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1.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 234-238, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093789

RESUMO

Sarcoid Associated Pulmonary Hypertension (SAPH) is a common complication of sarcoidosis and is associated with poor prognosis. SAPH can be due to multiple synergistic mechanisms and current therapeutic strategies treat systemic sarcoidosis and pulmonary hypertension separately. Several studies have been performed to develop an effective therapy for SAPH but have been met with mixed results. The AMBITION trial successfully treated incident patients with pulmonary arterial hypertension (PAH) with the upfront combination of ambrisentan and tadalafil; however combination therapy has not yet been studied in patients with SAPH. Here we report a cohort of patients with newly diagnosed SAPH who were treated with upfront combination therapy per the AMBITION study protocol. We report three subjects with newly diagnosed SAPH who were treated with combination ambrisentan and tadalafil. Baseline hemodynamics were compared with those from surveillance right heart catheterization while on therapy. Mean follow up period was 17 months. Each subject demonstrated clinical and hemodynamic improvement with combination therapy. This series is the first to evaluate upfront combination ambrisentan and tadalafil therapy for treatment of newly diagnosed SAPH. Despite the impressive clinical and hemodynamic improvement, the study is limited by its small size and retrospective nature. While these initial results are promising, further work is needed to fully evaluate this regimen for treatment of SAPH. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 234-238).


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Antagonistas do Receptor de Endotelina A/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Fenilpropionatos/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Artéria Pulmonar/efeitos dos fármacos , Piridazinas/uso terapêutico , Sarcoidose Pulmonar/complicações , Tadalafila/uso terapêutico , Adulto , Idoso , Quimioterapia Combinada , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Transplante de Pulmão , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/fisiopatologia , Estudos Retrospectivos , Sarcoidose Pulmonar/diagnóstico , Resultado do Tratamento
2.
Nat Commun ; 11(1): 4370, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873792

RESUMO

BRAF kinase, a critical effector of the ERK signaling pathway, is hyperactivated in many cancers. Oncogenic BRAFV600E signals as an active monomer in the absence of active RAS, however, in many tumors BRAF dimers mediate ERK signaling. FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which leads to tumor resistance. We found that Ponatinib, an FDA-approved drug, is an effective inhibitor of BRAF monomers and dimers. Ponatinib binds the BRAF dimer and stabilizes a distinct αC-helix conformation through interaction with a previously unrevealed allosteric site. Using these structural insights, we developed PHI1, a BRAF inhibitor that fully uncovers the allosteric site. PHI1 exhibits discrete cellular selectivity for BRAF dimers, with enhanced inhibition of the second protomer when the first protomer is occupied, comprising a novel class of dimer selective inhibitors. This work shows that Ponatinib and BRAF dimer selective inhibitors will be useful in treating BRAF-dependent tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Sítio Alostérico/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Sistema de Sinalização das MAP Quinases/genética , Simulação de Acoplamento Molecular , Mutação , Neoplasias/genética , Neoplasias/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Multimerização Proteica/efeitos dos fármacos , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas B-raf/ultraestrutura , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade
3.
Bratisl Lek Listy ; 121(8): 547-553, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726116

RESUMO

AIM: This study aims to compare the protective effects of ambrisentan, a selective endothelin typeA receptor antagonist, and bosentan, a dual endothelin typeA/B receptor antagonist, on experimental renal ischemia reperfusion injury. METHOD: The study sample consisted of 21 female rats, which were divided into 3 groups: Control, Ambrisentan and Bosentan. For the ischemia-reperfusion injury model, left­kidney nephrectomy was performed after sacrificing the animals. In the immunohistochemical examination, caspase-3 was examined, and then the apoptotic index was determined. In the biochemical examination, the activities of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase, and the levels of nitrite (NOx), TNF-α, and IL-1ß were determined. RESULTS: There were statistically significant differences between the groups in terms of total injury score grade in range of 0‒3 (p=0.001).The glomerular and tubular apoptotic indices were higher in the control group as compared to those of the ambrisentan and bosentan groups (p=0.001).There were no statistically significant differences in terms of SOD, CAT, GPx, MDA, IL-1ß and TNF-α measurements among the groups (p>0.05). CONCLUSIONS: In the experimentally created renal ischemia reperfusion model, both ambrisentan and bosentan increased the NOx level, decreased the apoptosis, and protected the kidney from renal ischemia reperfusion injury. However, no significant superiority was found between ambrisentan and bosentan in terms of their protective effects (Tab. 3, Fig. 2, Ref. 31).


Assuntos
Bosentana , Antagonistas dos Receptores de Endotelina , Fenilpropionatos , Piridazinas , Traumatismo por Reperfusão , Animais , Bosentana/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Endotelinas , Feminino , Fenilpropionatos/uso terapêutico , Piridazinas/uso terapêutico , Ratos , Receptor de Endotelina A , Traumatismo por Reperfusão/tratamento farmacológico , Sulfonamidas
4.
Int Heart J ; 61(4): 799-805, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32728000

RESUMO

Therapeutic strategies for pulmonary arterial hypertension (PAH) have made remarkable progress over the last two decades. Currently, 3 types of drugs can be used to treat PAH; prostacyclins, phosphodiesterase 5 inhibitors, and endothelin receptor antagonists (ERA). In Japan, the first generation ERA bosentan was reimbursed in 2005, following which the 2nd generation ERAs ambrisentan and macitentan were reimbursed in 2009 and 2015, respectively. The efficacy of each ERA on hemodynamics in PAH patients remains to be elucidated. The aims of this study were to evaluate the hemodynamic effects of ERAs and compare these effects among each generation of ERAs.We retrospectively examined the clinical parameters of 42 PAH patients who were prescribed an ERA (15 bosentan, 12 ambrisentan, and 15 macitentan) and who underwent a hemodynamic examination before and after ERA introduction at our institution from January 2007 to July 2019.In a total of 42 patients, mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were significantly decreased and cardiac index was significantly increased after ERA introduction (P < 0.001) and the World Health Organization-Functional class (WHO-Fc) was significantly improved after ERA introduction (P = 0.005). Next, in a comparison between 1st and 2nd generation ERAs, 2nd generation ERAs were found to have brought about greater improvements in hemodynamic parameters (mPAP and PVR. P < 0.01), heart rate, brain natriuretic peptide, arterial oxygen saturation, and mixed venous oxygen saturation than the 1st generation ERA bosentan.We conclude that all ERAs could successfully improve the hemodynamics of PAH patients and that the newer generation ERAs, ambrisentan and macitentan, seemed to be preferable to bosentan.


Assuntos
Bosentana/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Fenilpropionatos/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Administração Oral , Adulto , Idoso , Bosentana/administração & dosagem , Estudos de Casos e Controles , Antagonistas dos Receptores de Endotelina/administração & dosagem , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenilpropionatos/administração & dosagem , Inibidores da Fosfodiesterase 5/uso terapêutico , Placebos/administração & dosagem , Prostaglandinas I/uso terapêutico , Hipertensão Arterial Pulmonar/fisiopatologia , Pressão Propulsora Pulmonar/efeitos dos fármacos , Piridazinas/administração & dosagem , Pirimidinas/administração & dosagem , Estudos Retrospectivos , Sulfonamidas/administração & dosagem , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos
6.
N Engl J Med ; 383(10): 931-943, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32469185

RESUMO

BACKGROUND: A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. METHODS: In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. RESULTS: As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. CONCLUSIONS: Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Edema/induzido quimicamente , Éxons , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/genética , Piridazinas/efeitos adversos , Pirimidinas/efeitos adversos
8.
J Med Chem ; 63(11): 6028-6056, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32298582

RESUMO

Neutral sphingomyelinase 2 (nSMase2) catalyzes the cleavage of sphingomyelin to phosphorylcholine and ceramide, an essential step in the formation and release of exosomes from cells that is critical for intracellular communication. Chronic increase of brain nSMase2 activity and related exosome release have been implicated in various pathological processes, including the progression of Alzheimer's disease (AD), making nSMase2 a viable therapeutic target. Recently, we identified phenyl (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)carbamate 1 (PDDC), the first nSMase2 inhibitor that possesses both favorable pharmacodynamics and pharmacokinetic (PK) parameters, including substantial oral bioavailability, brain penetration, and significant inhibition of exosome release from the brain in vivo. Herein we demonstrate the efficacy of 1 (PDDC) in a mouse model of AD and detail extensive structure-activity relationship (SAR) studies with 70 analogues, unveiling several that exert similar or higher activity against nSMase2 with favorable pharmacokinetic properties.


Assuntos
Inibidores Enzimáticos/química , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Exossomos/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Piridazinas/química , Piridazinas/metabolismo , Piridazinas/uso terapêutico , Esfingomielina Fosfodiesterase/metabolismo , Esfingomielina Fosfodiesterase/farmacologia , Relação Estrutura-Atividade
9.
Jpn J Clin Oncol ; 50(8): 859-866, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32328660

RESUMO

OBJECTIVES: Tepotinib (MSC2156119J) is an oral, potent and highly selective small molecule mesenchymal-epithelial transition factor (MET) inhibitor for which the recommended Phase II dose of 500 mg once daily has been defined, based on the first-in-man trial conducted in the USA and Europe. We carried out a multicenter Phase I trial with a classic `3 + 3' design to determine the recommended Phase II dose in Japanese patients with solid tumors (NCT01832506). METHODS: Patients aged ≥20 years with advanced solid tumors (refractory to standard therapy or for whom no effective standard therapy was available) received tepotinib at 215, 300 or 500 mg once daily in a 21-day cycle. Occurrence of dose-limiting toxicities during cycle 1 was used to determine the maximum tolerated dose. Efficacy, safety and pharmacokinetics were also evaluated to support the dose assessment. RESULTS: Twelve patients were treated. Tepotinib was generally well tolerated with no observed dose-limiting toxicities; treatment-related adverse events were mainly grades 1-2. The tolerability profile of tepotinib was similar to that observed in non-Japanese populations. Pharmacokinetics in Japanese and Western patients was comparable. One patient with gastric cancer and one patient with urachal cancer had stable disease of ≥12 weeks in duration. The observed safety profile and pharmacokinetics are comparable with those in patients from the USA and Europe, and the recommended Phase II dose of tepotinib in Japanese patients was confirmed as 500 mg once daily. CONCLUSIONS: These results, including initial signals of antitumor activity, support further development of tepotinib in Japanese patients with cancer.


Assuntos
Grupo com Ancestrais do Continente Asiático , Neoplasias/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Feminino , Humanos , Japão , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/sangue , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-met/metabolismo , Piridazinas/efeitos adversos , Piridazinas/farmacocinética , Piridazinas/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Pirimidinas/farmacologia
10.
Int J Mol Sci ; 21(7)2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32276316

RESUMO

Neuroinflammation is considered to be one of the potential causes for the development of neurodegenerative diseases, including Alzheimer's disease. In this study, we evaluated the effect of four newly synthesized pyrrolo[3,4-d]pyridazinone derivatives on the neuron-like PC12 cells under simulated inflammation conditions by preincubation with lipopolysaccharide (LPS). Our novel derivatives are selective cyclooxygenase-2 (COX-2) inhibitors and have similar effects to nonsteroidal anti-inflammatory drugs (NSAIDs). We assessed viability (LDH assay), metabolic activity (MTT assay), DNA damage (number of double-strand breaks measured by fast halo assay), and the neuronal features of cells (average neurite length and neurite outgrowth measured spectrofluorimetrically). DCF-DA and Griess assays were also performed, which allowed determining the impact of the tested compounds on the level of oxygen free radicals and nitrites. LPS administration significantly negatively affected the results in all tests performed, and treatment with the tested derivatives in most cases significantly reduced this negative impact. Multiple-criteria decision analysis indicated that overall, the best results were observed for compounds 2a and 2b at a concentration of 10 µM. The new derivatives showed intense activity against free oxygen radicals and nitrites. Reduced reactive oxygen species level also correlated with a decrease in the number of DNA damage. The compounds improved neuronal features, such as neurite length and outgrowth, and they also increased cell viability and mitochondrial activity. Our results suggest that derivatives 2a and 2b may also act additionally on mechanisms other than 3a and 3b.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Inflamação/tratamento farmacológico , Neurônios/efeitos dos fármacos , Piridazinas/farmacologia , Doença de Alzheimer , Animais , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Neurônios/patologia , Células PC12 , Piridazinas/uso terapêutico , Ratos
11.
Oncology ; 98(7): 445-451, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348984

RESUMO

BACKGROUND: Target therapy can cause various cardiovascular complications. The aim of this study was to evaluate the burden of cardiovascular complications related to treatment with anti-BCR-ABL tyrosine kinase inhibitors (TKIs) and to determine if there are differences between the latest- and first-generation TKIs. METHODS: A retrospective observational study was carried out on 55 patients (39 men, 16 women; mean age ± SD: 58 ± 11 years) treated with TKIs targeting Bcr-Abl for a median period of 3.5 years. Patients were divided in two groups according to the type of treatment. Group A included patients treated with latest-generation TKI (nilotinib, dasatinib, and ponatinib), while group B included patients treated with first-generation TKI (imatinib). Cardiological evaluation included electrocardiogram, echocardiogram with global longitudinal strain of left ventricle (GLS), and carotid ultrasound scan with arterial stiffness measurement (pulse wave velocity, PWV). Adverse cardiovascular events were recorded in both groups. RESULTS: Statistical analysis showed that cardiovascular adverse events (myocardial ischemia, peripheral artery disease, deep vein thrombosis, and pleural effusion) were significantly more frequent in group A than group B (p value = 0.044). Moreover, there was a significant reduction in GLS and PWV in group A when compared to group B (respectively, p = 0.03 and p = 0.004). CONCLUSIONS: Our study confirms that imatinib is a relatively safe drug, while it reveals that the latest-generation TKIs may cause a burden of cardiovascular complications. GLS and PWV allow detection of early signs of cardiac and vascular toxicity in oncohematologic patients treated with TKI, and their use is advisable.


Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Doença da Artéria Coronariana/induzido quimicamente , Dasatinibe/efeitos adversos , Dasatinibe/uso terapêutico , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/uso terapêutico , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso , Piridazinas/efeitos adversos , Piridazinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
12.
Rev. chil. enferm. respir ; 36(1): 41-47, mar. 2020. tab, graf
Artigo em Espanhol | LILACS | ID: biblio-1115461

RESUMO

En los pacientes con Hipertensión Arterial Pulmonar (HAP) de alto riesgo, en clase funcional (CF)IV, la terapia específica debe ser combinada y debe incluir una prostaciclina (PGI2) de uso sistémico en espera de trasplante bipulmonar (TBP). En el sistema público la única PGI2 disponible para asociar a Sildenafil y algún inhibidor de endotelina (Ambrisentan o Bosentan) es Iloprost nebulizado, que si bien es efectiva, no logra estabilizar los casos graves con severa disfunción del ventrículo derecho (VD). Se presenta el primer caso en el Instituto del Tórax, centro de referencia nacional de HAP, del uso de treprostinil en una paciente de 24 años con HAP grave e indicación de TBP. Treprostinil es un análogo sintético de PGI2 de uso subcutáneo en dosis desde 1 a 40 ng/kg/min. La paciente presentaba una situación de extrema gravedad: CF IV, distancia recorrida en el test de caminata de 6 min (DRTC 6 min) < 300 m,derrame pericárdico y severa disfunción del VD con TAPSE (índice de disfunción del VD) de 13 cm/s asociado a ProBNP >2.500 pg/ml. Luego de 6 meses de hospitalización en intermedio, terapia triple (Sildenafil, Ambrisentan e Iloprost nebulizado) asociado a O2,diuréticos y milrinona, logró ser dada de alta a las 3 semanas del inicio de treprostinil, regresando al trabajo a los 2 meses y estabilizando su condición en CF III, con DRTC 6 min > 440 m, mejoría de la función del VD(TAPSE 19). El ProBNP persistió elevado, 1.491 pg/ml, indicando que su enfermedad es grave y progresiva; sin embargo, ha logrado un nivel de estabilidad clínica que le permite una adecuada vida de relación familiar y laboral.


In high risk Pulmonary Arterial Hypertension (PAH) patients with functional class (FC) IV, specific therapy must be combined and must include systemic prostacyclin (PGI2), meanwhile they are enlisted for double lung transplant (DLT). In Chilean Public Health System, nebulized Iloprost is the only PGI2 available to combine with Sildenafil and either Ambrisentan or Bosentan as endothelin receptor antagonist. This association is not enough for severe cases with right ventricular (RV) dysfunction. The first case from the National Institute of Thorax as a referral center is presented now in a 24 years-old lady treated with treprostinil. She has severe PAH with DLT indication. Treprostinil is a PGI2 analog, for subcutaneous use in a dose from 1 to 40 ng/kg/min. She was extremely sick, with FC IV, she walked < 300 m at 6 min walking test (6 MWT), presented pericardial effusion and severe RV dysfunction, with TAPSE (echocardiography index for RV dysfunction)=13 cm/s, ProBNP > 2,500 pg/ml. Six months after being at intensive care unit with triple therapy (Sildenafil, ambrisentan and nebulized Iloprost) plus oxygen, diuretics and milrinone, she was finally discharged after receiving a 3 weeks treprostinil course. She came back to work two months later and her condition was more stable: FC III, she walked > 440 m at 6MWT, with a significant improvement in RV function with TAPSE = 19. Although ProBNP decreased to 1,491pg/ml, it was still high, pointing out the progressive nature of her disease. However, she met a better clinical condition which allows her to reach a much better quality of life from a personal, familial and social point of view.


Assuntos
Humanos , Feminino , Adulto Jovem , Epoprostenol/análogos & derivados , Hipertensão Pulmonar/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Fenilpropionatos/uso terapêutico , Piridazinas/uso terapêutico , Radiografia Torácica , Epoprostenol/uso terapêutico , Combinação de Medicamentos , Citrato de Sildenafila/uso terapêutico , Angiografia por Tomografia Computadorizada , Hipertensão Pulmonar/diagnóstico por imagem
13.
J Vet Emerg Crit Care (San Antonio) ; 30(3): 295-301, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32077239

RESUMO

OBJECTIVE: To report on the spontaneous resolution of caval syndrome in 5 dogs selected for their response to medical stabilization prior to scheduled heartworm extraction. SERIES SUMMARY: Five dogs with heartworm caval syndrome were treated with sildenafil, fluid, and supplemental oxygen therapy. Moreover, 4 of 5 dogs were also administered pimobendan to achieve hemodynamic stabilization in preparation for percutaneous heartworm extraction. Spontaneous heartworm migration back into the pulmonary arteries was detected from 2 h to 5 days after treatment initiation. UNIQUE INFORMATION PROVIDED: Unanticipated spontaneous resolution of caval syndrome was documented in a low number of dogs after initiation of a patient stabilization protocol aiming at improving right ventricular hemodynamics and reducing pulmonary artery pressure prior to scheduled heartworm extraction. At this time, it is unknown if intervention to improve the hemodynamic status of the animal prior to heartworm extraction improves procedure outcome, and which factors contributed to the migration of the heartworms back into the pulmonary arteries in these selected cases. Therefore, this approach cannot be recommended in place of current recommendations for treatment of caval syndrome.


Assuntos
Dirofilariose/parasitologia , Doenças do Cão/parasitologia , Piridazinas/uso terapêutico , Animais , Cardiotônicos/uso terapêutico , Dirofilariose/complicações , Dirofilariose/patologia , Doenças do Cão/etiologia , Doenças do Cão/patologia , Cães , Feminino , Cardiopatias/complicações , Cardiopatias/tratamento farmacológico , Cardiopatias/parasitologia , Cardiopatias/veterinária , Hemodinâmica , Masculino
14.
Ann Hematol ; 99(4): 829-834, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32107574

RESUMO

A single-center retrospective was performed with consecutive de novo BCR-ABL1-positive acute lymphoblastic leukemia (ALL) patients who received TKI-containing therapy between January 2010 and December 2018 to review the incidence, treatment, and outcome of the T315I mutation. A total of 38 (18%) patients harbored the T315I mutation in this period. According to the type of salvage therapy, patients were divided into subgroups of hematopoietic stem cell transplantation (HSCT) recipients (n = 9) and HSCT nonrecipients (n = 29). In the latter subgroup, there were 7 patients who newly acquired the T315I mutation after HSCT, and the median time was 10.8 months. In addition to these 7 cases, 5 out of 22 patients were managed with chimeric antigen receptor (CAR) T cells and ponatinib. There were 4 patients in the HSCT recipient subgroup who were treated with CAR-T cells or ponatinib before HSCT. The complete molecular remission (CMR) and recurrence rate of HSCT recipients were both 67%, and the median recurrence time was 3.6 months. A better overall survival (OS) was observed in the HSCT recipient subgroup than in the HSCT nonrecipient subgroup (median of 12.3 months vs 3.3 months, respectively; p = 0.004). Compared with patients who were not bridging to HSCT, the patients who were treated with CAR-T cells and/or ponatinib and bridged to HSCT tended to have a better OS (median of 3.3 months vs 13.3, respectively; p = 0.09). In conclusion, the outcomes in ALL patients with the T315I BCR-ABL1 mutation were poor. A better OS can be achieved through ponatinib, CAR-T cells, and bridging to HSCT, but it also has a higher risk of recurrence.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Genes abl , Imidazóis/uso terapêutico , Terapia de Alvo Molecular , Mutação de Sentido Incorreto , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Adolescente , Adulto , Substituição de Aminoácidos , Terapia Combinada , Dasatinibe/uso terapêutico , Intervalo Livre de Doença , Feminino , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoterapia Adotiva , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Recidiva , Indução de Remissão , Risco , Terapia de Salvação , Adulto Jovem
15.
Anticancer Res ; 39(12): 6965-6971, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810968

RESUMO

BACKGROUND/AIM: The Philadelphia chromosome is the most frequent cytogenetic abnormality in chronic myelogenous (CML). More than 95% of CML patients are diagnosed with the e13a2 or e14a2 BCR-ABL1 fusion transcripts while, in about 1% of these individuals, the break generates the e1a2 rearrangement. Furthermore, about 5% of CML patients are diagnosed with rare BCR-ABL1 fusion transcripts, such as e19a2, e8a2, e13a3, e14a3, e1a3 and e6a2. However, there is limited evidence concerning the clinical and prognostic implications of these infrequent oncogenic variants for CML patients receiving tyrosine kinase inhibitors (TKIs). CASE REPORT: We describe a novel atypical e12a2 insertion/deletion (Ins/Del) BCR-ABL1 fusion identified in a CML 59-year-old man diagnosed with a common e13a2 BCR-ABL1 isoform. The use of primers recognizing more distant exons from the common BCR-ABL1 breakpoint region correctly identified and monitored in time the atypical e12a2 Ins/Del BCR-ABL1 fusion. CONCLUSION: Treatment with second- (nilotinib) and third-generation (ponatinib) TKIs was effective in suppressing leukemic clones exhibiting the atypical e12a2 Ins/Del BCR-ABL1.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Humanos , Mutação INDEL , Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Isoformas de Proteínas/genética , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Resultado do Tratamento
16.
Chemotherapy ; 64(4): 205-209, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31825920

RESUMO

Cardiovascular (CV) adverse events are considered common complications of ponatinib treatment. Recently, it has been demonstrated that ponatinib dose reductions in definite settings can obtain optimal responses and lower ponatinib-related CV events. In this study, we describe the management of 5 patients with chronic myeloid leukemia treated with ponatinib, from second to fourth line of tyrosine kinase inhibitor therapy, carrying high pre-ponatinib CV risk, who obtained optimal molecular response and developed no CV adverse event during follow-up. Among these 5 patients, 2 had diagnosis of ischemic heart disease and underwent percutaneous angioplasty, 2 had type 2 diabetes and arterial hypertension, and 1 had only arterial hypertension. Median follow-up for ponatinib therapy is 1,039 days (34.6 months). Median dosage administered is 30 mg a day. SCORE charts were used to estimate risk of CV death in 10 years and Charlson Comorbidity Index was applied to estimate age-adjusted risk of death related to comorbidities. Strict cardiologic follow-up (complete evaluation every 3 to 6 months) and maximum effort in the control of CV modifiable risk factors are strongly recommended in the management of ponatinib treatment in patients at high risk for CV events and may allow the use of ponatinib in patients belonging to CV risk category.


Assuntos
Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Idoso , Doenças Cardiovasculares/etiologia , Comorbidade , Feminino , Humanos , Imidazóis/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas/efeitos adversos , Fatores de Risco , Resultado do Tratamento
18.
Lancet ; 394(10213): 2012-2024, 2019 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-31727409

RESUMO

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. Resmetirom (MGL-3196) is a liver-directed, orally active, selective thyroid hormone receptor-ß agonist designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity. We aimed to assess the safety and efficacy of resmetirom in patients with NASH. METHODS: MGL-3196-05 was a 36-week randomised, double-blind, placebo-controlled study at 25 centres in the USA. Adults with biopsy confirmed NASH (fibrosis stages 1-3) and hepatic fat fraction of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned 2:1 by a computer-based system to receive resmetirom 80 mg or matching placebo, orally once a day. Serial hepatic fat measurements were obtained at weeks 12 and 36, and a second liver biopsy was obtained at week 36. The primary endpoint was relative change in MRI-PDFF assessed hepatic fat compared with placebo at week 12 in patients who had both a baseline and week 12 MRI-PDFF. This trial is registered with ClinicalTrials.gov, number NCT02912260. FINDINGS: 348 patients were screened and 84 were randomly assigned to resmetirom and 41 to placebo at 18 sites in the USA. Resmetirom-treated patients (n=78) showed a relative reduction of hepatic fat compared with placebo (n=38) at week 12 (-32·9% resmetirom vs -10·4% placebo; least squares mean difference -22·5%, 95% CI -32·9 to -12·2; p<0·0001) and week 36 (-37·3% resmetirom [n=74] vs -8·5 placebo [n=34]; -28·8%, -42·0 to -15·7; p<0·0001). Adverse events were mostly mild or moderate and were balanced between groups, except for a higher incidence of transient mild diarrhoea and nausea with resmetirom. INTERPRETATION: Resmetirom treatment resulted in significant reduction in hepatic fat after 12 weeks and 36 weeks of treatment in patients with NASH. Further studies of resmetirom will allow assessment of safety and effectiveness of resmetirom in a larger number of patients with NASH with the possibility of documenting associations between histological effects and changes in non-invasive markers and imaging. FUNDING: Madrigal Pharmaceuticals.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Piridazinas/uso terapêutico , Receptores beta dos Hormônios Tireóideos/agonistas , Uracila/análogos & derivados , Adulto , Alanina Transaminase/sangue , Biomarcadores/sangue , Diarreia/induzido quimicamente , Método Duplo-Cego , Feminino , Humanos , Inflamação/patologia , Lipídeos/sangue , Fígado/diagnóstico por imagem , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/patologia , Piridazinas/efeitos adversos , Uracila/efeitos adversos , Uracila/uso terapêutico
19.
Gan To Kagaku Ryoho ; 46(11): 1795-1797, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31748496

RESUMO

A man in his late 50s had lumbago and thrombocytopenia. He was diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia(Ph plus ALL). Remission induction chemotherapy was initiated with JALSG Ph plus ALL 208 protocol, but cerebral infarction in the right occipital lobe developed on day 2 and, to make matters worse, was accompanied by hemorrhagic cerebral infarction in the left occipital lobe on day 9. We decided that chemotherapy with multiple drugs was difficult to continue, and it was stopped. After improvement of the general condition, dasatinib therapy was started on day 52. After about 5 months, Ph plus ALL relapsed. Although mild disorientation and visual field defects remained due to old cerebral infarction, organ function was maintained, and patient performance status(PS)was classified as 1. Introduction of ponatinib was considered feasible, and ponatinib was started from a dose of 15mg/day to prevent the occurrence of vaso- occlusive adverse events. It was gradually increased to 30mg /day and continued about 4 months without recurrence of cerebral infarction. Complete molecular response was achieved with ponatinib therapy. It was suggested that, in patients with Ph plus ALL with a history of cerebral infarction, ponatinib could be a treatment option under careful risk management.


Assuntos
Imidazóis/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras , Piridazinas/uso terapêutico , Acidente Vascular Cerebral , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Indução de Remissão
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