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1.
Artigo em Inglês | MEDLINE | ID: mdl-34201096

RESUMO

Objective: To evaluate the cost-effectiveness of dabrafenib plus trametinib combination therapy versus vemurafenib as first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma from a healthcare system perspective in China. Methods: This study employed a partitioned survival model with three health states (progression-free survival, post-progression survival and dead) to parameterize the data derived from Combi-v trial and extrapolated to 30 years. Health states' utilities were measured by EQ-5D-3L, also sourced from the Combi-v trial. Costs including drug acquisition costs, disease management costs and adverse event costs were based on the Chinese Drug Bidding Database and physician survey in China. The primary outcomes of the model were lifetime costs, life-years (LYs), quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were conducted, respectively. Result: Dabrafenib plus trametinib is projected to increase a patient's life expectancy by 0.95 life-years over vemurafenib (3.03 vs. 2.08) and 1.09 QALY gains (2.48 vs. 1.39) with an incremental cost of $3833. The incremental cost-effectiveness ratio (ICER) was $3511 per QALY. In the probabilistic sensitivity analyses, at a threshold of $33,357 per QALY (three times the gross domestic product (GDP) per capita in China in 2020), the probability of dabrafenib plus trametinib being cost-effective was 90%. In the deterministic sensitivity analyses, the results were most sensitive to the dabrafenib plus trametinib drug costs, vemurafenib drug costs and discount rate of cost. Conclusion: Dabrafenib plus trametinib therapy yields more clinical benefits than vemurafenib. Using a threshold of $33,357 per QALY, dabrafenib plus trametinib is very cost-effective as compared with vemurafenib in China.


Assuntos
Melanoma , Proteínas Proto-Oncogênicas B-raf , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , China , Análise Custo-Benefício , Humanos , Imidazóis , Melanoma/tratamento farmacológico , Melanoma/genética , Mutação , Oximas , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas , Vemurafenib/uso terapêutico
2.
BMC Infect Dis ; 21(1): 595, 2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34157984

RESUMO

BACKGROUND: We aimed to assess the overall cardiovascular and metabolic effect of the switch to three different single tablet regimens (STRs) [tenofovir alafenamide/emtricitabine/rilpivirine (TAF/FTC/RPV), TAF/FTC/elvitegravir/cobi (TAF/FTC/EVG/cobi) and ABC/lamivudine/dolutegravir (ABC/3TC/DTG)] in a cohort of people living with HIV/AIDS (PLWH) under effective ART. METHODS: All PLWH aged above 18 years on antiretroviral treatment with an HIV-RNA < 50 cp/mL at the time of the switch to TAF/FTC/RPV, TAF/FTC/EVG/cobi and ABC/3TC/DTG were retrospectively included in the analysis. Framingham risk score modification after 12 months from the switch such as lipid profile and body weight modification were assessed. The change from baseline to 12 months in mean cardiovascular risk and body weight in each of the STR's group were assessed by means of Wilcoxon signed-rank test whereas a mixed regression model was used to assess variation in lipid levels. RESULTS: Five-hundred and sixty PLWH were switched to an STR regimen of whom 170 (30.4%) to TAF/FTC/EVG/cobi, 191 (34.1%) to TAF/FTC/RPV and 199 (35.5%) to ABC/3TC/DTG. No difference in the Framingham cardiovascular risk score was observed after 12 months from the switch in each of the STR's groups. No significant overtime variation in mean total cholesterol levels from baseline to 12 months was observed for PLWH switched to ABC/3TC/DTG [200 (SD 38) mg/dl vs 201 (SD 35) mg/dl; p = 0.610] whereas a significant increment was observed in PLWH switched to TAF/FTC/EVG/cobi [192 (SD 34) mg/dl vs 208 (SD 40) mg/dl; p < 0.0001] and TAF/FTC/RPV [187 (SD 34) mg/dl vs 195 (SD 35) mg/dl; p = 0.027]. In addition, a significant variation in the mean body weight from baseline to 12 months was observed in PLWH switched to TAF/FTC/EVG/cobi [72.2 (SD 13.5) kilograms vs 74.6 (SD 14.3) kilograms; p < 0.0001] and TAF/FTC/RPV [73.4 (SD 11.6) kilograms vs 75.6 (SD 11.8) kilograms; p < 0.0001] whereas no difference was observed in those switched to ABC/3TC/DTG [71.5 (SD 12.8) kilograms vs 72.1 (SD 12.6) kilograms; p = 0.478]. CONCLUSION: No difference in the cardiovascular risk after 1 year from the switch to these STRs were observed. PLWH switched to TAF/FTC/EVG/cobi and TAF/FTC/RPV showed an increase in total cholesterol levels and body weight 12 months after the switch.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Combinação Elvitegravir, Cobicistat, Emtricitabina e Fumarato de Tenofovir Desoproxila/uso terapêutico , Combinação Emtricitabina, Rilpivirina e Tenofovir/uso terapêutico , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Lamivudina/uso terapêutico , Oxazinas/uso terapêutico , Piperazinas/uso terapêutico , Piridonas/uso terapêutico , Adulto , Fármacos Anti-HIV/metabolismo , Peso Corporal/efeitos dos fármacos , Estudos de Coortes , Didesoxinucleosídeos/metabolismo , Combinação de Medicamentos , Combinação Elvitegravir, Cobicistat, Emtricitabina e Fumarato de Tenofovir Desoproxila/metabolismo , Combinação Emtricitabina, Rilpivirina e Tenofovir/metabolismo , Feminino , Fatores de Risco de Doenças Cardíacas , Compostos Heterocíclicos com 3 Anéis/metabolismo , Humanos , Itália/epidemiologia , Lamivudina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Oxazinas/metabolismo , Piperazinas/metabolismo , Piridonas/metabolismo , Estudos Retrospectivos , Comprimidos/uso terapêutico
3.
Epilepsy Behav ; 121(Pt A): 108069, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34077902

RESUMO

INTRODUCTION: The main of the present study was to assess the effectiveness and tolerability of perampanel (PER) in association with 1 or 2 concomitant antiseizure medications (ASMs) in patients with epilepsy throughout a follow-up period of 24 months or longer in a real-world setting. METHODS: This retrospective, observational, multi-center study collected data from both underage (<18 years old) and adult patients who had started PER in association with 1 or 2 ASMs. Only patients who had started PER and were followed up for at least 24 months were included. Response to treatment was analyzed at the 24-, 36-, and 48-month visits by considering the last visit undergone by patients. Subgroup analyses were performed according to age, gender, and epilepsy type and patients were categorized following PER treatment in concomitance with 1 or 2 ASMs to evaluate the factors affecting the achievement of seizure freedom (SF) at the 24-month FU. RESULTS: Ninety-four patients were included (mean age 36.89 years; 51.1% female). At the 24-month follow-up visit, 90 (95.74%) patients were still receiving PER concomitantly with 1 or 2 ASMs. The mean PER dose was 6.02 mg/day and SF was achieved by 33 (35.1%) patients. A significantly higher SF rate was found in patients who had started PER with only 1 ASM when compared to those who had started PER with 2 concomitant ASMs. Effectiveness was maintained also in the subgroups of patients with a 36- or 48-month follow-up visit. Adult patients had a higher final daily dosage of PER than underage patients. Logistic regression found that the lowest number of previously failed ASMs was associated with a higher SF rate (p = 0.036). CONCLUSION: Perampanel demonstrated a good effectiveness in association with 1 or 2 ASMs in both pediatric and adult patients, without having to use a high dose of the drug. The possibility to present SF was higher when PER was added early. Finally, the maintenance of effectiveness was observed also in the subgroups of patients with a follow-up of 36 and 48 months.


Assuntos
Anticonvulsivantes , Epilepsia , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Criança , Epilepsia/tratamento farmacológico , Feminino , Seguimentos , Humanos , Masculino , Piridonas/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
4.
Top Antivir Med ; 29(2): 309-327, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34107201

RESUMO

At the 2021 virtual Conference on Retroviruses and Opportunistic Infections ,several speakers described the disparities in both HIV and SARS-CoV-2 in-fections and outcomes in racial and ethnic minorities. A household survey suggested that there may have been more than 39 million SARS-CoV-2 infections in the United States by October 30, 2020, with an estimated infection fatality ratio of 0.64%; this compares with an estimated 7.3 million confirmed cases at that time. Several presentations found severe disruptions in HIV testing, prevention, and treatment services during COVID-19-related lockdowns; models suggest that severe interruption of antiretroviral therapy services could lead to a 1.5- to 3-fold increase in mortality. HIV testing remains the gateway to both treatment and prevention, and innovative strategies to improve testing uptake were presented. Preexposure prophylaxis (PrEP) agents may delay detection of HIV infection using standard testing algorithms. Data were presented on promising investigational PrEP agents, including cabotegravir, islatravir, and the dapivirine vaginal ring. Progress is being made in point-of-care assays to measure PrEP adherence with tenofovir-based regimens. HIV incidence remains low in populations of PrEP users, with higher rates among persons who never refilled their prescription. More work remains to be done to increase PrEP uptake among populations most heavily impacted by HIV.


Assuntos
COVID-19 , Controle de Doenças Transmissíveis/tendências , Infecções por HIV/etnologia , Infecções por HIV/epidemiologia , Teste de HIV/tendências , Disparidades em Assistência à Saúde , Profilaxia Pré-Exposição , COVID-19/epidemiologia , COVID-19/etnologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Inibidores de Integrase de HIV/uso terapêutico , Teste de HIV/estatística & dados numéricos , Humanos , Aceitação pelo Paciente de Cuidados de Saúde , Piridonas/uso terapêutico , Estados Unidos/epidemiologia
6.
Kardiol Pol ; 79(6): 622-630, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34029374

RESUMO

Direct oral anticoagulants (DOACs), apixaban, dabigatran, edoxaban, and rivaroxaban, are widely used for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation as well as for prevention and treatment of venous thromboembolism. Although DOACs do not require routine laboratory monitoring of anticoagulant effect, there are special situations in which laboratory assessment may be warranted. Laboratory tests include quantitative assays, which measure plasma DOAC levels, and qualitative or semi-quantitative assays, which may be used to screen for the presence of clinically relevant DOAC levels. Indications for laboratory assessment include emergent indications (serious bleeding, urgent surgery, acute ischemic stroke with consideration of thrombolysis) and elective indications (extremes of bodyweight, renal hypo- or hyperfunction, liver disease, suspected drug-drug interactions, suspected gastrointestinal malabsorption). In general, quantitative assays that measure DOAC levels may be used for elective indications, whereas screening assays may be necessary for emergent indications if a quantitative assay with sufficiently rapid turnaround time is not available. Therapeutic ranges for DOACs have not been defined. In lieu of therapeutic ranges, data from pharmacokinetic studies may be used to determine whether a patient's plasma DOAC level falls within the expected range. If it does not, a change in therapy may be warranted. Depending on the clinical scenario, a change in therapy may involve adjustment of the DOAC dose, a change to a different DOAC, or a change to a different class of anticoagulant.


Assuntos
Fibrilação Atrial , Isquemia Encefálica , Acidente Vascular Cerebral , Administração Oral , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/uso terapêutico , Humanos , Laboratórios , Piridonas/uso terapêutico , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle
7.
Lancet HIV ; 8(6): e324-e333, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34000227

RESUMO

BACKGROUND: Islatravir is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1 infection. We aimed to assess the efficacy and safety of islatravir-based regimens for the treatment of HIV-1. METHODS: We did a phase 2b, randomised, double-blind, comparator-controlled, dose-ranging trial at 24 clinics or hospitals in four countries (Chile, France, the UK, and the USA). Treatment-naive adults (≥18 years) with plasma HIV-1 RNA concentrations of at least 1000 copies per mL, CD4 T-cell counts of at least 200 cells per mL, and a calculated creatinine clearance of at least 50 mL/min (all within 60 days before study treatment) were eligible for inclusion. Participants were randomly assigned (1:1:1:1) with a block size of four via an interactive voice and web response system to receive oral treatment with one of three doses of islatravir (0·25 mg, 0·75 mg, or 2·25 mg) plus doravirine (100 mg) and lamivudine (300 mg) or to doravirine (100 mg) plus lamivudine (300 mg) plus tenofovir disoproxil fumarate (TDF; 300 mg) once daily with placebo (part 1). Treatment groups were stratified according to screening HIV-1 RNA concentration (≤100 000 copies per mL or >100 000 copies per mL). After at least 24 weeks of treatment, participants taking islatravir who achieved an HIV-1 RNA concentration lower than 50 copies per mL switched to a two-drug regimen of islatravir and doravirine (part 2). All participants and study investigators were masked to treatment in part 1; in part 2, the islatravir dose was masked to all participants and investigators, but the other drugs were given open label. The primary efficacy outcomes were the proportions of participants with an HIV-1 RNA concentration lower than 50 copies per mL at weeks 24 and 48 (US Food and Drug Administration snapshot approach). The primary safety outcomes were the number of participants experiencing adverse events and the number of participants discontinuing study drug owing to adverse events. All participants who received at least one dose of any study drug were included in the analyses. This trial is ongoing, but closed to enrolment of new participants; herein, we report study findings through 48 weeks of treatment. This trial is registered with ClinicalTrials.gov, NCT03272347. FINDINGS: Between Nov 27, 2017, and April 25, 2019, 121 participants (mean age 31 years [SD 10·9], 112 [93%] male, 92 [76%] white, 27 [22%] with HIV-1 RNA concentration >100 000 copies per mL) were randomly assigned: 29 to the 0·25 mg, 30 to the 0·75 mg, and 31 to the 2·25 mg islatravir groups, and 31 to the doravirine, lamivudine, and TDF group. At week 24, 26 (90%) of 29 participants in the 0·25 mg islatravir group, 30 (100%) of 30 in the 0·75 mg islatravir group, and 27 (87%) of 31 in the 2·25 mg islatravir group achieved HIV-1 RNA concentrations lower than 50 copies per mL compared with 27 (87%) of 31 in the doravirine plus lamivudine plus TDF group (difference 2·8%, 95% CI -14·9 to 20·4, for the 0·25 mg islatravir group; 12·9%, -1·6 to 27·5, for the 0·75 mg islatravir group; and 0·3%, -17·9 to 18·5, for the 2·25 mg islatravir group). At week 48, these data were 26 (90%) of 29 in the 0·25 mg islatravir group, 27 (90%) of 30 in the 0·75 mg islatravir group, and 24 (77%) of 31 in the 2·25 mg islatravir group compared with 26 (84%) of 31 in the doravirine plus lamivudine plus TDF group (difference 6·1%, 95% CI -12·4 to 24·4, for the 0·25 mg islatravir group; 6·2%, -12·2 to 24·6, for the 0·75 mg islatravir group; and -6·1%, -27·1 to 14·8, for the 2·75 mg islatravir group). 66 (73%) of participants in the islatravir groups combined and 24 (77%) of those in the doravirine plus lamivudine plus TDF group reported at least one adverse event. Two participants in the 2·25 mg islatravir group and one participant in the doravirine plus lamivudine plus TDF group discontinued owing to an adverse event. No deaths were reported up to week 48. INTERPRETATION: Treatment regimens containing islatravir and doravirine showed antiviral efficacy and were well tolerated regardless of dose. Doravirine in combination with islatravir has the potential to be a potent two-drug regimen that warrants further clinical development. FUNDING: Merck, Sharp, & Dohme Corp, a subsidiary of Merck & Co., Inc.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Desoxiadenosinas/uso terapêutico , Infecções por HIV/tratamento farmacológico , Lamivudina/uso terapêutico , Piridonas/uso terapêutico , Triazóis/uso terapêutico , Adulto , Fármacos Anti-HIV/análise , Desoxiadenosinas/análise , Cálculos da Dosagem de Medicamento , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Lamivudina/análise , Masculino , Piridonas/análise , Triazóis/análise , Adulto Jovem
8.
J Infect Chemother ; 27(8): 1223-1229, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34045119

RESUMO

INTRODUCTION: Baloxavir marboxil is an oral anti-influenza drug with demonstrated safety and efficacy in pediatric patients when a 2% granules formulation is administered at 1 mg/kg. This study assessed safety, effectiveness, and pharmacokinetics of a higher dose (2 mg/kg) of baloxavir marboxil 2% granules in pediatric patients weighing <20 kg. METHODS: This multicenter, open-label, noncontrolled study was conducted at 15 sites in Japan (January 2019-March 2020; JapicCTI-194577). Patients aged <12 years with confirmed influenza received a single oral dose of baloxavir marboxil at 2 mg/kg if body weight was <10 kg or 20 mg if ≥ 10 to <20 kg. Safety, pharmacokinetics, effectiveness (time to illness alleviation [TTIA] of influenza; time to resolution of fever; virus titer), and polymerase acidic protein (PA) substituted viruses were assessed over 22 days. RESULTS: 45 patients, all aged ≤6 years, were enrolled. Adverse events were reported in 24 (53.3%) patients, most commonly nasopharyngitis, diarrhea, and upper respiratory tract infection. Median (95% confidence interval [CI]) TTIA was 37.8 (27.5-46.7) hours; median (95% CI) time to resolution of fever was 22.0 (20.2-28.6) hours. A >4 log decrease in mean viral titer occurred at day 2 and a subsequent temporary 1-2 log increase in patients with influenza A(H3N2) and B. Treatment-emergent PA/I38X-substituted virus was detected in 16/39 (41.0%) patients, but no prolonged TTIA or time to resolution of fever was associated with its presence. CONCLUSIONS: Baloxavir granules administered at 2 mg/kg in children <20 kg were well tolerated, with symptom alleviation similar to 1 mg/kg.


Assuntos
Dibenzotiepinas , Influenza Humana , Antivirais/efeitos adversos , Criança , Dibenzotiepinas/uso terapêutico , Humanos , Vírus da Influenza A Subtipo H3N2 , Influenza Humana/tratamento farmacológico , Japão , Morfolinas/uso terapêutico , Oxazinas , Piridonas/uso terapêutico , Triazinas
9.
Epilepsy Behav ; 121(Pt A): 108073, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34058494

RESUMO

OBJECTIVE: To evaluate the effectiveness and tolerability of perampanel (PER) treatment for patients with highly drug-resistant epilepsies (HDRE) including nonsurgical candidates and failed surgery in real-world setting. METHODS: All patients who were treated with PER during June 2015 to August 2019 were selected. Primary outcomes were percentage of seizure reduction, responder rate, and seizure freedom rate. Seizure frequency after taking PER at 3 and 12 months were compared with baseline seizure frequency within the same time period prior to starting PER. Secondary outcomes were retention rate, side effects, and predictors for a response to PER. Descriptive statistics and the Kernel regression model were employed. RESULTS: Forty-one patients received PER treatment during the study period. Six patients who had no baseline seizure frequency recordings were excluded, for a total of 35 patients included for analysis. Mean age was 40.06 years (SD 12.34). All were highly resistant to several antiseizure drugs (ASDs) with a median number of previously failed ASDs of 8 items. Eleven, 16, 5, and 3 patients were lesional, nonlesional focal epilepsy, nonsurgical candidate, and failed surgery, respectively. At 3 months after PER treatment, the median percentage of seizure reduction was 20 % (-35.71, 100), the responder rate was 22.86 % (8/35), and the seizure freedom rate was 17.14% (6/35). At 12 months after PER treatment, the corresponding outcomes were 25% (-20.57, 91.60), 22.58% (7/31), and 9.68% (3/31), respectively. Retention rates at 3 and 12 months were 100% and 91.43% (32/35), respectively. Nineteen patients (54.29%) experienced side effects from PER. Side effects were somnolence (6/35), dizziness (3/35), irritability (2/35), and ataxia (2/35), and one each for weight loss, nausea, headache, insomnia, verbal aggressivity, and depression. Median duration for 2-mg dose increment was 2.2 months. CONCLUSIONS: In real-world practice, slow-titration PER regimen is well-tolerable and shows benefit in helping control seizures in patients with very difficult-to-treat HDRE.


Assuntos
Epilepsia Resistente a Medicamentos , Preparações Farmacêuticas , Adulto , Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Resistente a Medicamentos/cirurgia , Quimioterapia Combinada , Humanos , Piridonas/uso terapêutico , Resultado do Tratamento
10.
Epilepsy Behav ; 119: 107965, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33940525

RESUMO

OBJECTIVE: Perampanel is one of the most recently approved antiseizure medications. The aim of the present study was to assess clinical efficacy and tolerability, in combination with pharmacokinetic variability, of perampanel treatment in patients at a tertiary referral center for epilepsy. METHODS: We performed a retrospective observational study of patients given perampanel as adjunctive treatment in the period January 2013 - February 2019 at the National Center for Epilepsy at Oslo University Hospital, Norway. RESULTS: Clinical data were available for 175 mainly adult patients with drug-resistant epilepsy with mean treatment duration of 16.1 months. We found that 23% (40 patients) were responders (i.e., achieving more than 50% reduction in seizure frequency), four of whom became seizure free, 29% (51 patients) experienced a modest effect, whereas for 29% (50 patients) perampanel had no seizure-reducing effect. A paradoxical effect, with seizure aggravation, was reported in 9% (15 patients). The responder rate was significantly higher in those with slow vs. fast dosage titration. Logistic regression analysis showed better efficacy among those with generalized vs. those with focal epilepsy. Adverse effects were reported by 135 patients (77%), ranging from mild (34%), to moderate (41%) and severe (2%). In 55 patients (41%), these adverse effects resulted in discontinuation of treatment with perampanel. The most frequent adverse effects were psychiatric symptoms (34%), dizziness (31%), and sleepiness (26%). Of the 31 patients for whom serum concentration measurements were available, the mean daily perampanel dose was 6.3 mg (SD 3.0), with a mean serum concentration at steady state of 1.03 µmol/L (range: 0.15-3.59 µmol/L). There were pronounced differences between patients, as demonstrated by a 12-fold variability in the range of concentration/dose (C/D)-ratios (0.06 to 0.69 µmol/L/mg), where enzyme inducers contributed. CONCLUSION: Our results demonstrate that perampanel had a modest seizure-reducing effect in this very treatment-resistant patient group. Predictors of treatment success were generalized epilepsy and slow dosage titration. In patients without a history of psychiatric problems, clinicians could consider increasing dose of perampanel beyond 6 mg daily, taking co-medication and serum concentrations into account.


Assuntos
Epilepsia , Preparações Farmacêuticas , Adulto , Anticonvulsivantes/uso terapêutico , Quimioterapia Combinada , Epilepsia/tratamento farmacológico , Humanos , Noruega , Piridonas/uso terapêutico , Resultado do Tratamento
11.
J Pediatr Surg ; 56(7): 1233-1239, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33863557

RESUMO

PURPOSE: We reported the in vitro and in vivo anti-tumor effects of trametinib, an MEK inhibitor, on neuroblastoma. However, long-term trametinib administration for bulky tumors failed to prevent local relapse. In this study, we established a local minimal residual disease (L-MRD) model to develop an optimal clinical protocol. METHODS: We prepared an l-MRD model by implanting neuroblastoma cells (SK-N-AS) into the renal capsule of nude mice with total tumorectomy or sham operation 14 days later. These mice received post-operative administration of trametinib or vehicle for eight weeks. Relapse was measured once weekly. Flow cytometry was performed with SK-N-AS cells treated by trametinib. RESULTS: Tumorectomy+trametinib dramatically suppressed relapse, and all mice survived during trametinib administration, while other treatments failed to suppress relapse. The survival rates for other groups were 20% in sham+trametinib, 17% in tumorectomy+vehicle, and 0% in sham+vehicle. Relapse occurred in the tumorectomy+trametinib group after withdrawal of trametinib administration. Flow cytometry revealed G1 arrest in SK-N-AS cells treated with trametinib. CONCLUSION: These findings suggested that trametinib was able to suppress relapse from minimal residual tumor cells. Therefore, we propose that trametinib be administered as an option for maintenance therapy after surgical and chemotherapeutic treatments for neuroblastoma in future clinical protocols.


Assuntos
Recidiva Local de Neoplasia , Neuroblastoma , Animais , Linhagem Celular Tumoral , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasia Residual , Neuroblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases , Piridonas/farmacologia , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico
12.
BMJ Open ; 11(4): e042947, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33858866

RESUMO

INTRODUCTION: Patients with atrial fibrillation experience an irregular heart rate and have an increased risk of stroke; prophylactic treatment with anticoagulation medication reduces this risk. Direct-acting oral anticoagulants (DOACs) have been approved providing an alternative to vitamin K antagonists such as warfarin. There is interest from regulatory bodies on the effectiveness of medications in routine clinical practice; however, uncertainty remains regarding the suitability of non-interventional data for answering questions on drug effectiveness and on the most suitable methods to be used. In this study, we will use data from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)-the pivotal trial for the DOAC apixaban-to validate non-interventional methods for assessing treatment effectiveness of anticoagulants. These methods could then be applied to analyse treatment effectiveness in people excluded from or under-represented in ARISTOTLE. METHODS AND ANALYSIS: Patient characteristics from ARISTOTLE will be used to select a cohort of patients with similar baseline characteristics from two UK electronic health record (EHR) databases, Clinical Practice Research Datalink Gold and Aurum (between 1 January 2013 and 31 July 2019). Methods such as propensity score matching and coarsened exact matching will be explored in matching between EHR treatment groups to determine the optimal method of obtaining a balanced cohort.Absolute and relative risk of outcomes in the EHR trial-analogous cohort will be calculated and compared with the ARISTOTLE results; if results are deemed compatible the methods used for matching EHR treatment groups can then be used to examine drug effectiveness over a longer duration of exposure and in special patient groups of interest not studied in the trial. ETHICS AND DISSEMINATION: The study has been approved by the Independent Scientific Advisory Committee of the UK Medicines and Healthcare Products Regulatory Agency. Results will be disseminated in scientific publications and at relevant conferences.


Assuntos
Fibrilação Atrial , Acidente Vascular Cerebral , Administração Oral , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Estudos de Coortes , Humanos , Piridonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Reino Unido , Varfarina/uso terapêutico
13.
Epilepsy Behav ; 118: 107927, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33812233

RESUMO

OBJECTIVES: Combination regimens of antiepileptic drugs (AEDs) with various mechanisms of action (MOA) are commonly used in patients with refractory epilepsy. However, outcomes related to combination AEDs with novel MOA, such as perampanel (PER), are not well described. This study compared healthcare resource utilization (HRU) among recipients of PER-based combinations versus recipients of other non-PER-based combinations. METHODS: This retrospective study used claims data from the Symphony Health's IDV® (Integrated Dataverse) database (August 2012 to July 2018). Patients were aged ≥12 years with epilepsy or non-febrile convulsions, were treated with AED combinations, and had ≥12 and ≥6 months pre- and post-index date, respectively (date of initiation of the second AED in the combination). AEDs were categorized based on MOA: selective non-competitive antagonist of AMPA receptors (i.e., PER), sodium channel blocker (SC), synaptic vesicle protein 2A binding (SV2), and gamma-aminobutyric acid analog (G). Patients were then classified into MOA-based cohorts: PER + SC, PER + SV2, PER + G, SC + SC, SC + SV2, SC + G, SV2 + G, and G + G. HRU outcomes were evaluated during follow-up and compared between PER-based cohorts and non-PER-based cohorts. RESULTS: On average, patients in the PER + SC (N = 3,592), PER + SV2 (N = 2,200), and PER + G (N = 1,313) cohorts were younger and had a lower Quan-Charlson comorbidity index than those in non-PER-based cohorts. PER + SC and PER + SV2 users had significantly fewer all-cause hospitalizations than non-PER-based users (adjusted RR range: 0.66-0.89, all P < 0.05), while PER + G recipients had fewer all-cause hospitalizations than recipients of SV2 + G and G + G (adjusted RR range: 0.92-0.94). Similar trends were observed for epilepsy-related hospitalizations. Across all comparisons, PER-based combinations were associated with significantly lower rates of all-cause clinic/office/outpatient visits relative to non-PER-based combinations (adjusted RR range: 0.69-0.86, all P < 0.05). SIGNIFICANCE: Results showed that patients treated with PER-based combinations had fewer all-cause and epilepsy-related hospitalizations, and fewer all-cause clinic/office/outpatient visits compared with patients treated with most other non-PER-based combinations.


Assuntos
Anticonvulsivantes , Epilepsia , Idoso , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Humanos , Piridonas/uso terapêutico , Estudos Retrospectivos , Estados Unidos
14.
Eur J Endocrinol ; 184(6): 837-845, 2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-33852431

RESUMO

Background: Anaplastic thyroid cancer (ATC) has dismal prognosis and there is no effective treatment. We aimed to evaluate the efficacy of tyrosine kinase inhibitor (TKI) therapy in real-world clinic and to suggest the most effective treatment modality according to the combination of treatments. Methods: This retrospective study evaluated clinical outcomes and cause of death with multimodal treatments in patients with ATC at Samsung Medical Center. Results: A total of 120 patients received anti-cancer treatment for ATC. Seventy-seven (64.2%) patients underwent surgery, 64 (53.3%) received radiotherapy, 29 (24.2%) received cytotoxic chemotherapy, and 19 (15.8%) received TKI therapy. In the TKI therapy group, eight achieved partial response (three with lenvatinib and five with dabrafenib plus trametinib), and two patients with lenvatinib showed stable disease. Median progression-free survival (PFS) of the TKI therapy group was 2.7 months (range: 0.1-12.7) and their median overall survival (OS) was 12.4 months (range: 1.7-47.7). Patients who received surgery or radiotherapy for local control showed superior OS than those who did not. In a multivariate analysis, surgery, TKI therapy, younger age, and no distant metastasis were associated with favorable OS. The combination of surgery, radiotherapy, and TKI therapy (median OS: 34.3 months, 6-month survival rates: 77.8%) was the most effective. Compared to the era without TKI therapy, distant metastasis has recently become the major cause of death in ATC over airway problems. Conclusions: Multimodality treatment including TKI therapy demonstrated prolonged survival with dabrafenib plus trametinib as the most effective therapeutic option demonstrated for BRAF mutant ATC patients.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Fatores Etários , Idoso , Terapia Combinada , Feminino , Humanos , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oximas/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Prognóstico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Quinolinas/uso terapêutico , Estudos Retrospectivos , Carcinoma Anaplásico da Tireoide/patologia , Carcinoma Anaplásico da Tireoide/radioterapia , Carcinoma Anaplásico da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/radioterapia , Neoplasias da Glândula Tireoide/cirurgia , Resultado do Tratamento
15.
Epilepsy Behav ; 118: 107964, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33866126

RESUMO

Status epilepticus (SE) and acute repetitive seizure (ARS) are emergency conditions associated with significant morbidity and mortality in children. Anti-seizure medications (ASMs) need to terminate seizures to prevent brain damage and death. Common challenges that delay the management of SE and ARS in children at Phramongkutklao hospital are difficulty in accessing intravenous route for drug administration and inadequate number of intensive care units (which will be required in case of the use of adverse events to anesthetic ASMs). Oral, non-sedating ASMs could be a potential option to terminate seizures effectively in SE and ARS in children and further studies in this aspect are needed. We performed a prospective, descriptive study in children with SE or ARS < 18 years of age who had contraindication to or their seizures were refractory to the second-line ASMs after benzodiazepine and received oral perampanel. Demographic data, efficacy, and adverse effects of treatment were recorded. Fifteen patients with SE (13.3%) and acute repetitive seizure (86.6%) were enrolled. All patients received an oral perampanel loading dose and the maintenance dose depended on their body weight. The average loading and maintenance dose were 0.24 mg/kg/dose and 0.12 mg/kg/day, respectively. At 48 h after administration of loading dose of perampanel, eight of fifteen patients (53.3%) became seizure free, one patient had seizure reduction of >75% from baseline, and three patients had seizure reduction of 25-50% from baseline. No serious side effects were observed. These results indicate that oral perampanel may be potential treatment option for SE and ARS in children.


Assuntos
Anticonvulsivantes , Estado Epiléptico , Anticonvulsivantes/uso terapêutico , Criança , Humanos , Estudos Prospectivos , Piridonas/uso terapêutico , Convulsões/tratamento farmacológico , Estado Epiléptico/tratamento farmacológico , Centros de Atenção Terciária , Tailândia , Resultado do Tratamento
16.
Ther Drug Monit ; 43(4): 455-458, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33908408

RESUMO

ABSTRACT: In this article, we present a case of apixaban elimination prolonged by 450% in a patient with coronavirus disease 2019 because of multiple conditions, including drug-drug interaction, severe inflammation, and acute kidney injury. Therapeutic drug monitoring was used to explain unusual routine coagulation assays. This grand round highlights the importance of dialog between the clinician and a therapeutic drug monitoring consultant for optimal patient care.


Assuntos
Injúria Renal Aguda/metabolismo , COVID-19/metabolismo , Monitoramento de Medicamentos/métodos , Pirazóis/metabolismo , Piridonas/metabolismo , Eliminação Renal/efeitos dos fármacos , Visitas com Preceptor/métodos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Idoso de 80 Anos ou mais , Antivirais/efeitos adversos , Antivirais/metabolismo , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Interações Medicamentosas/fisiologia , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/metabolismo , Inibidores do Fator Xa/uso terapêutico , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/prevenção & controle , Masculino , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Piridonas/efeitos adversos , Piridonas/uso terapêutico , Eliminação Renal/fisiologia , Índice de Gravidade de Doença , Fatores de Tempo
17.
Sleep Med ; 81: 382-386, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33831666

RESUMO

This study aimed to evaluate the efficacy and tolerability of perampanel (PER) as adjunctive therapy in patients with pharmacoresistant sleep-related hypermotor epilepsy (SHE). Patients diagnosed with SHE who received PER treatment between 2016 and 2019 were included, and their data were reviewed retrospectively. Diagnosis was based on reports of patients or family members witnessing the events and clinical characteristics of seizures captured by video or during video-electroencephalography monitoring. Among 36 SHE patients, 20 with pharmacoresistant SHE (six female; mean age: 34.1 ± 9.0 years) who received PER as adjunctive therapy were included in this study. Fourteen out of the 20 patients received PER with mean length of PER exposure of 24.6 ± 15.7 months: 10 of them were responders and four non-responders. The remaining six patients discontinued PER for adverse events (n = 5) and patient choice (n = 1). Among the 10 responders, six (60%) reported seizure-free periods lasting ≥6 months. The most common PER-associated adverse event was dizziness (25%) followed by malaise (10%). Clinical experience with these patients demonstrated that PER might be considered as an add-on anti-seizure medication for patients with highly pharmacoresistant SHE.


Assuntos
Epilepsia , Piridonas/uso terapêutico , Receptores de AMPA/antagonistas & inibidores , Sono , Adulto , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Feminino , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento
18.
AAPS PharmSciTech ; 22(3): 127, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33835317

RESUMO

Being a candidate of BCS class II, dolutegravir (DTG), a recently approved antiretroviral drug, possesses solubility issues. The current research was aimed to improve the solubility of the DTG and thereby enhance its efficacy using the solid dispersion technique. In due course, the miscibility study of the drug was performed with different polymers, where Poloxamer 407 (P407) was found suitable to move forward. The solid dispersion of DTG and P407 was formulated using solvent evaporation technique with a 1:1 proportion of drug and polymer, where the solid-state characterization was performed using differential scanning calorimetry, Fourier transform infrared spectroscopy and X-ray diffraction. No physicochemical interaction was found between the DTG and P407 in the fabricated solid dispersion; however, crystalline state of the drug was changed to amorphous as evident from the X-ray diffractogram. A rapid release of DTG was observed from the solid dispersion (>95%), which is highly significant (p<0.05) as compared to pure drug (11.40%), physical mixture (20.07%) and marketed preparation of DTG (35.30%). The drug release from the formulated solid dispersion followed Weibull model kinetics. Finally, the rapid drug release from the solid dispersion formulation revealed increased Cmax (14.56 µg/mL) when compared to the physical mixture (4.12 µg/mL) and pure drug (3.45 µg/mL). This was further reflected by improved bioavailability of DTG (AUC: 105.99±10.07 µg/h/mL) in the experimental Wistar rats when compared to the AUC of animals administered with physical mixture (54.45±6.58 µg/h/mL) and pure drug (49.27±6.16 µg/h/mL). Therefore, it could be concluded that the dissolution profile and simultaneously the bioavailability of DTG could be enhanced by means of the solid dispersion platform using the hydrophilic polymer, P407, which could be projected towards improved efficacy of the drug in HIV/AIDS.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Oxazinas/administração & dosagem , Oxazinas/farmacocinética , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Piridonas/administração & dosagem , Piridonas/farmacocinética , Animais , Fármacos Anti-HIV/uso terapêutico , Área Sob a Curva , Disponibilidade Biológica , Composição de Medicamentos , Liberação Controlada de Fármacos , Excipientes , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Masculino , Oxazinas/uso terapêutico , Piperazinas/uso terapêutico , Poloxâmero , Piridonas/uso terapêutico , Ratos , Ratos Wistar , Solubilidade , Difração de Raios X
19.
Epilepsy Behav ; 119: 107935, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33930626

RESUMO

PURPOSE: To explore the efficacy and tolerability of adjuvant perampanel (PER) and their associated risk factors in late add-on drug-resistant epilepsy. METHOD: Retrospective multicenter 'real-world' observational study. Consecutively identified patients commenced on PER, with mixed epilepsy syndromes, from nine Australian epilepsy centers. Primary efficacy endpoints were at least 50% reduction in seizure frequency (responders), seizure freedom, and retention at 6 and 12 months, following a 3-month titration period. Tolerability endpoints were cessation of PER for any reason, cessation of PER due to treatment-emergent adverse events (TEAE), or cessation due to inefficacy. Outcomes were assessed for a-priori risk factors associated with efficacy and tolerability. RESULTS: Three-hundred and eighty seven adults were identified and followed up for a median of 12.1 months (IQR 7.0-25.2). Focal epilepsy accounted for 79.6% (FE), idiopathic generalized epilepsy (IGE), 10.3% and developmental epileptic encephalopathy (DEE) 10.1%, of the cohort. All patients had drug-resistant epilepsy, 71.6% had never experienced six months of seizure freedom, and the mean number of antiepileptic medications (AEDs) prior to starting PER was six. At 12 months, with missing cases classified as treatment failure, retention was 40.0%, responder 21.7%, and seizure freedom 9.0%, whereas, using last outcome carried forward (LOCF), responder and seizure freedom rates were 41.3% and 14.7%, respectively. Older age of epilepsy onset was associated with a marginal increase in the likelihood of seizure freedom at 12-month maintenance (OR 1.04, 95% CI 1.02, 1.06). Male sex (adjusted OR [aOR] 2.06 95% CI 1.33, 3.19), lower number of prior AEDs (aOR 0.84, 95% CI 0.74, 0.96) and no previous seizure-free period of at least 6-month duration (aOR 2.04 95% CI 1.21, 3.47) were associated with retention. Perampanel combined with a GABA receptor AED was associated with a lower responder rate at 12 months but reduced cessation of PER. The most common TEAEs were neuropsychiatric (18.86%), followed by dizziness (13.70%), and sleepiness (5.68%). CONCLUSIONS: Adjuvant PER treatment, even in late-add on drug-resistant epilepsy is an effective and well-tolerated treatment for drug-resistant epilepsy.


Assuntos
Epilepsia Resistente a Medicamentos , Epilepsia Generalizada , Síndromes Epilépticas , Adulto , Idoso , Anticonvulsivantes/uso terapêutico , Austrália , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Quimioterapia Combinada , Epilepsia Generalizada/tratamento farmacológico , Síndromes Epilépticas/tratamento farmacológico , Humanos , Masculino , Piridonas/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
20.
Kardiologiia ; 61(3): 18-22, 2021 Mar 30.
Artigo em Russo | MEDLINE | ID: mdl-33849414

RESUMO

Aim        To evaluate the effectiveness of the decision-making module in selecting an oral anticoagulant for patients with atrial fibrillation.Material and methods        638 patients with atrial fibrillation aged 68.2±4.5 years were evaluated. The CHA2DS2-VASc, HAS-BLED, and 2MАСЕ scales, the creatinine clearance calculator, and the Morisky-Green questionnaire were used.Results   311 (48.75 %) patients had paroxysmal atrial fibrillation, 138 (21.6%) had persistent atrial fibrillation, 44 (22.7%) had long-standing persistent atrial fibrillation, and 145 (22.7 %) had permanent atrial fibrillation. Mean CHADS2­VASc scale score was 4.82; НAS-BLED scale score was 2.9; 2MACE score was 2.28; and compliance score was 3.52. 172 (26.9 %) patients were treated with rivaroxaban; 166 (26 %), with apixaban; 84 (13.2 %), with dabigatran; 210 (32.9 %), with warfarin; and 6 (1 %), with acetylsalicylic acid.Conclusion            The developed decision-making module is based on scientific justification of personalized selection of the oral anticoagulant and updates the knowledge on major issues of prescription.


Assuntos
Fibrilação Atrial , Acidente Vascular Cerebral , Administração Oral , Idoso , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/uso terapêutico , Humanos , Pessoa de Meia-Idade , Piridonas/uso terapêutico , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Varfarina/uso terapêutico
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