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1.
Medicine (Baltimore) ; 99(42): e22793, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33080751

RESUMO

RATIONALE: Thrombocytepenia, anasarca, fever, renal insufficiency, and organomegaly (TAFRO) syndrome is a novel disease entity characterized by a constellation of symptoms (thrombocytopenia, anasarca, fever, renal insufficiency, and organomegaly). Here, we describe the development of TAFRO syndrome-like features during the treatment of rheumatoid arthritis with a Janus kinase (JAK) inhibitor. PATIENT CONCERNS: In this report, a 74-year-old woman treated with a JAK inhibitor (tofacitinib) for rheumatoid arthritis was admitted because of fever and thrombocytopenia. DIAGNOSES: On laboratory examination, marked thrombocytopenia and elevated creatinine and C-reactive protein levels were present. A computed tomography scan revealed lymphadenopathy, hepato-splenomegaly, and anasarca. A left axillary lymph node biopsy revealed Castleman's disease-like features. These clinical features satisfied the proposed diagnostic criteria for TAFRO syndrome. Since autoimmune disorders should be excluded when diagnosing TAFRO syndrome, it is not strictly correct to diagnose her as TAFRO syndrome. Therefore, we diagnosed her as rheumatoid arthritis complicated by TAFRO syndrome-like features. INTERVENTIONS: The patient was treated with high-dose glucocorticoid, tacrolimus, eltrombopag, intravenous immunoglobulin, and rituximab. OUTCOMES: Her condition was refractory to the above-mentioned treatment, and she eventually died because of multi-organ failure 6 months after the first admission. LESSONS: TAFRO syndrome-like features can develop during treatment with a JAK inhibitor for rheumatoid arthritis. Patients with autoimmune diseases complicated by TAFRO syndrome-like features can follow a fatal clinical course, and thus, an intensive combined treatment is warranted for such patients, especially in cases refractory to glucocorticoid.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Hiperplasia do Linfonodo Gigante/induzido quimicamente , Inibidores de Janus Quinases/efeitos adversos , Piperidinas/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Trombocitopenia/induzido quimicamente , Idoso , Evolução Fatal , Feminino , Humanos , Insuficiência de Múltiplos Órgãos/etiologia
2.
J Cancer Res Ther ; 16(4): 919-921, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930141

RESUMO

An 84-year-old male had a recurrence after surgical resection against Stage IIIA pulmonary adenocarcinoma and was treated with crizotinib due to harboring the anaplastic lymphoma kinase fusion gene. The patient exhibited crizotinib-induced interstitial lung disease (ILD), and alectinib was administered because of progressive disease. However, ILD appeared in both lungs again after alectinib treatment. This is the first case of ILD, resulting from alectinib administration after crizotinib-induced ILD. We should pay careful attention to patients who are treated with alectinib after crizotinib-induced ILD.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Carbazóis/efeitos adversos , Crizotinibe/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Carbazóis/uso terapêutico , Crizotinibe/uso terapêutico , Humanos , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Piperidinas/uso terapêutico , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico
4.
Expert Opin Pharmacother ; 21(15): 1793-1798, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32735148

RESUMO

INTRODUCTION: Schizophrenia has a prevalence of approximately 1% in the general population, with 15.2 per 100,000 persons affected. Iloperidone is a second-generation antipsychotic drug approved for the treatment of schizophrenia in adults. It acts primarily by D2/5HT2a receptor antagonism, with greater affinity for the 5HT2a receptor than for the D2 receptor. AREAS COVERED: This article discusses iloperidone and aims to provide useful information for clinicians to determine which circumstances would best suit the use of iloperidone to treat schizophrenic patients. In this review, the authors briefly discuss schizophrenia and its treatment, before they discuss properties of iloperidone, its indications, approval process, and adverse effects. Finally, the authors review the specific strengths and weaknesses of the medication. EXPERT OPINION: Iloperidone would be an attractive option in patients who are particularly prone to EPS, or who are showing prominent negative symptoms, as well as cognitive deficits. Its availability only in an oral formulation makes it a better option for patients with good medication adherence, and though it could be useful in patients prone to weight gain or hepatic dysfunction on other second generation antipsychotics, it should be used with caution in patients prone to side effects related to alpha adrenergic blockade.


Assuntos
Antipsicóticos/uso terapêutico , Isoxazóis/uso terapêutico , Piperidinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Humanos , Isoxazóis/administração & dosagem , Isoxazóis/efeitos adversos , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Esquizofrenia/metabolismo , Ganho de Peso/efeitos dos fármacos
5.
Dermatol Online J ; 26(3)2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32609446

RESUMO

With recent advancements in the understanding of vitiligo pathogenesis, Janus kinase (JAK) inhibitors have emerged as a promising new treatment modality, but their effects remain incompletely elucidated. Tofacitinib, an oral JAK 1/3 inhibitor approved for the treatment of rheumatoid arthritis, has previously been shown to induce significant re-pigmentation in vitiligo. However, as with other novel targeted therapies, cutaneous adverse effects have been observed. We report a 36-year-old woman with a history of rheumatoid arthritis, refractory to multiple pharmacotherapies, who was initiated on tofacitinib and subsequently developed progressive depigmented patches consistent with new-onset vitiligo. Although definitive causation cannot be established in this case without additional studies, it is important to note that many targeted therapies have the potential to induce paradoxical effects, that is, the occurrence or exacerbation of pathologic conditions that have been shown to respond to these medications. Paradoxical findings with other targeted therapies include the occurrence of melanoma during treatment with BRAF inhibitors, keratoacanthomas with PD-1 inhibitors, vitiligo and psoriasis with TNF-alpha inhibitors, and hidradenitis suppurativa with various biologic agents. Although JAK inhibitors hold therapeutic promise in the treatment of inflammatory skin disorders, further research is warranted to more fully comprehend their effects.


Assuntos
Inibidores de Janus Quinases/efeitos adversos , Piperidinas/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Vitiligo/induzido quimicamente , Adulto , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Feminino , Hidradenite Supurativa/induzido quimicamente , Humanos , Inibidores de Janus Quinases/uso terapêutico , Ceratoacantoma/induzido quimicamente , Melanoma/induzido quimicamente , Piperidinas/uso terapêutico , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico
6.
J Headache Pain ; 21(1): 66, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503415

RESUMO

BACKGROUND: Migraine has been recognized as one of common diseases in the world whose current treatment options are not ideal. Lasmiditan, an oral 5-hydroxytryptamine (HT)1F receptor agonist, appears more promising for the acute treatment of migraine because of considerably better effect profiles with no severe adverse events (AEs). This review aimed to systematically evaluate the efficacy and safety of lasmiditan from the results of randomized controlled trials (RCTs). METHODS: PubMed, Cochrane Library, Embase were searched on lasmiditan for the acute treatment of migraine from inception of the databases to Feb 1, 2020. Pain free and pain relief, global impression (very much/much better), and no/mild disability at 2 h in efficacy; total treatment-emergent adverse events (TEAEs), dizziness, nausea, fatigue, paraesthesia and somnolence in safety were extracted from the included studies. A systematic review and meta-analysis was performed using Review Manager Software version 5.3 (RevMan 5.3). RESULTS: Four RCTs with a total of 4960 subjects met our inclusion criteria. The overall effect estimate showed that lasmiditan was significantly superior to placebo in terms of pain free (RR 1.71, 95% CI 1.55-1.87), pain relief (RR 1.40, 95% CI 1.33-1.47), global impression (very much/much better) (RR 1.55, 95% CI 1.44-1.67), and no/mild disability (RR 1.15, 95% CI 1.10-1.20) at 2 h. For the safety, significant number of patients experienced TEAEs with lasmiditan than with placebo (RR 2.77, 95% CI 2.53-3.03), most TEAEs were central nervous system (CNS)-related and included dizziness (RR 5.81, 95% CI 4.72-7.14), nausea (RR 2.58, 95% CI 1.87-3.57), fatigue (RR 5.38, 95% CI 3.78-7.66), paraesthesia (RR 4.48, 95% CI 3.33-6.02), and somnolence (RR 2.82, 95% CI 2.18-3.66). CONCLUSIONS: This meta-analysis suggests that lasmiditan is effective for the acute treatment of migraine with a higher incidence of CNS-related adverse reactions compared with placebo. Long-term, open-label, multi-dose trials are required to verify the current findings.


Assuntos
Benzamidas/uso terapêutico , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Receptores de Serotonina/fisiologia , Agonistas do Receptor de Serotonina/uso terapêutico , Benzamidas/efeitos adversos , Tontura/induzido quimicamente , Humanos , Náusea/induzido quimicamente , Piperidinas/efeitos adversos , Piridinas/efeitos adversos , Agonistas do Receptor de Serotonina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Vertigem/induzido quimicamente
9.
Lancet ; 395(10240): 1835-1844, 2020 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-32534646

RESUMO

BACKGROUND: IMspire150 aimed to evaluate first-line combination treatment with BRAF plus MEK inhibitors and immune checkpoint therapy in BRAFV600 mutation-positive advanced or metastatic melanoma. METHODS: IMspire150 was a randomised, double-blind, placebo-controlled phase 3 study done at 112 institutes in 20 countries. Patients with unresectable stage IIIc-IV, BRAFV600 mutation-positive melanoma were randomly assigned 1:1 to 28-day cycles of atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) or atezolizumab placebo, vemurafenib, and cobimetinib (control group). In cycle 1, all patients received vemurafenib and cobimetinib only; atezolizumab placebo was added from cycle 2 onward. Randomisation was stratified by lactate dehydrogenase concentration and geographical region. Blinding for atezolizumab was achieved by means of an identical intravenous placebo, and blinding for vemurafenib was achieved by means of a placebo tablet. The primary outcome was investigator-assessed progression-free survival. This trial (ClinicalTrials.gov, NCT02908672) is ongoing but no longer recruiting patients. FINDINGS: Between Jan 13, 2017, and April 26, 2018, 777 patients were screened and 514 were enrolled and randomly assigned to the atezolizumab group (n=256) or control group (n=258). At a median follow-up of 18·9 months (IQR 10·4-23·8), progression-free survival as assessed by the study investigator was significantly prolonged with atezolizumab versus control (15·1 vs 10·6 months; hazard ratio [HR] 0·78; 95% CI 0·63-0·97; p=0·025). Common treatment-related adverse events (>30%) in the atezolizumab and control groups were blood creatinine phosphokinase increased (51·3% vs 44·8%), diarrhoea (42·2% vs 46·6%), rash (40·9%, both groups), arthralgia (39·1% vs 28·1%), pyrexia (38·7% vs 26·0%), alanine aminotransferase increased (33·9% vs 22·8%), and lipase increased (32·2% vs 27·4%); 13% of patients in the atezolizumab group and 16% in the control group stopped all treatment because of adverse events. INTERPRETATION: The addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAFV600 mutation-positive advanced melanoma. FUNDING: F Hoffmann-La Roche and Genentech.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azetidinas/uso terapêutico , Melanoma/tratamento farmacológico , Piperidinas/uso terapêutico , Vemurafenib/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azetidinas/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Estadiamento de Neoplasias , Piperidinas/efeitos adversos , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas B-raf/genética , Vemurafenib/efeitos adversos
10.
Cochrane Database Syst Rev ; 6: CD012906, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32501595

RESUMO

BACKGROUND: Worldwide, there is an increasing incidence of type 2 diabetes mellitus (T2DM). Metformin is still the recommended first-line glucose-lowering drug for people with T2DM. Despite this, the effects of metformin on patient-important outcomes are still not clarified. OBJECTIVES: To assess the effects of metformin monotherapy in adults with T2DM. SEARCH METHODS: We based our search on a systematic report from the Agency for Healthcare Research and Quality, and topped-up the search in CENTRAL, MEDLINE, Embase, WHO ICTRP, and ClinicalTrials.gov. Additionally, we searched the reference lists of included trials and systematic reviews, as well as health technology assessment reports and medical agencies. The date of the last search for all databases was 2 December 2019, except Embase (searched up 28 April 2017). SELECTION CRITERIA: We included randomised controlled trials (RCTs) with at least one year's duration comparing metformin monotherapy with no intervention, behaviour changing interventions or other glucose-lowering drugs in adults with T2DM. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles/records, assessed risk of bias, and extracted outcome data independently. We resolved discrepancies by involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall certainty of the evidence by using the GRADE instrument. MAIN RESULTS: We included 18 RCTs with multiple study arms (N = 10,680). The percentage of participants finishing the trials was approximately 58% in all groups. Treatment duration ranged from one to 10.7 years. We judged no trials to be at low risk of bias on all 'Risk of bias' domains. The main outcomes of interest were all-cause mortality, serious adverse events (SAEs), health-related quality of life (HRQoL), cardiovascular mortality (CVM), non-fatal myocardial infarction (NFMI), non-fatal stroke (NFS), and end-stage renal disease (ESRD). Two trials compared metformin (N = 370) with insulin (N = 454). Neither trial reported on all-cause mortality, SAE, CVM, NFMI, NFS or ESRD. One trial provided information on HRQoL but did not show a substantial difference between the interventions. Seven trials compared metformin with sulphonylureas. Four trials reported on all-cause mortality: in three trials no participant died, and in the remaining trial 31/1454 participants (2.1%) in the metformin group died compared with 31/1441 participants (2.2%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on SAE: in two trials no SAE occurred (186 participants); in the other trial 331/1454 participants (22.8%) in the metformin group experienced a SAE compared with 308/1441 participants (21.4%) in the sulphonylurea group (very low-certainty evidence). Two trials reported on CVM: in one trial no CVM was observed and in the other trial 4/1441 participants (0.3%) in the metformin group died of cardiovascular reasons compared with 8/1447 participants (0.6%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on NFMI: in two trials no NFMI occurred, and in the other trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 15/1441 participants (1.0%) in the sulphonylurea group (very low-certainty evidence). One trial reported no NFS occurred (very low-certainty evidence). No trial reported on HRQoL or ESRD. Seven trials compared metformin with thiazolidinediones (very low-certainty evidence for all outcomes). Five trials reported on all-cause mortality: in two trials no participant died; the overall RR was 0.88, 95% CI 0.55 to 1.39; P = 0.57; 5 trials; 4402 participants). Four trials reported on SAE, the RR was 0,95, 95% CI 0.84 to 1.09; P = 0.49; 3208 participants. Four trials reported on CVM, the RR was 0.71, 95% CI 0.21 to 2.39; P = 0.58; 3211 participants. Three trial reported on NFMI: in two trials no NFMI occurred and in one trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 25/1456 participants (1.7%) in the thiazolidinedione group. One trial reported no NFS occurred. No trial reported on HRQoL or ESRD. Three trials compared metformin with dipeptidyl peptidase-4 inhibitors (one trial each with saxagliptin, sitagliptin, vildagliptin with altogether 1977 participants). There was no substantial difference between the interventions for all-cause mortality, SAE, CVM, NFMI and NFS (very low-certainty evidence for all outcomes). One trial compared metformin with a glucagon-like peptide-1 analogue (very low-certainty evidence for all reported outcomes). There was no substantial difference between the interventions for all-cause mortality, CVM, NFMI and NFS. One or more SAEs were reported in 16/268 (6.0%) of the participants allocated to metformin compared with 35/539 (6.5%) of the participants allocated to a glucagon-like peptide-1 analogue. HRQoL or ESRD were not reported. One trial compared metformin with meglitinide and two trials compared metformin with no intervention. No deaths or SAEs occurred (very low-certainty evidence) no other patient-important outcomes were reported. No trial compared metformin with placebo or a behaviour changing interventions. Four ongoing trials with 5824 participants are likely to report one or more of our outcomes of interest and are estimated to be completed between 2018 and 2024. Furthermore, 24 trials with 2369 participants are awaiting assessment. AUTHORS' CONCLUSIONS: There is no clear evidence whether metformin monotherapy compared with no intervention, behaviour changing interventions or other glucose-lowering drugs influences patient-important outcomes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Adulto , Carbamatos/efeitos adversos , Carbamatos/uso terapêutico , Doenças Cardiovasculares/mortalidade , Causas de Morte , Diabetes Mellitus Tipo 2/mortalidade , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/uso terapêutico , Metformina/efeitos adversos , Infarto do Miocárdio/epidemiologia , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/epidemiologia , Compostos de Sulfonilureia/efeitos adversos , Compostos de Sulfonilureia/uso terapêutico
11.
N Engl J Med ; 383(10): 931-943, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32469185

RESUMO

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


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Edema/induzido quimicamente , Éxons , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/genética , Piridazinas/efeitos adversos , Pirimidinas/efeitos adversos
12.
Clin Drug Investig ; 40(7): 603-615, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32399853

RESUMO

BACKGROUND AND OBJECTIVE: SUVN-G3031 is a novel, potent, and selective histamine-3 receptor (H3R) inverse agonist in development for the treatment of narcolepsy. Our objective was to characterize the safety, tolerability, and pharmacokinetics of SUVN-G3031 in healthy young adults after single and multiple doses, and to evaluate the effect of food, gender, and age on the pharmacokinetics. METHODS: A single ascending dose (SAD) and a multiple ascending dose (MAD) study for 14 days was conducted in healthy young adults using a randomized, double-blind study design. The effect of food, gender, and age on SUVN-G3031 pharmacokinetics (6 mg as a single dose) was evaluated using an open-label, two-period, randomized, crossover design in fed and fasted states. Pharmacokinetics and safety assessments were conducted throughout the study. RESULTS: Single doses of SUVN-G3031 up to 20 mg and multiple doses up to 6 mg once daily were found to be safe and well tolerated in healthy young adults. The most frequently reported adverse events were abnormal dreams, dyssomnia, and hot flushes. SUVN-G3031 exposure was dose proportional across the tested doses. Steady state was achieved on day 6 after once-daily dosing. Renal excretion (~ 60%) of unchanged SUVN-G3031 was the major route of elimination. Food, gender, and age did not have any clinically meaningful effect on SUVN-G3031 exposure. CONCLUSION: SUVN-G3031 was found to be safe and well tolerated in healthy human subjects without any effect of age, gender, and food on the pharmacokinetics and safety profile. Clinical Trials Registration (https://clinicaltrials.gov): NCT04072380 and NCT02342041.


Assuntos
Morfolinas/efeitos adversos , Narcolepsia/tratamento farmacológico , Piperidinas/efeitos adversos , Administração Oral , Adulto , Estudos Cross-Over , Método Duplo-Cego , Agonismo Inverso de Drogas , Feminino , Voluntários Saudáveis , Histamina , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/farmacocinética , Piperidinas/farmacocinética
16.
Jpn J Clin Oncol ; 50(8): 859-866, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32328660

RESUMO

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


Assuntos
Grupo com Ancestrais do Continente Asiático , Neoplasias/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Feminino , Humanos , Japão , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/sangue , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-met/metabolismo , Piridazinas/efeitos adversos , Piridazinas/farmacocinética , Piridazinas/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Pirimidinas/farmacologia
18.
Gynecol Oncol ; 157(2): 500-507, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32173049

RESUMO

BACKGROUND: Olaparib was approved on December 19, 2014 by the US FDA as 4th-line therapy (and beyond) for patients with germline BRCA1/2 mutations; rucaparib was approved on December 19, 2016 as 3rd-line therapy (and beyond) for germline or somatic BRCA1/2-mutated recurrent disease. On October 23, 2019, niraparib was approved for treatment of women with damaging mutations in BRCA1/2 or other homologous recombination repair genes who had been treated with three or more prior regimens. We compared the cost-effectiveness of PARPi(s) with intravenous regimens for platinum-resistant disease. METHODS: Median progression-free survival (PFS) and toxicity data from regulatory trials were incorporated in a model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2017, each PARPi(s) was compared separately to non­platinum-based and bevacizumab-containing regimens. Costs of IV drugs, managing toxicities, infusions, and supportive care were estimated using 2017 Medicare data. Incremental cost-effectiveness ratios (ICERs) were calculated and PFS was reported in quality adjusted life months for platinum-resistant populations. RESULTS: Non­platinum-based intravenous chemotherapy was most cost effective ($6,412/PFS-month) compared with bevacizumab-containing regimens ($12,187/PFS-month), niraparib ($18,970/PFS-month), olaparib ($16,327/PFS-month), and rucaparib ($16,637/PFS-month). ICERs for PARPi(s) were 3-3.5× times greater than intravenous non­platinum-based regimens. CONCLUSION: High costs of orally administered PARPi(s) were not mitigated or balanced by costs of infusion and managing toxicities of intravenous regimens typically associated with lower response and shorter median PFS. Balancing modest clinical benefit with costs of novel therapies remains problematic and could widen disparities among those with limited access to care.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/economia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/economia , Administração Oral , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Bevacizumab/economia , Carcinoma Epitelial do Ovário/economia , Análise Custo-Benefício , Custos de Medicamentos , Feminino , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Indazóis/economia , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/economia , Infusões Intravenosas , Cadeias de Markov , Modelos Estatísticos , Recidiva Local de Neoplasia/economia , Neoplasias Ovarianas/economia , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Ftalazinas/economia , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperazinas/economia , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/economia , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Qualidade de Vida , Estados Unidos
20.
Sci Rep ; 10(1): 2585, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066817

RESUMO

Polypharmacology plays an important role in defining response and adverse effects of drugs. For some mechanisms, experimentally mapping polypharmacology is commonplace, although this is typically done within the same protein class. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. Here, we report the first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable, submicromolar concentrations. These kinases represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic. Moreover, broad kinome profiling is recommended for the development of PARP inhibitors as PARP-kinase polypharmacology could potentially be exploited to modulate efficacy and side-effect profiles.


Assuntos
Antineoplásicos/química , Indazóis/química , Indóis/química , Ftalazinas/química , Piperazinas/química , Piperidinas/química , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/química , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Sítios de Ligação , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Células HEK293 , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Indóis/administração & dosagem , Indóis/efeitos adversos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/patologia , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Polifarmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Especificidade por Substrato
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