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1.
Dermatol Online J ; 26(1)2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32155032

RESUMO

The combination of dabrafenib and trametinib is an important immunotherapy option for patients with BRAF V600 mutation-positive melanoma. This regimen has been reported to cause cutaneous eruptions. However, hair dysmorphology is not a reported side effect to these or any other medications to date. Herein, we highlight a case of pili multigemini formation in a patient with stage IV melanoma receiving treatment with dabrafenib and trametinib and the corresponding clinical findings.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças do Cabelo/induzido quimicamente , Folículo Piloso/anormalidades , Imidazóis/efeitos adversos , Oximas/efeitos adversos , Transtornos da Pigmentação/induzido quimicamente , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Cabelo , Humanos , Imidazóis/uso terapêutico , Masculino , Melanoma/tratamento farmacológico , Melanoma/secundário , Pessoa de Meia-Idade , Oximas/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico
4.
Cancer Sci ; 111(2): 536-547, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31778267

RESUMO

Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose-escalation results for capmatinib in advanced MET-positive solid tumor patients and dose expansion in advanced non-lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, Ctrough >EC90 (90% inhibition of c-MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose-expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near-complete immunohistochemically determined phospho-MET inhibition (H-score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high-level MET GCN (GCN ≥6) and MET-overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479).


Assuntos
Imidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Triazinas/administração & dosagem , Idoso , Cápsulas , Relação Dose-Resposta a Droga , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Comprimidos , Resultado do Tratamento , Triazinas/efeitos adversos , Triazinas/farmacocinética
5.
Gynecol Oncol ; 156(1): 23-31, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31791552

RESUMO

OBJECTIVE: This phase 1b/2 clinical trial (NCT01663857) evaluated the efficacy of ralimetinib in combination with gemcitabine (G) and carboplatin (C), followed by maintenance ralimetinib, for patients with recurrent platinum-sensitive epithelial ovarian cancer. METHODS: Phase 1b was to determine the recommended phase 2 dose (RP2D) of ralimetinib administered Q12H on Days 1-10 (q21d) in combination with G (1000 mg/m2, Days 3 and 10) and C (AUC 4, Day 3) for six cycles. In phase 2, patients were randomized double-blind 1:1 to ralimetinib (R)+GC or placebo (P)+GC, for six cycles, followed by ralimetinib 300 mg Q12H or placebo on Days 1-14, q28d. RESULTS: 118 patients received at least one dose of ralimetinib or placebo; eight in phase 1b and 110 in phase 2 (R+GC, N = 58; P+GC, N = 52). The RP2D for R+GC was 200 mg Q12H. The study met its primary objective of a statistically significant difference in PFS (median: R+GC, 10.3 mo vs. P+GC, 7.9 mo; hazard ratio [HR] = 0.773, P = 0.2464, against a two-sided false positive rate of 0.4). Secondary objectives were not statistically significant for median overall survival (R+GC, 29.2 mo vs. P+GC, 25.1 mo; HR = 0.827, P = 0.4686) or overall response rate (R+GC 46.6% vs. P+GC, 46.2%; P = 0.9667). The safety profile of R+GC therapy was mainly consistent with safety of the chemotherapy backbone alone. Grade 3/4 elevated alanine aminotransferase was more common in the ralimetinib arm. CONCLUSIONS: Addition of ralimetinib to GC resulted in a modest improvement in PFS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Método Duplo-Cego , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Adulto Jovem , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
6.
Wien Klin Wochenschr ; 131(19-20): 493-501, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31471672

RESUMO

Over the past 5 years several case reports and cohort studies have been published that describe a sprue-like enteropathy (SLE) with abdominal pain, chronic diarrhea and weight loss, after taking angiotensin type 1 receptor blockers (ARB). The initial case series from the Mayo Clinic, which described 22 cases of olmesartan-induced SLE, was followed by numerous case descriptions for almost all ARBs. A total of 73 case reports have been described so far that show evidence of ARB-associated enteropathy with villous atrophy and full recovery 3-12 months after discontinuation of the sartan in question. Of these, 59 cases were olmesartan-associated cases of SLE, another 14 case reports have been published for telmisartan (4), valsartan (3), losartan (2), candesartan (1) and eprosartan (1). Based on the available cohort studies, ARB-associated intestinal malabsorption occurs in 9.8-14 cases per 100,000 patients treated with ARBs, the number treated to harm is over 31,000 patient-years. Although the majority of case reports have been published with olmesartan, in the cohort studies no clear difference within the ARBs can be ruled out. The SLE is rare but must be suspected and diagnostically investigated in every patient presenting with abdominal discomfort, chronic diarrhea and weight loss who is being treated with an ARB, after other causes have been ruled out. In such cases, discontinuing the ARB leads to a full recovery.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Enteropatias , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Antagonistas de Receptores de Angiotensina , Diarreia/induzido quimicamente , Humanos , Imidazóis/efeitos adversos , Enteropatias/induzido quimicamente , Enteropatias/patologia , Síndromes de Malabsorção/induzido quimicamente , Tetrazóis/efeitos adversos
8.
Breast Cancer Res Treat ; 178(1): 121-133, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31368034

RESUMO

PURPOSE: This open-label, phase Ib, dose-escalation, and dose-expansion study (NCT01862081) evaluated taselisib with a taxane in locally advanced or metastatic breast cancer (BC) and/or non-small cell lung cancer (NSCLC). METHODS: Patients received taselisib (2-6 mg tablet or 3-6 mg capsule) plus docetaxel or paclitaxel. Primary endpoints were safety, dose-limiting toxicities, maximum tolerated dose, and identification of a recommended phase II dose. Secondary endpoints included pharmacokinetics and antitumor activity assessment. RESULTS: Eighty patients (BC: 72; NSCLC: 7; BC/NSCLC: 1) were enrolled (docetaxel-receiving arms: 21; paclitaxel-receiving arms: 59). Grade ≥ 3 adverse events (AEs), serious AEs, and AEs leading to death were reported in 90.5%, 42.9%, and 14.3% of patients, respectively (docetaxel-receiving arms), and 78.9%, 40.4%, and 3.5% of patients, respectively (paclitaxel-receiving arms). Eight patients experienced dose-limiting toxicities. The maximum tolerated dose was exceeded with 3 mg taselisib (capsule) for 21 consecutive days plus 75 mg/m2 docetaxel and not exceeded with 6 mg taselisib (tablet) for 5 days on/2 days off plus 80 mg/m2 paclitaxel. Objective response rates and clinical benefit rates were 35.0% and 45.0%, respectively (docetaxel-receiving arms), and 20.4% and 27.8%, respectively (paclitaxel-receiving arms). Exposure for paclitaxel or docetaxel plus taselisib was consistent with the single agents. CONCLUSIONS: Taselisib in combination with a taxane has a challenging safety profile. Despite evidence of antitumor activity, the benefit-risk profile was deemed not advantageous. Further development is not planned.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/administração & dosagem , Imidazóis/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Oxazepinas/administração & dosagem , Paclitaxel/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias da Mama/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Docetaxel/efeitos adversos , Docetaxel/farmacocinética , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Neoplasias Pulmonares/genética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Oxazepinas/efeitos adversos , Oxazepinas/farmacocinética , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Receptor ErbB-2/metabolismo , Análise de Sobrevida , Resultado do Tratamento
10.
BMJ Case Rep ; 12(8)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466958

RESUMO

Eluxadoline is a novel medication that was approved in the USA in 2015 for the treatment of diarrhoea-predominant irritable bowel syndrome. Due to its unique mechanism of action as both an opioid agonist and antagonist, it has been placed as a schedule IV controlled substance. Since its approval, there have been several cases of eluxadoline-induced pancreatitis reported in the literature. The majority of patients who presented with eluxadoline-induced pancreatitis were reported to have had a prior cholecystectomy. Due to this, the Food and Drug Administration released a warning in 2017 that eluxadoline should no longer be used in patients who do not have a gall bladder. We present a rare case of an adult man without prior cholecystectomy who presented with severe mid-epigastric pain and was found to have eluxadoline-induced pancreatitis.


Assuntos
Imidazóis/efeitos adversos , Pancreatite/diagnóstico , Fenilalanina/análogos & derivados , Dor Abdominal/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite/induzido quimicamente , Fenilalanina/efeitos adversos
11.
BMC Ophthalmol ; 19(1): 158, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340775

RESUMO

BACKGROUND: To report the first case of allergic contact dermatitis (ACD) associated with alcaftadine 0.25% ophthalmic solution. CASE PRESENTATION: The patient was a 51-year-old woman with no previous history of side effects to ophthalmic antihistamine agents. She had been prescribed alcaftadine 0.25% for allergic conjunctivitis. On first application of the medication, she did not experience any cutaneous reaction. One day later, after the second alcaftadine 0.25% application, both eyelids became swollen, and erythematous changes were evident. On slit-lamp examination, conjunctival injection was noted in the absence of conjunctival swelling or any other findings. Fundus examination was unremarkable. To evaluate the cause of ACD, a patch test was performed and 48 h later was noted to be positive for alcaftadine 0.25%. Based on the positive patch test, the patient was diagnosed with ACD caused by alcaftadine 0.25%. After 9 days of treatment, the swelling and erythema completely resolved. CONCLUSIONS: Although there have been no previous reports of alcaftadine 0.25%-associated ACD, it should be suspected in patients with swelling and erythematous change of both eyes after using alcaftadine 0.25%.


Assuntos
Benzazepinas/efeitos adversos , Dermatite Alérgica de Contato/etiologia , Imidazóis/efeitos adversos , Administração Oral , Benzazepinas/administração & dosagem , Conjuntivite Alérgica/tratamento farmacológico , Dermatite Alérgica de Contato/diagnóstico , Dermatite Alérgica de Contato/tratamento farmacológico , Feminino , Glucocorticoides/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Humanos , Imidazóis/administração & dosagem , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Soluções Oftálmicas , Órbita/diagnóstico por imagem , Tomografia Computadorizada por Raios X
12.
Acta Gastroenterol Belg ; 82(2): 319-321, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31314195

RESUMO

Olmesartan, an angiotensin receptor blocker, is a widely spread antihypertensive drug. Seronegative villous atrophy of the small intestine due to olmesartan use was first described in 2012. We present a new case of olmesartan-induced enteropathy and compare it to recent literature. This case might suggest a use of budesonide for treatment.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Budesonida/uso terapêutico , Imidazóis/efeitos adversos , Enteropatias/induzido quimicamente , Enteropatias/tratamento farmacológico , Tetrazóis/efeitos adversos , Diarreia/induzido quimicamente , Diarreia/tratamento farmacológico , Humanos , Hipertensão/tratamento farmacológico
13.
PLoS One ; 14(7): e0219022, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291311

RESUMO

AIMS: Drug-induced liver damage characterized by serum alanine aminotransferase (ALT) elevation often occurs in direct-acting antiviral (DAA) combination therapy for chronic hepatitis C virus (HCV) infection. This study explored single nucleotide polymorphisms (SNPs) at drug metabolism- or transport-related genes that were associated with ALT elevation in asunaprevir plus daclatasvir therapy. METHODS: Subjects were 185 Japanese patients with chronic HCV genotype 1b infection who received asunaprevir plus daclatasvir therapy. Tag SNPs at possible metabolizing enzyme and transporter genes, which were involved in the pharmacokinetics of asunaprevir and daclatasvir, were selected. RESULTS: Among the tag SNPs analyzed, CYP3A4 rs4646437 was significantly associated with ALT elevation (p = 0.013): maximum ALT values in patients with genotype CC were higher than those in patients with genotype non-CC (allele T). The proportion of grades 2-4 in genotype CC patients were significantly greater than those in genotype non-CC patients (p = 0.028). No patients with genotype non-CC showed grade ≥2 ALT elevation. In multivariate analysis, rs4646437 genotype CC and cirrhosis were significant, independent factors associated with grade ≥1 ALT elevation (odds ratio, 2.83 and 1.88; p = 0.040 and 0.045, respectively). In exploratory analyses, although serum concentrations of asunaprevir and daclatasvir were not correlated with maximum ALT values or rs4646437 genotypes, asunaprevir concentrations in patients with grade ≥1 ALT elevation were significantly higher than those in patients with grade <1 ALT elevation (P = 0.023). CONCLUSIONS: CYP3A4 rs4646437 was found to be significantly and independently associated with ALT elevation in Japanese patients receiving ASV plus DCV therapy. Notably, none of the patients with rs4646437 genotype non-CC (allele T) had grade ≥2 ALT elevation. SNP genotyping prior to treatment might be useful for carefully monitoring patients to complete treatment safely.


Assuntos
Alanina Transaminase/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Citocromo P-450 CYP3A/genética , Hepatite C Crônica/tratamento farmacológico , Imidazóis/administração & dosagem , Isoquinolinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Hepática Induzida por Substâncias e Drogas/sangue , Quimioterapia Combinada/efeitos adversos , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/sangue , Hepatite C Crônica/genética , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Isoquinolinas/efeitos adversos , Isoquinolinas/farmacocinética , Japão , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Regulação para Cima
14.
N Engl J Med ; 381(7): 626-636, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31166680

RESUMO

BACKGROUND: Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors. METHODS: We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively. RESULTS: A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years. CONCLUSIONS: First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline and Novartis; COMBI-d ClinicalTrials.gov number, NCT01584648; COMBI-v ClinicalTrials.gov number, NCT01597908.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imidazóis/administração & dosagem , Melanoma/tratamento farmacológico , Oximas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Seguimentos , Humanos , Imidazóis/efeitos adversos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Masculino , Melanoma/genética , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Mutação , Oximas/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Adulto Jovem
15.
J Dermatol ; 46(8): 716-719, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31180164

RESUMO

Pyrexia is the most common adverse event in patients with melanoma or other solid organ malignancies that are treated with the combination of dabrafenib and trametinib (combi-DT). Given the expanded indication for combi-DT, management of pyrexia is a high priority. No previous case series has revealed which blood markers reflect the course of pyrexia and there is no consensus on the management strategy for pyrexia. The current case series study describes the utility of neutrophil count (NC), neutrophil ratio (NR) and C-reactive protein (CRP) in 11 patients with metastatic melanoma and BRAF V600 mutations who experienced pyrexia during combi-DT in our department. We also described the clinical course of pyrexia episodes that were managed with the concomitant use of oral prednisolone and immediate withdrawal of combi-DT. Consequently, the analysis of 37 pyrexia episodes in 11 patients showed that the differences in NC, NR and CRP at the onset of pyrexia were significantly different from those at pyretolysis (P = 0.01, 0.006 and 0.03, respectively). Additionally, in the 24 pyrexia episodes treated with the concomitant use of oral prednisolone and the immediate withdrawal of combi-DT, the mean duration of pyrexia and the mean time to restart combi-DT were 3 and 6 days, respectively. Therefore, the blood markers that reflect the course of pyrexia during combi-DT may be helpful for the appropriate management of pyrexia; also, our management strategy for pyrexia successfully reduced the duration of pyrexia and did not require a long-term drug holiday. Further large-scale studies are required to verify our results.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteína C-Reativa/análise , Febre/diagnóstico , Imidazóis/efeitos adversos , Neutrófilos , Oximas/efeitos adversos , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Administração Oral , Adulto , Idoso , Biomarcadores/sangue , Estudos de Viabilidade , Feminino , Febre/sangue , Febre/induzido quimicamente , Febre/tratamento farmacológico , Humanos , Contagem de Leucócitos , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Estudos Retrospectivos , Neoplasias Cutâneas/tratamento farmacológico , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
16.
Thromb Haemost ; 119(7): 1112-1123, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079415

RESUMO

Both nilotinib, a second-generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukaemia (CML), and ponatinib, a third-generation TKI used in CML and Philadelphia positive acute lymphocytic leukaemia, have been associated with an increase in arterial occlusive events, in contrast to other TKIs such as imatinib and dasatinib. We have previously demonstrated evidence of a pro-thrombotic state associated with nilotinib, using microvascular and arterial thrombosis C57BL/6 mouse models. In this study, we examined ponatinib and determined if a calcium channel blocker could ameliorate the pro-thrombotic and pro-inflammatory phenotypes. In vitro treatment of whole human or murine blood with ponatinib and nilotinib increased platelet activation, adhesion and three-dimensional thrombi over time compared with vehicle control or other TKIs. Treatment of wild-type C57BL/6 mice with ponatinib and nilotinib but not imatinib, dasatinib or vehicle control for 4 hours significantly increased thrombus growth following ex vivo perfusion on collagen and FeCl3-induced vascular injury of mesenteric arterioles and carotid artery in vivo and increased plasma levels of soluble P-selectin, tumour necrosis factor-α, interleukin-6, interferon-γ and thromboxane B2 (TxB2). Ponatinib-treated CML patients had increased ex vivo thrombus formation and a pro-inflammatory phenotype compared with healthy controls. Pre-treatment of mice with the calcium channel antagonist, diltiazem, prior to ponatinib or nilotinib reversed the pro-thrombotic phenotype and the increase in cytokine levels. These observations suggest that the pro-thrombotic effect of nilotinib and ponatinib is partially related to calcium channel activation and TxA2 generation and this should be explored clinically as a mechanism to prevent vascular events.


Assuntos
Antineoplásicos/uso terapêutico , Plaquetas/fisiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Imidazóis/uso terapêutico , Inflamação/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/uso terapêutico , Trombose/imunologia , Animais , Antineoplásicos/efeitos adversos , Plaquetas/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Diltiazem/farmacologia , Humanos , Imidazóis/efeitos adversos , Inflamação/etiologia , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microfluídica , Ativação Plaquetária , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas/efeitos adversos , Trombose/etiologia
17.
Sci Total Environ ; 666: 1151-1160, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30970480

RESUMO

The occurrence of antimicrobials and other pharmaceuticals in streams is increasingly being reported, yet the impacts of these contaminants of emerging concern on aquatic ecosystems are relatively unknown. Bacteria and fungi are vital components of stream environments and, therefore, exposure to antimicrobials may have important consequences for ecosystem services, such as carbon cycling. The objective of this study was to investigate how two antimicrobials, ciprofloxacin and climbazole, impact detrital biofilm metabolism in urban and rural streams. To establish baseline conditions, the biological oxygen demand (BOD) of red maple (Acer rubrum) biofilms was measured in one urban and one rural stream. In mesocosm studies, the BOD of biofilms on single- and mixed-species leaf litter from the same sites was measured after exposure to 10 µg/L of the antimicrobials, both in combination and individually. The presence of ciprofloxacin and climbazole did not affect BOD compared to the controls at the urban site, although significant differences were identified for select treatments at the rural site. In addition, the BOD of mixed-leaf biofilms was not significantly different from that of single species litter after exposure. Overall, exposure to 10 µg/L of the antimicrobials did not significantly impact community-level carbon processing by the leaf biofilms, and leaf mixtures did not result in increased biofilm BOD compared to single species leaves. The outcomes of this work demonstrate a need for further research for the understanding the effects of antimicrobials on rural streams to prevent unintended consequences to ecological processes and biota from future development, leaking septic systems, and wastewater spills.


Assuntos
Antibacterianos/efeitos adversos , Antifúngicos/efeitos adversos , Fenômenos Fisiológicos Bacterianos/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Ciprofloxacino/efeitos adversos , Imidazóis/efeitos adversos , Rios/microbiologia , Análise da Demanda Biológica de Oxigênio , Cidades , Maryland , Folhas de Planta/microbiologia
18.
PLoS One ; 14(4): e0214884, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30939167

RESUMO

Panniculitis and vitiligo-like lesions have been recently identified as rare cutaneous side effects of the combination of BRAF and MEK inhibitors, a standard of care in metastatic and locally advanced BRAF V600 mutated melanoma. An immune-mediated mechanism has been advocated in the pathogenesis of these skin lesions. Herein we retrospectively reviewed our institutional experience with the aim to explore the association between the occurrence of panniculitis and vitiligo-like lesions during combination therapy with dabrafenib (D) and trametinib (T) and outcome of advanced melanoma patients. Among 52 consecutive BRAF V600 mutated melanoma patients submitted to DT in our center, 12 (23%) developed immune related skin lesions (IRSLs): 8 panniculitis and 4 vitiligo. Patients with IRSLs diagnosis obtained a better disease response (83% versus 25%) (p = 0.001) than their counterpart and had a longer progression free survival and overall survival. The association of IRSLs and lower risk of disease progression (HR 0.19; CI 95% 0.04-0.90; p = 0.043) was confirmed after adjusting for major prognostic factors in multivariate analysis. IRSLs might represent an easy predictive surrogate marker for treatment response and favourable outcome in melanoma patients submitted to DT combination therapy.


Assuntos
Antineoplásicos/efeitos adversos , Melanoma/tratamento farmacológico , Paniculite/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico , Vitiligo/induzido quimicamente , Adulto , Idoso , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Estimativa de Kaplan-Meier , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Melanoma/genética , Melanoma/mortalidade , Pessoa de Meia-Idade , Mutação , Oximas/administração & dosagem , Oximas/efeitos adversos , Paniculite/patologia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Estudos Retrospectivos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Resultado do Tratamento , Vitiligo/patologia
19.
Lasers Med Sci ; 34(9): 1873-1880, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31025207

RESUMO

Onychomycosis is a common chronic-resistant nail disease. Traditional treatment has its limitations and side effects. This study aimed to evaluate the role of fractional CO2 laser and topical tioconazole 28% nail lacquer in the treatment of fingernail onychomycosis, as sole treatment modalities and in combination. Thirty patients with culture-proven onychomycosis were included and randomly divided into three equal groups. Laser group received six fractional carbon dioxide (CO2) laser sessions at monthly intervals; topical group received topical tioconazole 28% nail lacquer twice daily for 6 months, and combined group received six fractional CO2 laser sessions at monthly intervals with topical tioconazole twice daily for 6 months. Treatment outcome was evaluated through physician's evaluation of improvement using onychomycosis severity index score (OSI), patients' satisfaction, side effect evaluation, and mycological culture (assessed after the end of treatment). At the end of treatment, both laser and combined groups showed significantly better degrees of improvement (P = 0.036, 0.024, respectively) and patient's satisfaction (P = 0.046, 0.003, respectively) in comparison with topical group. Mycological clearance in fungal cultures was significantly higher in combined group than topical group after the end of treatment (P = 0.007). Fractional CO2 laser is a safe and effective treatment modality for onychomycosis. Its efficacy approximates that of fractional CO2 laser combined with topical tioconazole 28% nail lacquer and surpasses that of topical tioconazole 28% monotherapy. It is expected to be an excellent choice for patients in whom systemic antifungals are contraindicated or who are unresponsive or intolerant to topical antifungals.


Assuntos
Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Lasers de Gás/uso terapêutico , Onicomicose/tratamento farmacológico , Onicomicose/cirurgia , Administração Tópica , Adulto , Antifúngicos/uso terapêutico , Terapia Combinada , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacologia , Lasers de Gás/efeitos adversos , Masculino , Satisfação do Paciente , Resultado do Tratamento
20.
Hematol Oncol ; 37(3): 296-302, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30892724

RESUMO

Arterial occlusive events (AOEs) represent emerging complications in chronic myeloid leukemia (CML) patients treated with ponatinib. We identified 85 consecutive CML adult patients who were treated with ponatinib in 17 Italian centers. Patients were stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels. The 60-month cumulative incidence rate of AOEs excluding hypertension was 25.7%. Hypertension was reported in 14.1% of patients. The median time of exposure to ponatinib was 28 months (range, 3-69 months). Patients with a high to very high SCORE risk showed a significantly higher incidence rate of AOEs (74.3% vs 15.2%, P < 0.001). Patients aged ≥60 years showed a significantly higher incidence rate of AOEs (51.5% vs 16.9%, P = 0.008). In multivariate analysis, no association was found between AOEs and positive history of CV disease, age, dose of ponatinib, previous exposure to nilotinib, and comorbidities. Only the SCORE risk was confirmed as a significant predictive factor (P = 0.01; HR = 10.9; 95% C.I. = 1.7-67.8). Patients aged ≥60 years who were treated with aspirin had a lower incidence rate of AOEs (33.3% vs 61.8%). Among the 14 reported AOEs, 78.6% of them showed grade 3 to 4 toxicity. This real-life study confirmed the increased incidence of AOEs in CML patients treated with ponatinib, with high to very high SCORE risk. We suggest that patients aged ≥60 years who were treated with ponatinib should undergo prophylaxis with 100 mg/day of aspirin. Our findings emphasize personalized prevention strategies based on CV risk factors.


Assuntos
Oclusão Coronária/induzido quimicamente , Imidazóis/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piridazinas/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Aspirina/uso terapêutico , Cardiologia/métodos , Oclusão Coronária/complicações , Sistemas de Apoio a Decisões Clínicas , Feminino , Humanos , Hipertensão/induzido quimicamente , Imidazóis/uso terapêutico , Incidência , Itália/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Masculino , Oncologia/métodos , Pessoa de Meia-Idade , Piridazinas/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
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