpected side effects. CASE REPORT: A 52-year-old male presented with a right hilar lung mass, and workup revealed a stage IIIA adenocarcinoma. He underwent treatment with concurrent chemoradiation; however, disease recurred one year later with a right hilar mass and contralateral mediastinal lymphadenopathy, biopsy of which resulted positive for adenocarcinoma. Molecular analysis showed anaplastic lymphoma kinase rearrangement and alectinib was started. Six months into therapy, he presented with hematochezia, nausea, and epigastric pain and was diagnosed with acute pancreatitis. Triglyceride level resulted above the measurable level at >5680mg/dL, thought to be the inciting event of pancreatitis.Management and outcome: Despite treatment with intravenous hydration, insulin infusion, and antibiotics, he decompensated with development of respiratory failure, shock requiring intensive care. Therapeutic plasmapheresis was initiated due to persistently elevated triglyceride. Following the third plasmapheresis, triglyceride level decreased to 359 mg/dL. With aggressive multidisciplinary management, he made a complete recovery. Follow-up imaging studies at three and six months show a stable mass-like abnormality in the right hilum without evidence of disease progression. DISCUSSION: Prior to starting alectinib, our patient's triglyceride level was 420 mg/dL. While he consumed alcohol, he had no other traditional risk factor. To our knowledge, this is the first reported case of hypertriglyceridemia-induced acute pancreatitis related to treatment with an anaplastic lymphoma kinase inhibitor.


Assuntos
Antineoplásicos/efeitos adversos , Carbazóis/efeitos adversos , Hipertrigliceridemia/induzido quimicamente , Pancreatite/induzido quimicamente , Piperidinas/efeitos adversos , Doença Aguda , Adenocarcinoma/tratamento farmacológico , Quinase do Linfoma Anaplásico/genética , Antineoplásicos/administração & dosagem , Biópsia , Carbazóis/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico
6.
Dig Dis Sci ; 65(6): 1735-1747, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31617131

RESUMO

BACKGROUND: Acute hypertriglyceridemic pancreatitis (HTGP) is more likely to be severe and complicated with extrapancreatic organ injury. NOX may be involved in the occurrence and development of high fat acute pancreatitis, but the specific mechanism is not clear. AIMS: To investigate the protective effects of apocynin, an inhibitor of NOX, on kidney injury associated with the HTGP and its potential mechanisms in a rat model. METHODS: In this study, HTGP rat model was induced by intraperitoneal injection of P-407 and L-Arg in combination. Apocynin was given by subcutaneously injection 30 min before the model was induced. The pancreatic and renal histopathology changes were analyzed. Serum AMY, BUN, Cr levels were measured by the Automatic Biochemistry Analyzer. The expression levels of protein associated with NOX/Akt pathway in the kidney were detected. ROS level in kidney and serum was measured by DHE staining and MDA, SOD kits, respectively. Serum TNF-α and IL-6 were detected by ELISA kits. RESULTS: In HTGP group, the levels of serum AMY, BUN, Cr, TNF- α, and IL-6 were significantly increased, and the injury of pancreas and kidney was aggravated. The levels of NOX4, NOX2, ROS, p-Akt, GSK-3ß, NF-κB, and TNF-α in the kidney were detected, suggesting that NOX may regulate the activity of downstream p-Akt and GSK-3ß by regulating ROS levels, thereby affecting the release of inflammatory mediators and regulating HTGP-related kidney injury. After application of apocynin, the expression of NOX4 and NOX2 and the level of ROS in the kidney were reduced, the release of inflammatory mediators decreased, and the histopathology injury of pancreas and kidney was improved obviously. CONCLUSION: NOX may play an important role in HTGP-associated kidney injury through Akt/GSK-3ß pathway. Apocynin can significantly downregulate the level of NOX and play a protective role in HTGP-related kidney injury through Akt/GSK-3ß pathway.


Assuntos
Acetofenonas/farmacologia , Lesão Renal Aguda/prevenção & controle , Arginina/toxicidade , Hipertrigliceridemia/complicações , Inflamação/prevenção & controle , Pancreatite/complicações , Lesão Renal Aguda/etiologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Arginina/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertrigliceridemia/induzido quimicamente , Inflamação/etiologia , Injeções Intraperitoneais , NADPH Oxidase 2/genética , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Pancreatite/induzido quimicamente , Ratos , Ratos Sprague-Dawley
7.
Pediatr Blood Cancer ; 67(1): e28040, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31612640

RESUMO

BACKGROUND: Glucocorticoids and asparaginase, used to treat acute lymphoblastic leukemia (ALL), can cause hypertriglyceridemia. We compared triglyceride levels, risk factors, and associated toxicities in two ALL trials at St. Jude Children's Research Hospital with identical glucocorticoid regimens, but different asparaginase formulations. In Total XV (TXV), native Escherichia coli l-asparaginase was front-line therapy versus the pegylated formulation (PEG-asparaginase) in Total XVI (TXVI). PROCEDURE: Patients enrolled on TXV (n = 498) and TXVI (n = 598) were assigned to low-risk (LR) or standard/high-risk (SHR) treatment arms (ClinicalTrials.gov identifiers: NCT00137111 and NCT00549848). Triglycerides were measured four times and were evaluable in 925 patients (TXV: n = 362; TXVI: n = 563). The genetic contribution was assessed using a triglyceride polygenic risk score (triglyceride-PRS). Osteonecrosis, thrombosis, and pancreatitis were prospectively graded. RESULTS: The largest increase in triglycerides occurred in TXVI SHR patients treated with dexamethasone and PEG-asparaginase (4.5-fold increase; P <1 × 10-15 ). SHR patients treated with PEG-asparaginase (TXVI) had more severe hypertriglyceridemia (>1000 mg/dL) compared to native l-asparaginase (TXV): 10.5% versus 5.5%, respectively (P = .007). At week 7, triglycerides did not increase with dexamethasone treatment alone (LR patients) but did increase with dexamethasone plus asparaginase (SHR patients). The variability in triglycerides explained by the triglyceride-PRS was highest at baseline and declined with therapy. Hypertriglyceridemia was associated with osteonecrosis (P = .0006) and thrombosis (P = .005), but not pancreatitis (P = .4). CONCLUSION: Triglycerides were affected more by PEG-asparaginase than native l-asparaginase, by asparaginase more than dexamethasone, and by drug effects more than genetics. It is not clear whether triglycerides contribute to thrombosis and osteonecrosis or are biomarkers of the toxicities.


Assuntos
Asparaginase/efeitos adversos , Asparaginase/química , Composição de Medicamentos , Hipertrigliceridemia/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Hipertrigliceridemia/induzido quimicamente , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico
8.
Curr Vasc Pharmacol ; 18(3): 254-261, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30843488

RESUMO

Supplementary estrogen plays important roles for female patients as convenient birth control, relief of postmenopausal symptoms, and in the management of other selected problems. However, as is the case for essentially all medications, there are side effects. Short of a major pulmonary embolus, the most severe side effect of estrogen would appear to be sporadic, rare, and severe hypertriglyceridemia associated with acute pancreatitis. The occurrence of this fortunately rare problem usually happens in the presence of some preexisting and usually mild increase in triglycerides (TG). A case of chronic and severe recurrent acute pancreatitis is described in the introduction and the management was complete estrogen avoidance. Started close to menopause and continued for a relatively short period, estrogens may have some cardiovascular (CV) benefit but the general recommendation is not to prescribe them for CV disease prevention. Estrogens may contribute to decreased diabetes mellitus (DM) risk and control. Administration of estrogens by the transdermal route may decrease some problems such as venous thromboembolism (VTE) and elevation of TG. Administration of estrogen in the right situation brings significant benefit to the female patient but skillful, careful, and knowledgeable use is essential.


Assuntos
Anticoncepcionais Orais Hormonais/efeitos adversos , Terapia de Reposição de Estrogênios/efeitos adversos , Estrogênios/efeitos adversos , Hipertrigliceridemia/induzido quimicamente , Triglicerídeos/sangue , Animais , Biomarcadores/sangue , Tomada de Decisão Clínica , Estrogênios/administração & dosagem , Feminino , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/epidemiologia , Pancreatite/induzido quimicamente , Pancreatite/epidemiologia , Seleção de Pacientes , Prognóstico , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Regulação para Cima
9.
J Oncol Pharm Pract ; 26(1): 193-199, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30823860

RESUMO

Pegaspargase, a long acting formulation of L-asparaginase, is an asparagine specific enzyme that selectively kills leukemic cells by depleting plasma asparagine. Pegaspargase is FDA approved for the first-line treatment of adult acute lymphoblastic leukemia and is a critical component of numerous multi-chemotherapeutic regimens. Pegaspargase is associated with well-described toxicities including hypersensitivity reactions, hepatotoxicity, and thrombosis. However, hypertriglyceridemia is a much rarer complication of pegaspargase and has only been described in a limited number of reports. We present a case of severe hypertriglyceridemia after a single dose of pegaspargase. The patient was re-challenged with pegaspargase and again developed hypertriglyceridemia which was complicated by pancreatitis. Here, we summarize published reports and a literature review describing the incidence of pegaspargase-induced hypertriglyceridemia in common acute lymphoblastic leukemia protocols.


Assuntos
Antineoplásicos/efeitos adversos , Asparaginase/efeitos adversos , Hipertrigliceridemia/induzido quimicamente , Polietilenoglicóis/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto , Feminino , Humanos
10.
Sci Rep ; 9(1): 17601, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31772301

RESUMO

To explore the differences in glucose-lipid metabolism profiles among the 3 TKIs, we designed a retrospective study to compare the onset of hyperglycaemia, hypertriglyceridemia, hypercholesterolemia and hyper-low density lipoprotein (LDL)-cholesterolemia in the patients with normal baseline glucose-lipid profiles and had no medical record of cardio- or cerebro-vascular diseases and/or metabolic syndrome diseases, and identify variables associated with them. 370 chronic myeloid leukaemia patients receiving dasatinib, nilotinib or imatinib therapy ≥3 months were retrospectively reviewed. During TKI-therapy, the mean fasting glucose, triglyceride, cholesterol, and LDL-cholesterol levels increased significantly in both dasatinib and nilotinib cohorts compared with the imatinib cohort. In multivariate analyses, dasatinib was the factor significantly associated with both poor hyperglycaemia- and hypertriglyceridemia-free survival. In addition, nilotinib was significantly associated with more occurrences of hyperglycaemia and hypercholesterolemia; increasing age was significantly associated with more occurrences of hyperglycaemia and hypertriglyceridemia. We concluded that dasatinib, similar to nilotinib, has the adverse impact on glucose-lipid metabolism compared with imatinib.


Assuntos
Antineoplásicos/efeitos adversos , Dasatinibe/efeitos adversos , Glucose/metabolismo , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Inibidores de Proteínas Quinases/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , LDL-Colesterol/sangue , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Feminino , Seguimentos , Humanos , Hiperglicemia/sangue , Hiperglicemia/induzido quimicamente , Hipertrigliceridemia/sangue , Hipertrigliceridemia/induzido quimicamente , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Leucemia Mieloide de Fase Crônica/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Terapia de Salvação , Adulto Jovem
11.
Physiol Res ; 68(6): 1021-1026, 2019 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-31647302

RESUMO

High levels of fructose induce hypertriglyceridemia, characterized by excessive levels of triglyceride-rich lipoproteins such as very low-density lipoprotein (VLDL); however, the underlying mechanisms are poorly understood. The aim of this short communication was to examine hepatic changes in the expression of genes related to cholesterol metabolism in rats with hypertriglyceridemia induced by high-fructose or high-glucose diets. Rats were fed a 65 % (w/w) glucose diet or a 65 % (w/w) fructose diet for 12 days. Serum levels of triglycerides, total cholesterol, and VLDL+LDL-cholesterol, hepatic levels of triglycerides and cholesterol, and ACAT2 expression at the gene and protein levels were significantly higher in the fructose diet group compared to the glucose diet group. The hepatic levels of Abcg5/8 were lower in the fructose group than in the glucose group. Serum high-density lipoprotein (HDL)-cholesterol and hepatic expression levels of Hmgcr, Ldlr, Acat1, Mttp, Apob, and Cyp7a1 did not differ significantly between groups. These findings suggest that high-fructose diet-induced hypertriglyceridemia is associated with increased hepatic ACAT2 expression.


Assuntos
Frutose/efeitos adversos , Hipertrigliceridemia/induzido quimicamente , Hipertrigliceridemia/metabolismo , Fígado/metabolismo , Esterol O-Aciltransferase/biossíntese , Animais , Frutose/administração & dosagem , Expressão Gênica , Hipertrigliceridemia/genética , Fígado/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Esterol O-Aciltransferase/genética
13.
Transfus Apher Sci ; 58(5): 634-637, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31515171

RESUMO

Asparaginase (ASP) and steroids are a main part of treatment for ALL, in both front-line and relapse setting. It is known, that ASP can cause several toxicities such as hypersensitivity, pancreatitis, as well as severe lipid and coagulation disturbances. Administered steroids can result in diabetes, obesity, hyponatremia and also mild hyperlipemia, which can intensify side effects of asparaginase. When triglyceride elevation is greater than 1000 mg/dl, the risk of pancreatitis is significantly increased. We report two patients who were hospitalized in Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin in Poland and developed severe hypertriglyceridemia after receiving asparaginase and steroid therapy for acute lymphoblastic leukemia. These patients were treated using plasmapheresis. This procedure was performed with a venous catheter in the femoral vein and 5% albumin or fresh frozen plasma as the replacement fluid. We analysed the laboratory and clinical data of these children. Plasmapheresis was well tolerated in both cases and a decrease of hypertriglyceridemia was quickly observed. However, the girl developed pancreatitis. In our opinion, plasmapheresis appears to be safe and effective in reducing hypertriglyceridemia. We could recommend that this procedure should be performed early, as soon as the triglyceride level is above 1000 mg/dl, in order to prevent severe complications. Patients should continue chemotherapy without ASP. It is important to regularly monitor of the lipid profile, pancreatic enzymes and coagulation during ASP and steroids therapy.


Assuntos
Asparaginase , Hipertrigliceridemia , Plasmaferese , Leucemia-Linfoma Linfoblástico de Células Precursoras , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/induzido quimicamente , Hipertrigliceridemia/diagnóstico por imagem , Hipertrigliceridemia/terapia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico por imagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Triglicerídeos/sangue
14.
J Dermatol ; 46(7): 557-563, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31090237

RESUMO

The present study (B-1201 clinical trial) was conducted as a multicenter, open-label, single-arm phase II study to evaluate the long-term safety, tolerability and efficacy of bexarotene. This study enrolled 10 Japanese adults aged more than 20 years with cutaneous T-cell lymphoma (CTCL) who completed the 24-week study period of the B-1101 trial. The objective response rate (ORR) was 53.8% (95% confidence interval, 25.1-80.8). In the early stage (IB), the ORR was 60% (3/5 cases). In the advanced stage (IIB and IIIA), the ORR was 57.1% (4/7 cases). The median time to response was 58 days (range, 27-168). The median treatment duration was 380 days (range, 33-1674). The median duration of response (DOR) could not be reached during the study period. The longest DOR reached 1618 days at the end of the B-1201 trial. Nine patients (56.3%) in the full analysis set (FAS) population experienced dose reduction of bexarotene. Common drug-related adverse events in the FAS population included hypothyroidism (93.8%), hypertriglyceridemia (81.3%), hypercholesterolemia (81.3%), leukopenia (68.8%) and neutropenia (56.3%). Dose-limiting toxicity (DLT) was present in five (38.5%) of the 13 patients in the 300 mg/m2 cohort. Of the five patients, four developed grade 3 neutropenia and one developed grade 4 hypertriglyceridemia. All DLT cases recovered after the discontinuation of bexarotene. None of the five patients discontinued this trial because of DLT. The B-1201 trial shows the long-term safety of oral bexarotene for Japanese patients with CTCL, despite frequent dose reduction.


Assuntos
Antineoplásicos/administração & dosagem , Bexaroteno/administração & dosagem , Linfoma Anaplásico Cutâneo Primário de Células Grandes/tratamento farmacológico , Micose Fungoide/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Antineoplásicos/efeitos adversos , Bexaroteno/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Hipercolesterolemia/induzido quimicamente , Hipercolesterolemia/epidemiologia , Hipertrigliceridemia/induzido quimicamente , Hipertrigliceridemia/epidemiologia , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/epidemiologia , Japão , Leucopenia/induzido quimicamente , Leucopenia/epidemiologia , Linfoma Anaplásico Cutâneo Primário de Células Grandes/patologia , Masculino , Micose Fungoide/patologia , Estadiamento de Neoplasias , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Neoplasias Cutâneas/patologia , Fatores de Tempo , Adulto Jovem
16.
Cardiol Young ; 29(4): 541-543, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30957734

RESUMO

We report a case of severe hypertriglyceridemia associated with an everolimus drug-eluting stent in an infant with pulmonary vein stenosis. We review from current literature the mechanisms by which everolimus may cause dyslipidaemia, pharmacokinetics of everolimus in drug-eluting stents, and treatments of hypertriglyceridemia. This case demonstrates the need to closely monitor serum triglyceride levels after everolimus drug-eluting stent placement in infants.


Assuntos
Stents Farmacológicos/efeitos adversos , Everolimo/efeitos adversos , Hipertrigliceridemia/induzido quimicamente , Estenose de Veia Pulmonar/terapia , Angiografia Coronária , Dieta com Restrição de Gorduras , Evolução Fatal , Humanos , Hipertrigliceridemia/terapia , Lactente , Masculino , Resultado do Tratamento , Triglicerídeos/sangue
17.
Can J Cardiol ; 35(3): 238-248, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30825947

RESUMO

Although the initial reports of increased cardiovascular (CV) disease in the setting of advanced AIDS were reported approximately 30 years ago, advances in antiretroviral therapy and immediate initiation of therapy on diagnosis have transformed what was once a deadly infectious disease into a chronic health condition. Accordingly, the types of CV diseases occurring in HIV have shifted from pericardial effusions and dilated cardiomyopathy to atherosclerosis and heart failure. The underlying pathophysiology of HIV-associated CV disease remains poorly understood, partly because of the rapidly evolving nature of HIV treatment and because clinical endpoints take many years to develop. The gut plays an important role in the early pathogenesis of HIV infection as HIV preferentially infects CD4+ T cells, 80% of which are located in gut mucosa. The loss of these T cells damages gut mucosa resulting in increased gut permeability and microbial translocation, which incites chronic inflammation and immune activation. Antiretroviral therapy does not cure HIV infection and immune abnormalities persist. These abnormalities correlate with mortality and CV events. The effects of antiretroviral therapy on CV risk are complex; treatment reduces inflammation and other markers of CV risk but induces lipid abnormalities, most commonly hypertriglyceridemia. On a molecular level, monocytes/macrophages, platelet reactivity, and immune cell activation, which play a role in the general population, may be heightened in the setting of HIV and contribute to HIV-associated atherosclerosis. Chronic inflammation represents an inviting therapeutic target in HIV, as it does in uninfected persons with atherosclerosis.


Assuntos
Antirretrovirais/farmacologia , Doenças Cardiovasculares , Infecções por HIV , Inflamação/imunologia , Doenças Cardiovasculares/classificação , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/prevenção & controle , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/fisiopatologia , Humanos , Hipertrigliceridemia/induzido quimicamente , Fatores de Risco
19.
Arterioscler Thromb Vasc Biol ; 39(3): 373-386, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30700132

RESUMO

Objective- APOA5 variants are strongly associated with hypertriglyceridemia, as well as increased risks of cardiovascular disease and acute pancreatitis. Hypertriglyceridemia in apo AV dysfunction often aggravates by environmental factors such as high-carbohydrate diets or aging. To date, the molecular mechanisms by which these environmental factors induce hypertriglyceridemia are poorly defined, leaving the high-risk hypertriglyceridemia condition undertreated. Previously, we reported that LXR (liver X receptor)-SREBP (sterol regulatory element-binding protein)-1c pathway regulates large-VLDL (very low-density lipoprotein) production induced by LXR agonist. However, the pathophysiological relevance of the finding remains unknown. Approach and Results- Here, we reconstitute the environment-induced hypertriglyceridemia phenotype of human APOA5 deficiency in Apoa5-/- mice and delineate the role of SREBP-1c in vivo by generating Apoa5-/- ;Srebp-1c-/- mice. The Apoa5-/- mice, which showed moderate hypertriglyceridemia on a chow diet, developed severe hypertriglyceridemia on high-carbohydrate feeding or aging as seen in patients with human apo AV deficiency. These responses were nearly completely abolished in the Apoa5-/- ;Srebp-1c-/- mice. Further mechanistic studies revealed that in response to these environmental factors, SREBP-1c was activated to increase triglyceride synthesis and to permit the incorporation of triglyceride into abnormally large-VLDL particles, which require apo AV for efficient clearance. Conclusions- Severe hypertriglyceridemia develops only when genetic factors (apo AV deficiency) and environmental effects (SREBP-1c activation) coexist. We demonstrate that the regulated production of large-sized VLDL particles via SREBP-1c determines plasma triglyceride levels in apo AV deficiency. Our findings explain the long-standing enigma of the late-onset hypertriglyceridemia phenotype of apo AV deficiency and suggest a new approach to treat hypertriglyceridemia by targeting genes that mediate environmental effects.


Assuntos
Apolipoproteína A-V/deficiência , Hipertrigliceridemia/sangue , Lipoproteínas VLDL/biossíntese , Proteína de Ligação a Elemento Regulador de Esterol 1/fisiologia , Envelhecimento/metabolismo , Ração Animal/efeitos adversos , Animais , Apolipoproteína A-V/genética , Apolipoproteínas/sangue , Quilomícrons/metabolismo , Feminino , Frutose/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Interação Gene-Ambiente , Humanos , Hidrocarbonetos Fluorados/farmacologia , Hipertrigliceridemia/induzido quimicamente , Hipertrigliceridemia/genética , Lipídeos/sangue , Receptores X do Fígado/agonistas , Receptores X do Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Azeite de Oliva/toxicidade , Proteína de Ligação a Elemento Regulador de Esterol 1/deficiência , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Sulfonamidas/farmacologia
20.
J Lipid Res ; 60(4): 805-818, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30723097

RESUMO

Dyslipidemia and insulin resistance are significant adverse outcomes of consuming high-sugar diets. Conversely, dietary fish oil (FO) reduces plasma lipids. Diet-induced dyslipidemia in a rhesus model better approximates the pathophysiology of human metabolic syndrome (MetS) than rodent models. Here, we investigated relationships between metabolic parameters and hypertriglyceridemia in rhesus macaques consuming a high-fructose diet (n = 59) and determined the effects of FO supplementation or RNA interference (RNAi) on plasma ApoC3 and triglyceride (TG) concentrations. Fructose supplementation increased body weight, fasting insulin, leptin, TGs, and large VLDL particles and reduced adiponectin concentrations (all P < 0.001). In multiple regression analyses, increased plasma ApoC3 was the most consistent and significant variable related to diet-induced hypertriglyceridemia. FO supplementation, which attenuated increases of plasma TG and ApoC3 concentrations, reversed fructose-induced shifts of lipoprotein particle size toward IDL and VLDL, a likely mechanism contributing to beneficial metabolic effects, and reduced hepatic expression of genes regulated by the SREBP pathway, particularly acetyl-CoA carboxylase. Furthermore, RNAi-mediated ApoC3 inhibition lowered plasma TG concentrations in animals with diet-induced hypertriglyceridemia. In summary, ApoC3 is an important independent correlate of TG-rich lipoprotein concentrations in rhesus macaques consuming a high-fructose diet. ApoC3 is a promising therapeutic target for hypertriglyceridemia in patients with MetS and diabetes.


Assuntos
Apolipoproteína C-III/metabolismo , Óleos de Peixe/farmacologia , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/metabolismo , Interferência de RNA , Animais , Suplementos Nutricionais , Óleos de Peixe/administração & dosagem , Frutose , Hipertrigliceridemia/induzido quimicamente , Macaca mulatta , Masculino
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