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1.
J Med Case Rep ; 15(1): 109, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653337

RESUMO

BACKGROUND: Pneumatosis intestinalis (PI) is a rare entity which refers to the presence of gas within the wall of the small bowel or colon which is a radiographic sign. The etiology and clinical presentation are variable. Patients with PI may present either with chronic mild non-specific symptoms or with acute abdominal pain with peritonitis. Some cases of intestinal pneumatosis have been reported as adverse events of new oncological treatments such as targeted therapies that are widely used in multiple tumors. CASE PRESENTATION: A 59-year-old caucasian female with radioactive iodine-refractory metastatic thyroid papillary carcinoma with BRAFV600E mutation was treated with dabrafenib and trametinib as a compassionate use. After 4 months treatment, positron emission tomography-computed tomography (PET-CT) showed PI. At the time of diagnosis, the patient was asymptomatic without signs of peritonitis. The initial treatment was conservative and no specific treatment for PI was needed. Unfortunately, after dabrafenib-trametinib withdrawal, the patient developed tumor progression with significant clinical worsening. CONCLUSIONS: This case report is, in our knowledge, the first description of PI in a patient treated with dabrafenib-trametinib. Conservative treatment is feasible if there are no abdominal symptoms.


Assuntos
Enfisema/diagnóstico por imagem , Imidazóis/efeitos adversos , Enteropatias/diagnóstico por imagem , Oximas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Neoplasias da Base do Crânio/tratamento farmacológico , Câncer Papilífero da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia , Enfisema/induzido quimicamente , Feminino , Humanos , Enteropatias/induzido quimicamente , Radioisótopos do Iodo/uso terapêutico , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Base do Crânio/diagnóstico por imagem , Neoplasias da Base do Crânio/genética , Neoplasias da Base do Crânio/secundário , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/secundário
2.
Clin Drug Investig ; 41(1): 89-97, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33355910

RESUMO

BACKGROUND AND OBJECTIVES: Tegoprazan is one of the potassium-competitive acid blockers (P-CABs). It exhibits its anti-secretory effects by competitively and reversibly blocking the availability of K+ of the H+, K+-ATPase. This study was designed to investigate the safety and pharmacokinetics of tegoprazan in healthy Chinese subjects. METHODS: Thirty-eight healthy Chinese subjects were recruited in this randomized, single-center, double-blind, placebo-controlled study, with a single ascending dose of 50, 100, 200 mg and a multiple dose of 100 mg for 10 days. The plasma concentration of tegoprazan was determined by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetics were evaluated via non-compartmental and compartmental model analysis. Safety was assessed by physical examinations, vital signs, clinical laboratory tests, and electrocardiograms. RESULTS: No serious adverse event was observed in this study. After single-dose administration (50, 100 and 200 mg), tegoprazan was rapidly absorbed with a median maximum measure plasma concentration (Tmax) at 0.5 h and declined with a terminal (elimination) half-life (t1/2) of 3.87-4.57 h. The maximum measured plasma concentration (Cmax) for tegoprazan was 813.80, 1494.60 and 2829.00 ng/mL. Meanwhile, the corresponding area under the concentration-time curve (AUC) from time zero to infinity (AUC0-inf) was 2761.00, 5980.05 and 11,044.72 ng∙h/mL in 50, 100, 200 mg group, respectively. Dose-dependent increase was observed in the value of Cmax and AUC after administration of tegoprazan 50 to 200 mg. The two-compartment model well described the pharmacokinetic profile of tegoprazan. In the steady state, no accumulation was found after repeated administration at the 100-mg dose level. No experimental differences were found based on gender. CONCLUSIONS: Tegoprazan was well tolerated in the dose range of 50-200 mg in single- and 100 mg in multiple-dose studies. Tegoprazan shows dose linearity with oral administration after a single dose of 50 to 200 mg and less drug accumulation after 10 days of continuous administration in 100 mg.


Assuntos
Derivados de Benzeno/administração & dosagem , Cromatografia Líquida , Imidazóis/administração & dosagem , Espectrometria de Massas em Tandem , Administração Oral , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Derivados de Benzeno/efeitos adversos , Derivados de Benzeno/farmacocinética , Método Duplo-Cego , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Adulto Jovem
4.
N Z Med J ; 133(1527): 83-94, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33332330

RESUMO

AIM: Drug-induced ocular inflammation is rare and may be overlooked as a cause of uveitis. The main objective was to describe the causes of drug-induced ocular inflammation. Secondary objectives included uveitis complications and drug rechallenge reactions. METHODS: A retrospective chart review at Auckland District Health Board's tertiary uveitis clinic (Auckland, New Zealand) was performed. Participants were identified using the uveitis database, which consists of 2,750 subjects. Fifty eyes of 35 subjects had drug-induced inflammation. RESULTS: Drug-induced inflammation occurred in 1.3% of subjects with uveitis. Mean age was 66.8±15.6 years, and 25 subjects (71.4%) were female. Drugs responsible were bisphosphonates (24 subjects, 68.6%), brimonidine (one subject, 2.9%), etanercept (three subjects, 8.6%), immune checkpoint inhibitors (two subjects, 5.7%), BRAF inhibitors (three subjects, 8.6%), EGFR inhibitors (one subject, 2.9%) and allopurinol/perindopril (one subject, 2.9%). In subjects with bisphosphonate inflammation, anterior uveitis occurred in 22 (91.7%) and scleritis in two (8.3%). A positive rechallenge reaction occurred in two subjects with zoledronate and one with alendronate. Uveitis occurred in six subjects (17.1%) treated with cancer drugs including immune checkpoint inhibitors, BRAF inhibitors and EGFR protein kinase inhibitors. Subjects with cancer-drug-induced uveitis were managed with corticosteroids and five subjects were able to continue therapy; in one subject uveitis was uncontrollable and required drug cessation. CONCLUSIONS: Ocular inflammation caused by bisphosphonates is usually mild and resolves on medication withdrawal. Uveitis seen in association with newer cancer medications can be more severe, but in most cases it can be managed without medication cessation.


Assuntos
Difosfonatos/efeitos adversos , Uveíte Anterior/induzido quimicamente , Ácido Zoledrônico/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alendronato/efeitos adversos , Alopurinol/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Tartarato de Brimonidina/efeitos adversos , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/efeitos adversos , Etanercepte/efeitos adversos , Feminino , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Oximas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Estudos Retrospectivos , Esclerite/induzido quimicamente , Vemurafenib/efeitos adversos
5.
N Engl J Med ; 383(10): 944-957, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32877583

RESUMO

BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation. METHODS: We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status (MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments. RESULTS: A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2. CONCLUSIONS: Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imidazóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Triazinas/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 , Dosagem de Genes , Humanos , Imidazóis/efeitos adversos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/genética , Triazinas/efeitos adversos
6.
Lancet Oncol ; 21(9): 1234-1243, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32818466

RESUMO

BACKGROUND: Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAFV600E-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAFV600E-mutated biliary tract cancer. METHODS: This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAFV600E-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAFV600E-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting. FINDINGS: Between March 12, 2014, and July 18, 2018, 43 patients with BRAFV600E-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6-15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36-67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31-62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported. INTERPRETATION: Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAFV600E-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAFV600E mutations should be considered in patients with biliary tract cancer. FUNDING: GlaxoSmithKline and Novartis.


Assuntos
Neoplasias do Sistema Biliar/tratamento farmacológico , Imidazóis/administração & dosagem , Oximas/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/genética , Neoplasias do Sistema Biliar/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Oximas/efeitos adversos , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Resultado do Tratamento
7.
J Stroke Cerebrovasc Dis ; 29(9): 105085, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807481

RESUMO

Ponatinib is a third-generation Tyrosine Kinase Inhibitor (TKI), approved as first-line treatment for Chronic Myeloid Leukaemia (CML) chronic phase. Here we describe a CML patient with a history of subsequent TIAs and an ischemic stroke during Ponatinib treatment. Patient was admitted for a 3-day history of sudden onset left hemiparesis due to an acute ischemic stroke. MRI showed bilaterally the almost total absence of signal in the intracranial tract of anterior circulation and low signal of cerebral posterior circulation. Digital Subtraction Angiography showed multiple steno-occlusions of both anterior and posterior circulation large vessels. The association between cerebrovascular events and TKIs of second and third-generation has been widely described. So Ponatinib was stopped. To our knowledge, this is the first case of multiple ischemic strokes and recurrent TIAs during treatment with Ponatinib, pointing out the importance of accurate quantification of cardiovascular risk before starting Ponatinib.


Assuntos
Antineoplásicos/efeitos adversos , Imidazóis/efeitos adversos , Trombose Intracraniana/induzido quimicamente , Ataque Isquêmico Transitório/induzido quimicamente , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas/efeitos adversos , Acidente Vascular Cerebral/induzido quimicamente , Tomada de Decisão Clínica , Humanos , Trombose Intracraniana/diagnóstico por imagem , Ataque Isquêmico Transitório/diagnóstico por imagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Recidiva , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico por imagem , Resultado do Tratamento
8.
Cancer Sci ; 111(9): 3327-3337, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32639651

RESUMO

Tirabrutinib is a second-generation Bruton's tyrosine kinase inhibitor with greater selectivity than ibrutinib. Here, we conducted a multicenter, phase II study of tirabrutinib in patients with treatment-naïve (Cohort A) or with relapsed/refractory (Cohort B) Waldenström's macroglobulinemia (WM). Patients were treated with tirabrutinib 480 mg once daily. The primary endpoint was major response rate (MRR; ≥ partial response). Secondary endpoints included overall response rate (ORR; ≥ minor response), time to major response (TTMR), progression-free survival (PFS), overall survival (OS), and safety. In total, 27 patients (18 in Cohort A; 9 in Cohort B) were enrolled. The median age was 71 y, and the median serum immunoglobulin M level was 3600 mg/dL. Among the patients, 96.2% had the MYD88L265P mutation. MRR and ORR were 88.9% and 96.3%, respectively (Cohort A: MRR, 88.9%; ORR, 94.4%; Cohort B: MRR, 88.9%; ORR, 100%). Median TTMR was 1.87 mo. PFS and OS were not reached with a median follow-up of 6.5 and 8.3 mo for Cohorts A and B, respectively. The most common adverse events (AEs) were rash (44.4%), neutropenia (25.9%), and leukopenia (22.2%), with most AEs classified as grade 1 or 2. Grade ≥ 3 AEs included neutropenia (11.1%), lymphopenia (11.1%), and leukopenia (7.4%). No grade 5 AEs were noted. All bleeding events were grade 1; none were associated with drug-related atrial fibrillation or hypertension. Although the follow-up duration was relatively short, the study met the primary endpoint. Therefore, tirabrutinib monotherapy is considered to be highly effective for both untreated and relapsed/refractory WM with a manageable safety profile. (JapicCTI-173646).


Assuntos
Imidazóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Genótipo , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mutação , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Gradação de Tumores , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/etiologia
9.
Arq Neuropsiquiatr ; 78(6): 342-348, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32609193

RESUMO

BACKGROUND: Hepatitis C can be defined as an infectious disease that develops an inflammatory activity, which may cause an impairment in the central nervous system, may cause cognitive impairments and symptoms of depression. OBJECTIVE: The objective of this study was to verify the cognitive performance of patients with chronic hepatitis C before and after treatment with simeprevir, sofosbuvir, and daclatasvir. METHODS: A prospective study was carried out in three stages: before, right after treatment, and six months after. Fifty-eight patients under clinical follow-up were evaluated at the Emílio Ribas Infectology Institute, in São Paulo, Brazil. The following instruments were used: sociodemographic questionnaire, Lawton's Scale, Beck's Depression Inventory, and a battery of neuropsychological tests that evaluated: intellectual function, memory, attention, executive function, and motor and processing speed). For statistical analysis, the analyses described (mean, frequency, and standard deviation), chi-square, and ANOVA were used. RESULTS: Most of the participants were male (n=30, 51.7%), with a mean of 58.23±8.79 years, mean schooling of 9.75±4.43 years. Comparing the results of neuropsychological evaluations (before, just after completion of drugs, and six months), a significant improvement was observed in relation to the acquisition of new knowledge (p=0.03), late visual memory (p=0.01), and tendency towards alternate attention (p=0.07). CONCLUSION: The treatment of the hepatitis C virus improved cognitive performance, especially in relation to memory.


Assuntos
Antivirais , Sofosbuvir , Antivirais/efeitos adversos , Brasil , Cognição , Quimioterapia Combinada , Genótipo , Hepacivirus , Humanos , Imidazóis/efeitos adversos , Masculino , Estudos Prospectivos , Simeprevir/efeitos adversos , Sofosbuvir/efeitos adversos , Sofosbuvir/uso terapêutico , Resultado do Tratamento
11.
Lancet Gastroenterol Hepatol ; 5(9): 809-818, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32526210

RESUMO

BACKGROUND: Highly effective direct-acting antiviral drugs provide the opportunity to eliminate hepatitis C virus (HCV) infection, but established pathways can be ineffective. We aimed to examine whether a community pharmacy care pathway increased treatment uptake, treatment completion, and cure rates for people receiving opioid substitution therapy, compared with conventional care. METHODS: This cluster-randomised trial was done in Scottish community pharmacies. Before participants were recruited, pharmacies were randomly assigned (1:1) to refer patients with evidence of HCV antibodies to conventional care or offered them care in the pharmacy (pharmacist-led care). Pharmacies were stratified by location. All pharmacies were trained to offer dried blood spot testing. All eligible participants had received opioid substitution therapy for approximately 3 months, and those eligible to receive treatment in the pharmacist-led care pathway were HCV PCR positive, were infected with HCV genotype 1 or 3, and were willing to have a pharmacist supervise their antiviral drug administration. Neither pharmacists nor patients were masked to treatment allocation. In both groups, assessment blood samples were taken, infection with HCV was confirmed, and daily oral ledipasvir-sofosbuvir (90 mg ledipasivir plus 400 mg sofosbuvir) for 8 weeks for genotype 1 or daily oral sofosbuvir (400 mg) plus oral daclatasvir (60 mg) for 12 weeks for genotype 3 was prescribed by a nurse (conventional care group) or pharmacist (pharmacist-led care group). In the conventional care group, the patient received care at a treatment centre. Once prescribed, medication in both groups was delivered as daily modified directly observed therapy alongside opioid substitution therapy in the participants' pharmacy where treatment was observed on 6 days per week. The primary outcome was the number of patients with sustained virological response 12 weeks after completion of treatment (SVR12) as a proportion of the number of people receiving opioid substitution therapy at participating pharmacies. Participants were monitored at each visit for nausea and fatigue; other adverse events were recorded as free text. Secondary outcomes compared key points on treatment pathway between the two groups. These key points were the proportion of patients having dry blood spot testing, the proportion of patients initiating HCV treatment, the proportion of patients completing the 8 or 12 week HCV course of treatment, and the proportion of patients with sustained virological response at 12 months. This study is registered with ClinicalTrials.gov, NCT02706223. FINDINGS: 56 pharmacies were randomly assigned (28 to each group; one pharmacy withdrew from the conventional care group). The 55 participating pharmacies included 2718 patients receiving opioid substitution therapy (1365 in the pharmacist-led care group and 1353 in the conventional care group). More patients met the primary endpoint of SVR12 in the pharmacist-led care group (98 [7%] of 1365) than in the conventional care group (43 [3%] of 1353; odds ratio 2·375, 95% CI 1·555-3·628, p<0·0001). More users of opioid substitution therapy in the pharmacist-led care group versus the conventional care group agreed to dry blood spot testing (245 [18%] of 1365 vs 145 [11%] of 1353, 2·292, 0·968-5·427, p=0·059); initiated treatment (112 [8%] of 1365 vs 61 [4%] of 1353, 1·889, 1·276-2·789, p=0·0015) and completed treatment (108 [8%] of 1365 vs 58 [4%] of 1353, 1·928, 1·321-2·813, p=0·0007). The data for sustained virological response at 12 months are not reported in this study: patients remain in follow-up for this outcome. No serious adverse events were recorded. INTERPRETATION: Using pharmacists to deliver an HCV care pathway made testing and treatment more accessible for patients, improved engagement, and maintained high treatment success rates. The use of this pathway could be a key part of an integrated and effective approach to HCV elimination at a community level. FUNDING: Partnership between the Scottish Government, Gilead Sciences, and Bristol-Myers Squib.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C/tratamento farmacológico , Tratamento de Substituição de Opiáceos/métodos , Uridina Monofosfato/análogos & derivados , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Quimioterapia Combinada , Feminino , Fluorenos/administração & dosagem , Fluorenos/efeitos adversos , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C/sangue , Hepatite C/epidemiologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Farmacêuticos/normas , Escócia/epidemiologia , Sofosbuvir/administração & dosagem , Sofosbuvir/efeitos adversos , Sofosbuvir/uso terapêutico , Resposta Viral Sustentada , Resultado do Tratamento , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/uso terapêutico
13.
Dent Med Probl ; 57(2): 131-136, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32463600

RESUMO

BACKGROUND: Bisphosphonates (BPs) are widely used as anti-bone-resorptive agents. Despite the great benefits of BPs, they may cause local and systemic adverse side effects. OBJECTIVES: The aim of this study was to evaluate the histopathological effect zoledronic acid (ZA), which belongs to BPs, has on the intrinsic tongue muscles in a rat model. MATERIAL AND METHODS: A total of 30 adult male albino rats were divided into 3 groups (10 rats each): group I served as a control; group II was given an intraperitoneal (i.p.) injection of 0.2 mg/kg of ZA once per week for 3 weeks; and group III received the same dosage of ZA, but for 8 weeks. After the animals were euthanized, the tongue tissue was dissected and examined histologically, histochemically and immunohistochemically. RESULTS: Histologically, a normal architecture of the muscle fascicles was observed in the control group. Group II showed degenerated muscle fibers with an indistinct sarcolemma. In group III, the muscle fibers were degenerated with severe sarcoplasmic dissolution. The histochemical examination using Masson's trichrome (MT) demonstrated a significant increase in collagen fibers in groups II and III as compared to the control group. The immunohistochemical results revealed a statistically significantly higher expression of nuclear factor kappa B (NF­κB) in the ZA-treated groups (II and III) as compared to the control group, with the highest mean value recorded in group III. CONCLUSIONS: Zoledronic acid induced histopathological changes to the intrinsic tongue muscles, and this effect was exaggerated with a longer duration of administration.


Assuntos
Difosfonatos , Imidazóis , Animais , Difosfonatos/efeitos adversos , Imidazóis/efeitos adversos , Masculino , Ratos , Língua , Ácido Zoledrônico
14.
Vasc Med ; 25(3): 246-254, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32303152

RESUMO

Tyrosine kinase inhibitors (TKIs) of the BCR-ABL fusion protein have dramatically changed the mortality of chronic myeloid leukemia (CML) but they carry a risk of serious vascular morbidity. While TKIs do not cure CML, daily oral administration of a TKI can control CML and TKIs are chronic medications. Interestingly, vascular complications can occur at any time a patient is on a TKI. Therefore, it is imperative that all care team members and patients are aware of and watching for possible vascular complications. In the following review, a case of arterial thrombosis secondary to the TKI ponatinib is presented as well as a discussion of thrombotic and vascular adverse events reported with TKIs. TKIs are metabolized through the cytochrome P450 system and important drug interactions to consider are reviewed. Finally, we present a multidisciplinary approach to the management of patients with CML on TKIs.


Assuntos
Anticoagulantes/uso terapêutico , Antineoplásicos/efeitos adversos , Estenose das Carótidas/tratamento farmacológico , Imidazóis/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas/efeitos adversos , Acidente Vascular Cerebral/tratamento farmacológico , Trombose/tratamento farmacológico , Idoso , Estenose das Carótidas/induzido quimicamente , Estenose das Carótidas/diagnóstico por imagem , Interações Medicamentosas , Feminino , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Terapia de Alvo Molecular/efeitos adversos , Fatores de Risco , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/diagnóstico por imagem , Trombose/induzido quimicamente , Trombose/diagnóstico por imagem , Resultado do Tratamento
15.
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
16.
J Gastroenterol Hepatol ; 35(9): 1477-1487, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32246857

RESUMO

BACKGROUND AND AIM: Various all-oral direct-acting antiviral (DAA) regimens are being widely used in the treatment of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients; however, the comparative efficacy and safety of different types and combinations of DAAs are not completely clear. There is still a lack of integration of evidence for optimized therapies for HIV/HCV co-infection. METHODS: We conducted a systematic literature search in several databases up to January 1, 2020. All the studies that reported the sustained virologic response (SVR) and adverse events of DAAs in HIV/HCV co-infected patients were included. The Bayesian Markov Chain Monte Carlo method was used for the pooled estimates of network meta-analysis. RESULTS: We identified 33 eligible articles with 7 combinations of all-oral DAAs for the analyses of efficacy and safety. Grazoprevir-elbasvir ± ribavirin (GZR/EBR ± RBV: 95.6%; 95% CrI, 91.7-98.1%), ombitasvir/paritaprevir/ritonavir and dasabuvir ± ribavirin (3D ± RBV: 95.3%; 95% CrI, 93.4-96.9%), sofosbuvir-ledipasvir ± ribavirin (SOF/LDV ± RBV: 95.2%; 95% CrI, 93.7-96.6%), and sofosbuvir-daclatasvir ± ribavirin (SOF/DCV ± RBV: 94.8%; 95% CrI, 92.5-96.6%) were the most effective combinations for HIV/HCV co-infected patients, with SVR rates of approximately 94% and above while severe adverse events were rare. However, the SVR rates of sofosbuvir-ribavirin (SOF/RBV) and sofosbuvir-simeprevir ± ribavirin (SOF/SMV ± RBV) both failed to reach 90%, and the incidences of adverse events were higher than 5%. CONCLUSIONS: Efficacy and safety of all-oral DAAs were in prospect for HIV/HCV co-infection patients. GZR/EBR ± RBV was the optimal combination recommended for HIV/HCV co-infected patients based on the excellent treatment effects and insignificant adverse events.


Assuntos
Antivirais/administração & dosagem , Benzofuranos/administração & dosagem , Coinfecção/tratamento farmacológico , Infecções por HIV/diagnóstico por imagem , Hepatite C Crônica/tratamento farmacológico , Imidazóis/administração & dosagem , Quinoxalinas/administração & dosagem , Ribavirina/administração & dosagem , Administração Oral , Adulto , Idoso , Amidas , Antivirais/efeitos adversos , Benzofuranos/efeitos adversos , Carbamatos , Ciclopropanos , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Hepatite C Crônica/virologia , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Quinoxalinas/efeitos adversos , Ribavirina/efeitos adversos , Segurança , Sulfonamidas , Resposta Viral Sustentada , Resultado do Tratamento
18.
BMC Cancer ; 20(1): 177, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32131760

RESUMO

BACKGROUND: Dabrafenib and trametinib combination therapy is approved for the treatment of patients with BRAF V600E positive tumors including melanoma and lung cancer. The effect of BRAF and MEK inhibitors on the immune system is not fully understood although a number of case reports indicate autoimmune side effects related to the use of these drugs. Here, we discuss a case of a patient diagnosed with granulomatosis with polyangiitis (GPA) shortly after starting treatment with dabrafenib and trametinib for BRAF V600E positive metastatic lung adenocarcinoma. CASE PRESENTATION: A 57 years old female patient was diagnosed with recurrent lung adenocarcinoma following initial lobectomy for early stage disease. A BRAF V600E mutation was identified at the time of recurrence and she received combination dabrafenib and trametinib therapy. Shortly after commencement of treatment, she developed persistent fevers necessitating withholding both drugs. Pyrexia continued and was followed by left vision loss and acute kidney injury. Further rheumatological workup led to the unifying diagnosis of GPA. The patient was then treated with rituximab for GPA to the present date while all antineoplastic drugs were held. Lung cancer oligoprogression was addressed with radiation therapy and has not required further systemic treatment whereas GPA has been controlled to-date with rituximab. CONCLUSIONS: This case report raises awareness among clinicians treating patients with lung cancer for the possibility of triggering a flare of autoimmune diseases like GPA in patients with BRAF V600E positive lung cancer receiving treatment with BRAF directed therapy.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Granulomatose com Poliangiite/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/radioterapia , Substituição de Aminoácidos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Granulomatose com Poliangiite/tratamento farmacológico , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Pessoa de Meia-Idade , Oximas/administração & dosagem , Oximas/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Rituximab/uso terapêutico , Resultado do Tratamento
19.
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
20.
Int J Clin Pharmacol Ther ; 58(5): 268-273, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32101521

RESUMO

OBJECTIVE: This work aims to evaluate the therapeutic survey of adverse events during antiviral treatment of hepatitis in the three major University Hospitals in Abidjan. MATERIALS AND METHODS: A retrospective cross-sectional descriptive study of 203 patients from August 1, 2015, to July 31, 2018, enumerated adverse events during antiviral treatments, drugs used for their management, and their clinical or biological impact. RESULTS: The following was seen: hematological disorders during treatment with pegylated interferon α-2a (88.61%) and ribavirin (77.55%), pain syndrome when using pegylated interferon α-2a (90.5%), and digestive disorders while taking sofosbuvir (60.71%) and daclatasvir (66.67%). Hematological disorders were managed with filgrastim for neutropenia and oral iron or blood transfusion for anemia and/or thrombocytopenia. Pain syndrome was treated with paracetamol. As for digestive disorders, they were most often managed with activated charcoal. CONCLUSION: Correction of the adverse events was made either using causal treatment or using symptomatic drugs. However, some drugs, in particular hematopoietic factors, have been less used due to their costs.


Assuntos
Antivirais/efeitos adversos , Hepatite C Crônica/tratamento farmacológico , Antivirais/uso terapêutico , Costa do Marfim , Estudos Transversais , Quimioterapia Combinada , Genótipo , Hospitais Universitários , Humanos , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Interferon-alfa/efeitos adversos , Interferon-alfa/uso terapêutico , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Ribavirina/efeitos adversos , Ribavirina/uso terapêutico , Sofosbuvir/efeitos adversos , Sofosbuvir/uso terapêutico , Resultado do Tratamento
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