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1.
PLoS Negl Trop Dis ; 14(8): e0007857, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866170

RESUMO

Buruli ulcer (BU), caused by Mycobacterium ulcerans, is currently treated with a daily combination of rifampin and either injectable streptomycin or oral clarithromycin. An intermittent oral regimen would facilitate treatment supervision. We first evaluated the bactericidal activity of newer antimicrobials against M. ulcerans using a BU animal model. The imidazopyridine amine telacebec (Q203) exhibited high bactericidal activity whereas tedizolid (an oxazolidinone closely related to linezolid), selamectin and ivermectin (two avermectine compounds) and the benzothiazinone PBTZ169 were not active. Consequently, telacebec was evaluated for its bactericidal and sterilizing activities in combined intermittent regimens. Telacebec given twice a week in combination with a long-half-life compound, either rifapentine or bedaquiline, sterilized mouse footpads in 8 weeks, i.e. after a total of only 16 doses, and prevented relapse during a period of 20 weeks after the end of treatment. These results are very promising for future intermittent oral regimens which would greatly simplify BU treatment in the field.


Assuntos
Antituberculosos/administração & dosagem , Úlcera de Buruli/tratamento farmacológico , Imidazóis/administração & dosagem , Mycobacterium ulcerans/efeitos dos fármacos , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Animais , Antituberculosos/uso terapêutico , Úlcera de Buruli/microbiologia , Diarilquinolinas , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Imidazóis/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Oxazolidinonas , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Rifampina/análogos & derivados , Tetrazóis
2.
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
3.
Lancet Diabetes Endocrinol ; 8(9): 748-761, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32730798

RESUMO

BACKGROUND: Cushing's disease is a rare endocrine disorder characterised by cortisol overproduction with severe complications. Therapies for cortisol reduction are often necessary. Here we report the outcomes from the pivotal phase III study of osilodrostat (a potent oral inhibitor of cytochrome P450 11B1, mitochondrial [11ß-hydroxylase]; Novartis Pharma AG, Basel, Switzerland) in patients with Cushing's disease. METHODS: LINC 3 was a prospective, multicentre, open-label, phase III study with a double-blind randomised withdrawal period, that comprised four periods. Patients aged 18-75 years, with confirmed persistent or recurrent Cushing's disease (defined as mean 24-h urinary free cortisol [UFC] concentration >1·5 times the upper limit of normal [ULN] and morning plasma adrenocorticotropic hormone above the lower limit of normal) who had previously had pituitary surgery or irradiation, or were newly diagnosed and who refused surgery or were not surgical candidates, were recruited from 66 hospital sites and private clinical practices in 19 countries. In period 1, open-label osilodrostat was initiated in all participants and adjusted every 2 weeks (1-30 mg twice daily; film-coated tablets for oral administration) on the basis of mean 24-h UFC concentration and safety until week 12. In period 2, weeks 13-24, osilodrostat was continued at the therapeutic dose determined during period 1. In period 3, beginning at week 26, participants who had a mean 24-h UFC concentration of less than or equal to the ULN at week 24, without up-titration after week 12, were randomly assigned (1:1), via an interactive-response technology, stratified by osilodrostat dose at week 24 and history of pituitary irradiation, to continue osilodrostat or switch to placebo for 8 weeks. Participants and investigators were masked to treatment assignment. Ineligible participants continued open-label osilodrostat. In period 4, weeks 35-48, all participants were given open-label osilodrostat until core-study end. The primary objective was to compare the efficacy of osilodrostat versus placebo at the end of period 3. The primary endpoint was the proportion of participants who had been randomly assigned to treatment or placebo with a complete response (ie, mean 24-h UFC concentration of ≤ULN) at the end of the randomised withdrawal period (week 34), without up-titration during this period. The key secondary endpoint was the proportion of participants with a complete response at the end of the single-arm, open-label period (ie, period 2, week 24) without up-titration during weeks 13-24. Analysis was by intention-to-treat for all patients who received at least one dose of osilodrostat (full analysis set; key secondary endpoint) or randomised treatment (randomised analysis set; primary endpoint) and safety was assessed in all enrolled patients who received at least one dose of osilodrostat and had at least one post-baseline safety assessment. LINC 3 is registered with ClinicalTrials.gov, NCT02180217, and is now complete. FINDINGS: Between Nov 12, 2014, and March 22, 2017, 202 patients were screened and 137 were enrolled. The median age was 40·0 years (31·0-49·0) and 106 (77%) participants were female. 72 (53%) participants were eligible for randomisation during the withdrawal phase, of whom 36 were assigned to continue osilodrostat and 35 were assigned to placebo; one patient was not randomly assigned due to investigator decision and continued open-label osilodrostat. More patients maintained a complete response with osilodrostat versus with placebo at week 34 (31 [86%] vs ten [29%]; odds ratio 13·7 [95% CI 3·7-53·4]; p<0·0001). At week 24, 72 (53%; 95% CI 43·9-61·1) of 137 patients maintained a complete response without up-titration after week 12. Most common adverse events (ie, occurred in >25% of participants) were nausea (57 [42%]), headache (46 [34%]), fatigue (39 [28%]), and adrenal insufficiency (38 [28%]). Hypocortisolism occurred in 70 (51%) patients and adverse events related to adrenal hormone precursors occurred in 58 (42%) patients. One patient died, unrelated to study drug, after the core study phase. INTERPRETATION: Twice-daily osilodrostat rapidly reduced mean 24-h UFC and sustained this reduction alongside improvements in clinical signs of hypercortisolism; it was also generally well tolerated. Osilodrostat is an effective new treatment option that is approved in Europe for the treatment of endogenous Cushing's syndrome and in the USA for Cushing's disease. FUNDING: Novartis Pharma AG.


Assuntos
Citocromo P-450 CYP11B2/antagonistas & inibidores , Imidazóis/administração & dosagem , Hipersecreção Hipofisária de ACTH/diagnóstico , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Piridinas/administração & dosagem , Administração Oral , Adulto , Citocromo P-450 CYP11B2/metabolismo , Método Duplo-Cego , Feminino , Humanos , Hidrocortisona/antagonistas & inibidores , Hidrocortisona/metabolismo , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/metabolismo , Estudos Prospectivos , Resultado do Tratamento
4.
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
5.
Med Mycol J ; 61(2): 17-21, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32475885

RESUMO

Wood's lamp was demonstrated to be useful in three cases of dermatophytoma treated during clinical dermatological practice. Clinical signs of onychomycosis are longitudinal yellow and white striae on the nail plate and are diagnosed by KOH direct microscopic examination. For its treatment, surgical debridement is recommended. Usefulness of the Wood's lamp for diagnosis of tinea capitis caused by Microsporum canis is standard. In the first and second cases, we used Wood's lamp (Woody™) to make a clear margin for debridement of onychomycosis. In the third case, onychomycosis was unsuccessfully treated using topical 5% luliconazole nail solution for 1 year and 10 months with yellow nail discoloration. Under Wood's lamp, we were able to distinguish luliconazole crystal staining from onychomycosis. This method is simple and quick, and useful for nail observation in dermatology clinics.


Assuntos
Dermatologia/métodos , Onicomicose/diagnóstico , Idoso , Humanos , Imidazóis/administração & dosagem , Masculino , Microsporum/patogenicidade , Pessoa de Meia-Idade , Unhas/microbiologia , Unhas/patologia , Onicomicose/tratamento farmacológico , Onicomicose/microbiologia , Onicomicose/patologia , Fatores de Tempo
6.
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
7.
Arch Virol ; 165(7): 1633-1639, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32356185

RESUMO

The aim of this work was assessment of the efficacy and tolerability of two different regimens for retreatment of hepatitis C virus (HCV) patients who failed to respond to SOF/DCV-based therapy. This prospective study included 104 HCV patients who failed to respond to SOF/DCV-based therapy. Patients were randomly allocated to two groups. Efficacy and tolerability were assessed. The 12-week sustained virological response (SVR12) rates were 96% and 94.4% in groups B and A, respectively, with no significant difference (p = 1.000). Most adverse events reported were mild to moderate, with no deaths during the study. Multi-target direct-acting antiviral (DAA) combinations are efficient for retreatment of HCV patients after failure of SOF/DCV-based therapy in real-world management.ClinicalTrials.gov identifier: NCT02992457.


Assuntos
Antivirais/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Adulto , Anilidas/administração & dosagem , Carbamatos/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Imidazóis/administração & dosagem , Compostos Macrocíclicos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ribavirina/administração & dosagem , Ritonavir/administração & dosagem , Simeprevir/administração & dosagem , Sofosbuvir/administração & dosagem , Resultado do Tratamento
8.
Proc Natl Acad Sci U S A ; 117(22): 11987-11994, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32424082

RESUMO

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis worldwide and kills more Americans than 59 other infections, including HIV and tuberculosis, combined. While direct-acting antiviral (DAA) treatments are effective, limited uptake of therapy, particularly in high-risk groups, remains a substantial barrier to eliminating HCV. We developed a long-acting DAA system (LA-DAAS) capable of prolonged dosing and explored its cost-effectiveness. We designed a retrievable coil-shaped LA-DAAS compatible with nasogastric tube administration and the capacity to encapsulate and release gram levels of drugs while resident in the stomach. We formulated DAAs in drug-polymer pills and studied the release kinetics for 1 mo in vitro and in vivo in a swine model. The LA-DAAS was equipped with ethanol and temperature sensors linked via Bluetooth to a phone application to provide patient engagement. We then performed a cost-effectiveness analysis comparing LA-DAAS to DAA alone in various patient groups, including people who inject drugs. Tunable release kinetics of DAAs was enabled for 1 mo with drug-polymer pills in vitro, and the LA-DAAS safely and successfully provided at least month-long release of sofosbuvir in vivo. Temperature and alcohol sensors could interface with external sources for at least 1 mo. The LA-DAAS was cost-effective compared to DAA therapy alone in all groups considered (base case incremental cost-effectiveness ratio $39,800). We believe that the LA-DAA system can provide a cost-effective and patient-centric method for HCV treatment, including in high-risk populations who are currently undertreated.


Assuntos
Antivirais/administração & dosagem , Sistemas de Liberação de Medicamentos , Hepatite C Crônica/tratamento farmacológico , Animais , Antivirais/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Análise Custo-Benefício , Modelos Animais de Doenças , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/economia , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Fluorenos/administração & dosagem , Fluorenos/farmacocinética , Hepacivirus/efeitos dos fármacos , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Cirrose Hepática/tratamento farmacológico , Modelos Animais , Ribavirina/administração & dosagem , Ribavirina/farmacocinética , Sofosbuvir/administração & dosagem , Sofosbuvir/farmacocinética , Suínos
9.
Artigo em Inglês | MEDLINE | ID: mdl-32415362

RESUMO

Recent studies have reported interspecific differences in how bee species respond to various stressors. Evaluating the exposure and responses of different bee species to plant protection products is considered an essential part of their risk assessment. This study was conducted to assess the impacts of thiacloprid-prochloraz mixture on buff-tailed bumblebees (Bombus terrestris) and red mason bees (Osmia bicornis) in a worst-case scenario under semi-field conditions. Bumblebee colonies or solitary bee trap nests were confined in tunnels with flowering oilseed rape. The recommended maximum application rates of 72 g thiacloprid/ha and 675 g prochloraz/ha were applied as a tank mixture during bee flight in full flowering oilseed rape. Several parameters such as flight and foraging activity, population parameters, and exposure level were investigated. Our results show adverse effects of the combination of thiacloprid and prochloraz on the reproductive performance of red mason bees. The number of cocoons produced by O. bicornis was significantly reduced in the treatment compared to the control group. Regarding bumblebees, we found no effects of the thiacloprid-prochloraz mixture on any observed parameters of colony development. The maximum detected concentrations of both active substances three days after application were higher in O. bicornis pollen mass compared to B. terrestris stored pollen. We conclude that this worst-case scenario of thiacloprid-prochloraz exposure poses a high risk to solitary bees and thus the use of such mixture should be restricted.


Assuntos
Abelhas/efeitos dos fármacos , Voo Animal/efeitos dos fármacos , Imidazóis/administração & dosagem , Inseticidas/administração & dosagem , Neonicotinoides/administração & dosagem , Tiazinas/administração & dosagem , Animais , Comportamento Alimentar/efeitos dos fármacos , Alemanha , Dinâmica Populacional , Reprodução
10.
Gastroenterol Clin North Am ; 49(2): 253-277, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32389362

RESUMO

The World Health Organization has called for the elimination of hepatitis C virus (HCV) as a public health threat by 2030. Highly effective direct-acting antiviral agents provide the therapeutic tools required for elimination. In the absence of a vaccine, HCV elimination will require enhanced primary prevention and an increase in the proportions of people diagnosed and treated. Given that globally only 20% of people with chronic HCV are diagnosed, and around 5% have initiated HCV treatment, the task ahead is enormous. But, global public health needs optimism, and countries currently on track for HCV elimination provide a pathway forward.


Assuntos
Antivirais/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/prevenção & controle , Anilidas/administração & dosagem , Antivirais/economia , Benzofuranos/administração & dosagem , Carbamatos/administração & dosagem , Quimioterapia Combinada , Saúde Global , Custos de Cuidados de Saúde , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/economia , Humanos , Imidazóis/administração & dosagem , Sofosbuvir/administração & dosagem , Sulfonamidas/administração & dosagem , Uracila/administração & dosagem , Uracila/análogos & derivados , Organização Mundial da Saúde
11.
Arq Gastroenterol ; 57(1): 45-49, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294735

RESUMO

BACKGROUND: Direct-acting antivirals have revolutionized hepatitis C treatment, also for patients with chronic kidney disease (CKD), but some controversy exists regarding the use of sofosbuvir (SOF) in patients with glomerular filtration rate (GFR) <30 mL/min. OBJECTIVE: To evaluate the efficacy and safety of these regimens for hepatitis C treatment of patients with CKD and after renal transplantation, as well as the impact of SOF on renal function in non-dialysis patients. METHODS: All patients with hepatitis C and CKD or renal transplant treated with direct-acting antivirals at a referral center in Brazil between January 2016 and August 2017 were included. Efficacy was evaluated based on viral load (HCV RNA) and a sustained virological response (SVR) consisting of undetectable RNA 12 and/or 24 weeks after the end of treatment (SVR12 and SVR24) was defined as cure. Safety was determined by adverse events and ribavirin, when combined, was administered in escalating doses to all patients with GFR <60 mL/min. The impact of SOF on renal function was determined by the measurement of baseline creatinine during and after the end of treatment and its increase was evaluated using the Acute Kidney Injury Network (AKIN) classification. RESULTS: A total of 241 patients (52.7% females) with a mean age of 60.72±10.47 years were included. The combination of SOF+daclatasvir was the predominant regimen in 75.6% of cases and anemia was present in 28% of patients who used ribavirin (P=0.04). The SVR12 and SVR24 rates were 99.3% and 97.1%, respectively. The treatment was well tolerated and there were no major clinically relevant adverse events, with the most prevalent being asthenia (57.7%), itching (41.1%), headache (40.7%), and irritability (40.2%). Among conservatively treated and renal transplant patients, oscillations of creatinine levels (AKIN I) were observed in 12.5% of cases during treatment and persisted in only 8.5% after the end of treatment. Of these, 2.0% had an initial GFR <30 mL/min and this percentage decreased to 1.1% after SOF use. Only 0.5% and 1.6% of the patients progressed to AKIN II and AKIN III elevation, respectively. CONCLUSION: The direct-acting antivirals were safe and efficacious in CKD patients treated with SOF-containing regimens, with the observation of high SVR rates, good tolerability and few severe adverse events. The combination with ribavirin increased the risk of anemia and the administration of escalating doses seems to be useful in patients with GFR <60 mL/min. In patients with GFR <30 mL/min, SOF had no significant renal impact, with serum creatinine returning to levels close to baseline after treatment.


Assuntos
Antivirais/administração & dosagem , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Transplante de Rim/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Feminino , Genótipo , Taxa de Filtração Glomerular , Humanos , Imidazóis/administração & dosagem , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/cirurgia , Ribavirina/administração & dosagem , Simeprevir/administração & dosagem , Sofosbuvir/administração & dosagem , Resposta Viral Sustentada , Resultado do Tratamento , Carga Viral
12.
Arq Gastroenterol ; 57(1): 39-44, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294734

RESUMO

BACKGROUND: Hepatitis C virus (HCV) infection is the most common hepatotropic viral infection affecting the patients on maintenance hemodialysis. Treatment of chronic HCV infection in stage 4 and 5 CKD includes a combination of elbasvir/grazoprevir and glecaprevir/pibrentasvir, which are not available in many countries. OBJECTIVE: Hence, we have conducted this study to look for the safety and efficacy of sofosbuvir combination therapy in this difficult to treat population. METHODS: We conducted a single-center, prospective, open-label study in which Stage 5 CKD patients on maintenance hemodialysis with HCV infection. Total of 18 patients was included. sofosbuvir with daclatasvir or ledipasvir was used according to genotype for 12 weeks. HCV RNA, genotype, transient elastography (TE) was considered for every patient. HCV RNA was quantified at 4th week, 12th week and 12 weeks post-treatment to look for sustained virologic response (SVR 12). RESULTS: Infection due to genotype 1 was seen in 12 (66.7%) patients followed by genotype 3 in 4 (22.3%) with each patient of genotype 2 and 5. The median value of HCV RNA was 2,35,000 IU/mL. On TE, all had liver stiffness of <9.4 KPa. All patients had HCV RNA of <15 IU/mL at 4th and 12th week of treatment and 12 weeks post-treatment. No significant change in hemoglobin, eGFR and liver stiffness was observed. CONCLUSION: Full dose sofosbuvir i.e. 400 mg, in combination with NS5A inhibitors daclatasvir or ledipasvir is found to be safe and effective in patients with end stage renal disease, who are on maintenance hemodialysis.


Assuntos
Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Fluorenos/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Imidazóis/administração & dosagem , Sofosbuvir/administração & dosagem , Adulto , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral , Diálise Renal , Índice de Gravidade de Doença , Resposta Viral Sustentada , Resultado do Tratamento
13.
Zoolog Sci ; 37(2): 159-167, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282147

RESUMO

Kawai et al. (2011) recently introduced a mixture of three anesthetic agents (here called MMB) that has an effect similar to ketamine/xylazine in mice, which might allow more effective reaction to changes in the animal condition, as an antagonist is available, and which can be used without license for handling narcotic drugs. Using Kawai's study as a baseline, we tested whether this anesthesia and its antagonist can also be used in avian studies. In the present study, we used two species, the zebra finch and the Bengalese finch, of the avian family Estrildidae. In zebra finches, anesthesia effects similar to the use of ketamine/xylazine and to those obtained in mice can be reached by the use of MMB if a higher dose is applied. MMB leads to more variable anesthesia, but has the advantage of a longer time window of deep anesthesia. An antagonist to one component of MMB reduced the awaking time, but was not as effective as in mice. For Bengalese finches, MMB cannot be generally recommended because of difficult handling and high mortality rate when used without antagonist, but could be used for perfusions instead of pentobarbital.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Anestésicos Combinados/administração & dosagem , Butorfanol/administração & dosagem , Imidazóis/farmacologia , Medetomidina/administração & dosagem , Midazolam/administração & dosagem , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Analgésicos Opioides/administração & dosagem , Animais , Feminino , Tentilhões , Hipnóticos e Sedativos/administração & dosagem , Imidazóis/administração & dosagem , Injeções Intramusculares , Ketamina/administração & dosagem , Masculino , Medetomidina/antagonistas & inibidores , Xilazina/administração & dosagem
15.
PLoS One ; 15(3): e0229745, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32163446

RESUMO

Ionic liquids are salts used in a variety of industrial processes, and being relatively non-volatile, are proposed as environmentally-friendly replacements for existing volatile liquids. Methylimidazolium ionic liquids resist complete degradation in the environment, likely because the imidazolium moiety does not exist naturally in biological systems. However, there is limited data available regarding their mammalian effects in vivo. This study aimed to examine the effects of exposing mice separately to 2 different methylimidazolium ionic liquids (BMI and M8OI) through their addition to drinking water. Potential effects on key target organs-the liver and kidney-were examined, as well as the gut microbiome. Adult male mice were exposed to drinking water containing ionic liquids at a concentration of 440 mg/L for 18 weeks prior to examination of tissues, serum, urine and the gut microbiome. Histopathology was performed on tissues and clinical chemistry on serum for biomarkers of hepatic and renal injury. Bacterial DNA was isolated from the gut contents and subjected to targeted 16S rRNA sequencing. Mild hepatic and renal effects were limited to glycogen depletion and mild degenerative changes respectively. No hepatic or renal adverse effects were observed. In contrast, ionic liquid exposure altered gut microbial composition but not overall alpha diversity. Proportional abundance of Lachnospiraceae, Clostridia and Coriobacteriaceae spp. were significantly greater in ionic liquid-exposed mice, as were predicted KEGG functional pathways associated with xenobiotic and amino acid metabolism. Exposure to ionic liquids via drinking water therefore resulted in marked changes in the gut microbiome in mice prior to any overt pathological effects in target organs. Ionic liquids may be an emerging risk to health through their potential effects on the gut microbiome, which is implicated in the causes and/or severity of an array of chronic disease in humans.


Assuntos
Microbioma Gastrointestinal , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Líquidos Iônicos/administração & dosagem , Líquidos Iônicos/farmacologia , Administração Oral , Animais , Bactérias/classificação , Bile/metabolismo , Biodiversidade , Microbioma Gastrointestinal/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Metaboloma , Camundongos Endogâmicos C57BL
17.
BMC Infect Dis ; 20(1): 171, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32087692

RESUMO

BACKGROUND: Trichophyton benhamiae is a zoophilic dermatophyte that can cause tinea in humans and animals. Lesions caused by T. benhamiae tend to be highly inflammatory, and patients are often infected by animals or other patients infected with T. benhamiae. In this paper, we report the first case of tinea faciei caused by T. benhamiae in a Chinese girl who might be transmitted from a fox. CASE PRESENTATION: A 4-year-old girl from HaiNing city developed an itchy, erythematous, and annular plaque on her right face for the past 2 months. Before the lesion appeared, she was in close contact with the fur of a fox for almost 1 week. Septate hyaline hyphae were detected by direct mycological examination of the scales. Cultures grew on Sabouraud's dextrose agar (SDA) at 26 °C for 2 weeks revealed the presence of T. mentagrophytes. A molecular sequencing test confirmed that the isolate was consistent with reference strains to T. benhamiae. Then, the diagnosis of tinea faciei due to T. benhamiae was made. Treatment with terbinafine (oral 125 mg/d) and sertaconazole nitrate cream (topical, twice daily) for 4 weeks was initiated and achieved significant improvement of the skin lesions. CONCLUSIONS: This rare dermatophytosis case highlights the importance of ITS sequencing in helping to recognize rare pathogenic fungi that can be easily misdiagnosed with a conventional morphological diagnosis.


Assuntos
Arthrodermataceae/genética , Dermatomicoses/diagnóstico , Tinha/diagnóstico , Trichophyton/genética , Administração Oral , Administração Tópica , Animais , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Arthrodermataceae/isolamento & purificação , Pré-Escolar , China , Dermatomicoses/tratamento farmacológico , Dermatomicoses/microbiologia , Face/patologia , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Pele/patologia , Terbinafina/administração & dosagem , Terbinafina/uso terapêutico , Tiofenos/administração & dosagem , Tiofenos/uso terapêutico , Tinha/tratamento farmacológico , Tinha/microbiologia , Resultado do Tratamento , Trichophyton/isolamento & purificação
18.
Lancet Oncol ; 21(3): 358-372, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32007138

RESUMO

BACKGROUND: Adjuvant dabrafenib plus trametinib reduced the risk of relapse versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma in the phase 3 COMBI-AD trial. This prespecified exploratory biomarker analysis aimed to evaluate potential prognostic or predictive factors and mechanisms of resistance to adjuvant targeted therapy. METHODS: COMBI-AD is a randomised, double-blind, placebo-controlled, phase 3 trial comparing dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily versus two matched placebos. Study participants were at least 18 years of age and underwent complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma, per American Joint Committee on Cancer 7th edition criteria, with a BRAFV600E or BRAFV600K mutation. Patients were randomly assigned (1:1) to the two treatment groups by an interactive voice response system, stratified by mutation type and disease stage. Patients, physicians, and the investigators who analysed data were masked to treatment allocation. The primary outcome was relapse-free survival, defined as the time from randomisation to disease recurrence or death from any cause. Biomarker assessment was a prespecified exploratory outcome of the trial. We assessed intrinsic tumour genomic features by use of next-generation DNA sequencing and characteristics of the tumour microenvironment by use of a NanoString RNA assay, which might provide prognostic and predictive information. This trial is registered with ClinicalTrials.gov, number NCT01682083, and is ongoing but no longer recruiting participants. FINDINGS: Between Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled in the trial. Median follow-up at data cutoff (April 30, 2018) was 44 months (IQR 38-49) in the dabrafenib plus trametinib group and 42 months (21-49) in the placebo group. Intrinsic tumour genomic features were assessed in 368 patients (DNA sequencing set) and tumour microenvironment characteristics were assessed in 507 patients (NanoString biomarker set). MAPK pathway genomic alterations at baseline did not affect treatment benefit or clinical outcome. An IFNγ gene expression signature higher than the median was prognostic for prolonged relapse-free survival in both treatment groups. Tumour mutational burden was independently prognostic for relapse-free survival in the placebo group (high TMB, top third; hazard ratio [HR] 0·56, 95% CI 0·37-0·85, p=0·0056), but not in the dabrafenib plus trametinib group (0·83, 95% CI 0·53-1·32, p=0·44). Patients with tumour mutational burden in the lower two terciles seem to derive a substantial long-term relapse-free survival benefit from targeted therapy (HR [versus placebo] 0·49, 95% CI 0·35-0·68, p<0·0001). However, patients with high tumour mutational burden seem to have a less pronounced benefit with targeted therapy (HR [versus placebo] 0·75, 95% CI 0·44-1·26, p=0·27), especially if they had an IFNγ signature lower than the median (HR 0·88 [95% CI 0·40-1·93], p=0·74). INTERPRETATION: Tumour mutational burden alone or in combination with IFNγ gene expression signature or other markers for an adaptive immune response might be of relevance for identifying patients with stage III melanoma who might derive clinical benefit from targeted therapy. Further validation in prospective clinical trials is warranted. FUNDING: Novartis Pharmaceuticals.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Melanoma/tratamento farmacológico , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Imidazóis/administração & dosagem , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Oximas/administração & dosagem , Prognóstico , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Terapia de Salvação , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Adulto Jovem
19.
BMC Cancer ; 20(1): 156, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093631

RESUMO

BACKGROUND: A BRAF V600E mutation is found as driver oncogene in patients with non-small cell lung cancer. Although combined treatment with dabrafenib and trametinib is highly effective, the efficacy of reduced doses of the drugs in combination therapy has not yet been reported. CASE PRESENTATION: A Japanese man in his mid-sixties was diagnosed with unresectable lung adenocarcinoma and was unresponsive to cytotoxic chemotherapy and immune checkpoint inhibitors. The BRAF V600E mutation was detected by next generation sequencing, and the patient was subjected to treatment with dabrafenib and trametinib in combination. Although the treatment reduced the tumor size, he experienced myalgia and muscle weakness with elevated serum creatine kinase and was diagnosed with rhabdomyolysis induced by dabrafenib and trametinib. After the patient recovered from rhabdomyolysis, the treatment doses of dabrafenib and trametinib were reduced, which prevented further rhabdomyolysis and maintained tumor shrinkage. CONCLUSION: The reduction of the doses of dabrafenib and trametinib was effective in the treatment of BRAF V600E-mutant NSCLC, and also prevented the incidence of rhabdomyolysis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Uso Off-Label/normas , Proteínas Proto-Oncogênicas B-raf/genética , Rabdomiólise/prevenção & controle , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Imidazóis/administração & dosagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Estadiamento de Neoplasias , Oximas/administração & dosagem , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Rabdomiólise/induzido quimicamente , Resultado do Tratamento
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