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1.
Expert Opin Investig Drugs ; 29(1): 15-21, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31847605

RESUMO

Introduction: Selinexor is a first-in-class, oral therapeutic that selectively inhibits nuclear export. It has received fast track designation from the FDA for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) recently, and continues to be evaluated as a potential treatment for DLBCL.Area covered: This article reviews the available data from clinical trials regarding the efficacy of selinexor in DLBCL and highlights the key toxicity issues and how they may best be managed. Ongoing and future studies in DLBCL are also discussed.Expert opinion: More translational studies are necessary to leverage the unique mechanism action and rationally inform the use of selinexor in combination strategies. There are several different genetic subtypes of DLBCL, but it is not clear if these classifications will identify patients that may benefit from targeted therapies. The broad potential mechanism of action of selinexor will require careful analysis to inform predictive or prognostic biomarkers. Further evaluation of selinexor in combination with standard lymphoma regimens could identify deliverable promising regimens. Future randomized trials are key for registration and to determine the optimal role for this first-in-class agent.


Assuntos
Antineoplásicos/administração & dosagem , Hidrazinas/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Triazóis/administração & dosagem , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Humanos , Hidrazinas/efeitos adversos , Hidrazinas/farmacologia , Linfoma Difuso de Grandes Células B/patologia , Terapia de Alvo Molecular , Triazóis/efeitos adversos , Triazóis/farmacologia
2.
Expert Opin Drug Saf ; 18(11): 1109-1118, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31478753

RESUMO

Objectives: Suvorexant is a dual orexin receptor antagonist used for treating insomnia. The authors elucidated the safety profiles and clinical course of insomnia therapy with suvorexant under different initial treatment status seen in daily routine practice. Methods: Subgroup analysis of a post-marketing survey (PMS; 2015-2017) divided patients based on their initial treatment status with suvorexant into 'hypnotic-naïve (Group N)', 'switching from a prior sleep medication (Group S),' 'add-on therapy (Group A),' and 'others (Group O).' Results: Among 3248 patients analyzed in the PMS, the number of patients in Groups N, S, A, and O was 1946 (59.9%), 703 (21.6%), 536 (16.5%), and 63 (1.9%), respectively. The incidence of insomnia-related adverse drug reactions (ADRs) in Group S (5.3%) tended to be higher than that in Groups N (0.46%) and A (1.5%). Discontinuation rate due to an inadequate effect at 6 months in Group S (14.9%) tended to be higher than that in Groups N (9.6%) and A (10.4%). Conclusion: The results suggest that initiating suvorexant treatment after switching from other insomnia medication must require careful monitoring of insomnia-related ADRs, which might be due to abrupt discontinuation of the prior insomnia medication use.


Assuntos
Azepinas/uso terapêutico , Antagonistas dos Receptores de Orexina/uso terapêutico , Medicamentos Indutores do Sono/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/uso terapêutico , Idoso , Azepinas/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Orexina/efeitos adversos , Vigilância de Produtos Comercializados , Estudos Prospectivos , Medicamentos Indutores do Sono/efeitos adversos , Inquéritos e Questionários , Resultado do Tratamento , Triazóis/efeitos adversos
3.
N Engl J Med ; 381(8): 727-738, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31433920

RESUMO

BACKGROUND: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options. METHODS: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point. RESULTS: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients. CONCLUSIONS: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Hidrazinas/administração & dosagem , Carioferinas/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/administração & dosagem , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/sangue , Dexametasona/efeitos adversos , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Hidrazinas/efeitos adversos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Trombocitopenia/induzido quimicamente , Triazóis/efeitos adversos , Adulto Jovem
4.
Clin Drug Investig ; 39(11): 1109-1116, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31432392

RESUMO

BACKGROUND AND OBJECTIVES: New intravenous and solid oral formulations of the antifungal agent posaconazole have been developed. This randomized, open-label, crossover study in 18 healthy adult Chinese male and female subjects evaluated the pharmacokinetics of single-dose posaconazole (oral 300-mg posaconazole tablet fasted, intravenous 300-mg posaconazole solution fasted, and oral 300-mg posaconazole tablet with standard high-fat breakfast). Primary objectives were to determine the single-dose pharmacokinetics of posaconazole in healthy Chinese subjects when administered as an intravenous solution and as an oral tablet under fasted conditions and the effect of food on the absorption of posaconazole. METHODS: The three treatments consisted of the following: a single oral dose of posaconazole 300 mg (fasted), a single oral dose of posaconazole 300 mg (high-fat breakfast), and a single intravenous dose of posaconazole 300 mg (fasted). Blood samples for pharmacokinetic analysis were collected before dosing and at regular intervals after dosing. Adverse events were monitored throughout. The pharmacokinetic population included the per-protocol population. The safety population included all subjects who received one or more doses of the study drug. RESULTS: Time to maximum plasma concentration of intravenous posaconazole coincided with the end of infusion; the half-life (t½) was 25.76 h. Geometric mean (% coefficient of variation) values of area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) and maximum plasma concentration (Cmax) were 59,925 (36.2%) h·ng/mL and 3999 (28.5%) ng/mL, respectively. The posaconazole tablet had a time to maximum plasma concentration of 4 h and a t½ of 25.21 h after fasting. Geometric mean (coefficient of variation) values of AUC0-∞ and Cmax were 25,263 (39.9%) h·ng/mL and 674.5 (29.6%) ng/mL, respectively. Standard high-fat breakfast increased the exposure of posaconazole approximately twofold with geometric mean ratios (high-fat breakfast/fasted) for AUC0-∞ and Cmax of 2.06 (90% confidence interval 1.86-2.30) and 1.95 (90% confidence interval 1.65-2.31), respectively. The geometric mean absolute bioavailability of the tablet formulation was 42.2% in the fasted state and 87.1% under high-fat breakfast conditions. The most commonly reported adverse events were nausea, vomiting, dizziness, and first-degree atrioventricular block for intravenous posaconazole 300 mg and nausea for oral posaconazole 300 mg (high-fat breakfast). All adverse events were mild and resolved without sequelae. CONCLUSIONS: Posaconazole was generally well tolerated in healthy Chinese male and female subjects. The safety and the high-fat breakfast and fasted pharmacokinetics of posaconazole in healthy Chinese subjects are within exposures demonstrated to be generally well tolerated and efficacious and compare reasonably well with the overall posaconazole data across Western countries.


Assuntos
Antifúngicos/efeitos adversos , Antifúngicos/farmacocinética , Jejum/fisiologia , Interações Alimento-Droga/fisiologia , Triazóis/efeitos adversos , Triazóis/farmacocinética , Administração Intravenosa , Administração Oral , Adulto , Antifúngicos/administração & dosagem , Estudos Cross-Over , Dieta Hiperlipídica , Feminino , Voluntários Saudáveis , Humanos , Masculino , Náusea/induzido quimicamente , Náusea/diagnóstico , Comprimidos , Triazóis/administração & dosagem , Adulto Jovem
5.
JAMA ; 322(4): 315-325, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31334793

RESUMO

Importance: Patients with active rheumatoid arthritis (RA) despite treatment with biologic disease-modifying antirheumatic drug (bDMARD) therapy need treatment options. Objective: To evaluate the effects of filgotinib vs placebo on the signs and symptoms of RA in a treatment-refractory population. Design, Setting, and Participants: A 24-week, randomized, placebo-controlled, multinational phase 3 trial conducted from July 2016 to June 2018 at 114 sites internationally, randomizing 449 adult patients (and treating 448) with moderately to severely active RA and inadequate response/intolerance to 1 or more prior bDMARDs. Interventions: Filgotinib, 200 mg (n = 148); filgotinib, 100 mg (n = 153); or placebo (n = 148) once daily; patients continued concomitant stable conventional synthetic DMARDs (csDMARDs). Main Outcomes and Measures: The primary end point was the proportion of patients who achieved 20% improvement in the American College of Rheumatology criteria (ACR20) at week 12. Secondary outcomes included week 12 assessments of low disease activity (disease activity score in 28 joints-C-reactive protein [DAS28-CRP] ≤3.2) and change in Health Assessment Questionnaire-Disability Index, 36-Item Short-Form Health Survey Physical Component, and Functional Assessment of Chronic Illness Therapy-Fatigue scores, as well as week 24 assessment of remission (DAS28-CRP <2.6) and adverse events. Results: Among 448 patients who were treated (mean [SD] age, 56 [12] years; 360 women [80.4%]; mean [SD] DAS28-CRP score, 5.9 [0.96]; 105 [23.4%] with ≥3 prior bDMARDs), 381 (85%) completed the study. At week 12, more patients receiving filgotinib, 200 mg (66.0%) or 100 mg (57.5%), achieved ACR20 response (placebo, 31.1%; difference vs placebo: 34.9% [95% CI, 23.5%-46.3%] and 26.4% [95% CI, 15.0%-37.9%], respectively; both P < .001), including among patients with prior exposure to 3 or more bDMARDs (70.3%, 58.8%, and 17.6%, respectively; difference vs placebo: 52.6% [95% CI, 30.3%-75.0%] for filgotinib, 200 mg, and 41.2% [95% CI, 17.3%-65.0%] for filgotinib, 100 mg; both P < .001). The most common adverse events were nasopharyngitis (10.2%) for filgotinib, 200 mg; headache, nasopharyngitis, and upper respiratory infection (5.9% each) for filgotinib, 100 mg; and RA (6.1%) for placebo. Four uncomplicated herpes zoster cases and 1 retinal vein occlusion were reported with filgotinib; there were no opportunistic infections, active tuberculosis, malignancies, gastrointestinal perforations, or deaths. Conclusions and Relevance: Among patients with active RA who had an inadequate response or intolerance to 1 or more bDMARDs, filgotinib, 100 mg daily or 200 mg daily, compared with placebo resulted in a significantly greater proportion achieving a clinical response at week 12. However, further research is needed to assess longer-term efficacy and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02873936.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Adulto , Idoso , Antirreumáticos/efeitos adversos , Biomarcadores/sangue , Proteína C-Reativa/análise , Relação Dose-Resposta a Droga , Método Duplo-Cego , Tolerância a Medicamentos , Feminino , Testes Hematológicos , Humanos , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Indução de Remissão , Índice de Gravidade de Doença , Triazóis/administração & dosagem , Triazóis/efeitos adversos
6.
Crit Care ; 23(1): 205, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171022

RESUMO

BACKGROUND: The population pharmacokinetics of total and unbound posaconazole following intravenous administration has not yet been described for the critically ill patient population. The aim of this work was, therefore, to describe the total and unbound population pharmacokinetics of intravenous posaconazole in critically ill patients and identify optimal dosing regimens. METHODS: This was a prospective observational population pharmacokinetic study in critically ill adult patients with presumed/confirmed invasive fungal infection. A single dose of 300 mg posaconazole was administered intravenously as an add-on to standard antifungal therapy, and serial plasma samples were collected over 48 h. Total and unbound posaconazole concentrations, measured by chromatographic method, were used to develop a population pharmacokinetic model and perform dosing simulations in R using Pmetrics. RESULTS: From eight patients, 93 pairs of total and unbound concentrations were measured. A two-compartment linear model with capacity-limited plasma protein binding best described the concentration-time data. Albumin and body mass index (BMI) were included as covariates in the final model. Mean (SD) parameter estimates for the volume of the central compartment (V) and the elimination rate constant were 72 (43) L and 42.1 (23.7) h-1, respectively. Dosing simulations showed that high BMI was associated with a reduced probability of achieving target total and unbound posaconazole concentrations. Low serum albumin concentration was associated with a reduced probability of attaining target total but not unbound posaconazole concentrations. CONCLUSIONS: An important clinical message of this study is that critically ill patients with increased BMI may require larger than approved loading doses of intravenous posaconazole when considering currently recommended dosing targets. Variability in plasma albumin concentration appears unlikely to affect dosing requirements when the assessment is based on unbound concentrations. Where available, therapeutic drug monitoring of unbound concentrations may be useful.


Assuntos
Plasma/química , Triazóis/farmacocinética , Administração Intravenosa , Adulto , Albuminas/análise , Antifúngicos/efeitos adversos , Antifúngicos/farmacocinética , Índice de Massa Corporal , Estado Terminal/terapia , Feminino , Humanos , Unidades de Terapia Intensiva/organização & administração , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Plasma/efeitos dos fármacos , Estudos Prospectivos , Ligação Proteica , Índice de Gravidade de Doença , Triazóis/efeitos adversos
7.
J Dermatol ; 46(8): 641-651, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31206779

RESUMO

We evaluated the efficacy of efinaconazole 10% topical solution in long-term use, for up to 72 weeks, for onychomycosis, including severe cases. Among 605 participants, 219 patients diagnosed as having onychomycosis were evaluated for the efficacy of efinaconazole. The treatment success rate (<10% clinical involvement of the target toenail) at the final assessment time point was 56.6%, the complete cure rate was 31.1% and the mycological cure rate was 61.6%, all of which increased over time, demonstrating that continuous application contributed to the improvement of cure rate. Even in severe cases, reduction of the affected nail area was observed, showing the potential efficacy of the treatment. Responses to a quality of life questionnaire among patients with onychomycosis, OnyCOE-t, suggested that efinaconazole treatment improved the patients' quality of life. The incidence of adverse drug reaction in the patients eligible for the assessment was 6.3%, and this developed only in the administration site in all cases. No systemic adverse event was observed. In addition, no increase in the incidence of adverse drug reaction due to long-term use was found. Efinaconazole therapy was proved to exhibit excellent balance between efficacy and safety, and thus may serve as a useful treatment option for onychomycosis.


Assuntos
Antifúngicos/administração & dosagem , Dermatoses do Pé/tratamento farmacológico , Onicomicose/tratamento farmacológico , Triazóis/administração & dosagem , Administração Tópica , Idoso , Antifúngicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Dermatoses do Pé/diagnóstico , Humanos , Incidência , Assistência de Longa Duração/métodos , Masculino , Pessoa de Meia-Idade , Onicomicose/diagnóstico , Qualidade de Vida , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Triazóis/efeitos adversos
8.
J Pharmacol Exp Ther ; 370(1): 127-136, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31085697

RESUMO

AZD8871 is a novel muscarinic antagonist and ß 2-adrenoceptor agonist in development for chronic obstructive pulmonary disease. This study describes the pharmacological profile of AZD8871 in in vitro and in vivo assays. AZD8871 is potent at the human M3 receptor (pIC50 in binding assays: 9.5) and shows kinetic selectivity for the M3 (half-life: 4.97 hours) over the M2 receptor (half-life: 0.46 hour). It is selective for the ß 2-adrenoceptor over the ß 1 and ß 3 subtypes (3- and 6-fold, respectively) and shows dual antimuscarinic and ß 2-adrenoceptor functional activity in isolated guinea pig tissue (pIC50 in electrically stimulated trachea: 8.6; pEC50 in spontaneous tone isolated trachea: 8.8, respectively), which are sustained over time. AZD8871 exhibits a higher muscarinic component than batefenterol in human bronchi, with a shift in potency under propranolol blockade of 2- and 6-fold, respectively, together with a persisting relaxation (5.3% recovery at 8 hours). Nebulized AZD8871 prevents acetylcholine-induced bronchoconstriction in both guinea pig and dog with minimal effects on salivation and heart rate at doses with bronchoprotective activity. Moreover, AZD8871 shows long-lasting effects in dog, with a bronchoprotective half-life longer than 24 hours. In conclusion, these studies demonstrate that AZD8871 is a dual-acting molecule with a high muscarinic component and a long residence time at the M3 receptor; moreover, its preclinical profile in animal models suggests a once-daily dosing in humans and a favorable safety profile. Thus, AZD8871 has the potential to be a next generation of inhaled bronchodilators in respiratory diseases.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/farmacologia , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Receptor Muscarínico M3/antagonistas & inibidores , Receptores Adrenérgicos beta 2/metabolismo , Segurança , Triazóis/efeitos adversos , Triazóis/farmacologia , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Animais , Brônquios/efeitos dos fármacos , Brônquios/fisiologia , Sistema Cardiovascular/efeitos dos fármacos , Cães , Cobaias , Humanos , Masculino , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacocinética , Quinolinas/administração & dosagem , Quinolinas/farmacocinética , Receptor Muscarínico M2/metabolismo , Distribuição Tecidual , Traqueia/efeitos dos fármacos , Traqueia/fisiologia , Triazóis/administração & dosagem , Triazóis/farmacocinética
9.
PLoS One ; 14(3): e0212837, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30913226

RESUMO

BACKGROUND: Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia. METHODS: This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to <18 years; AG2, 2 to <7 years; and AG3, 3 months to <2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7-28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL. RESULTS: The percentage of subjects meeting the PK target was <90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to <7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to <18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to <18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects' underlying diseases. CONCLUSION: The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01716234.


Assuntos
Antifúngicos/farmacocinética , Área Sob a Curva , Hospedeiro Imunocomprometido , Triazóis/farmacocinética , Administração Oral , Adolescente , Fatores Etários , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Antineoplásicos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Lactente , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/imunologia , Infecções Fúngicas Invasivas/prevenção & controle , Masculino , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamente , Neutropenia/complicações , Neutropenia/imunologia , Estudos Prospectivos , Triazóis/administração & dosagem , Triazóis/efeitos adversos
10.
Drug Des Devel Ther ; 13: 809-816, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30880914

RESUMO

Purpose: Although patients with suspected obstructive sleep apnea (OSA) might suffer difficulty in falling asleep during overnight polysomnography (PSG), standard hypnotics to obtain sleep during PSG have not been established. The aim of this study was to investigate the safety and efficacy of a new hypnotic agent, suvorexant, a dual orexin receptor antagonist, for insomnia in suspected OSA patients during in-laboratory PSG. Patients and methods: An observational study was conducted during PSG for 149 patients with suspected OSA who had no insomnia at home. Patients with difficulty in falling asleep during PSG were optionally permitted to take single-use suvorexant. Patients with residual severe insomnia (>1 hour) after taking suvorexant were permitted to take an add-on use zolpidem. Clinical data and sleep questionnaire results were analyzed between a no insomnia group (without hypnotics) and an insomnia group (treated with suvorexant). Results: Among 84 patients who experienced insomnia during PSG and required hypnotics (the insomnia group; treated with suvorexant), 44 (52.4%) achieved sufficient subjective sleep with single-use of suvorexant, while the other 40 (47.6%) required suvorexant plus zolpidem. An apnea hypopnea index (AHI) of ≥5 was observed in 144 out of 149 patients with predominantly obstructive respiratory events. Among those patients, 70.8% in the no insomnia group and 63.1% in the insomnia group had severe OSA. Regarding both subjective sleep time and morning mood, significant differences between the no insomnia group and the insomnia group were not observed. No patient taking suvorexant had an adverse event, such as delirium or falling. Conclusion: Single-use suvorexant seems to be a safe and effective (but mild) hypnotic agent for suspected OSA patients with insomnia during in-laboratory PSG.


Assuntos
Azepinas/administração & dosagem , Azepinas/uso terapêutico , Polissonografia/métodos , Medicamentos Indutores do Sono/administração & dosagem , Medicamentos Indutores do Sono/uso terapêutico , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/diagnóstico , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/administração & dosagem , Triazóis/uso terapêutico , Azepinas/efeitos adversos , Humanos , Medicamentos Indutores do Sono/efeitos adversos , Triazóis/efeitos adversos
11.
Drugs ; 79(5): 531-541, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30868398

RESUMO

Cardiovascular disease affects more than 90 million Americans. Recent studies support an increased cardiovascular disease risk in inflammatory conditions, such as gout. Increased serum urate levels, or hyperuricemia, are a precursor to gout. Data from meta-analyses have shown hyperuricemia to be linked to hypertension and coronary heart disease. Similarly, gout has been associated with an increased risk of myocardial infarction, cerebrovascular accidents, and death from cardiovascular disease in randomized clinical trials. Urate-lowering therapy reduces serum urate and may decrease systemic inflammation, generation of oxidative species, and reverses endothelial dysfunction through hyperuricemia-dependent or hyperuricemia-independent pathways. Cardioprotective benefits of allopurinol, a first-line agent for the treatment of gout, have been demonstrated to potentially prevent myocardial infarction, stroke, atrial fibrillation, and other cardiovascular diseases in observational studies in select populations. Randomized controlled trials (RCTs) have also examined the role of newer urate-lowering therapies, such as febuxostat and lesinurad, and their risk of cardiovascular-specific mortality in comparison to allopurinol. A large post-marketing study of febuxostat vs. allopurinol showed higher all-cause and cardiovascular-specific mortality in the febuxostat group than in the allopurinol group; a major study limitation was that large numbers of patients were lost to follow-up or discontinued treatment. RCTs are required to assess the comparative effectiveness of urate-lowering therapies, validate findings of observational studies, and to determine which subgroup populations of gout are most likely to benefit from appropriate long-term urate-lowering therapy. This review examines the data for increased cardiovascular disease in gout and potential underlying mechanisms (including hyperuricemia, inflammation, endothelial dysfunction, oxidative stress) and the effect of urate-lowering therapy on cardiovascular disease.


Assuntos
Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Gota/complicações , Gota/tratamento farmacológico , Ácido Úrico/antagonistas & inibidores , Alopurinol/efeitos adversos , Alopurinol/uso terapêutico , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/uso terapêutico , Febuxostat/efeitos adversos , Febuxostat/uso terapêutico , Feminino , Supressores da Gota/uso terapêutico , Humanos , Hiperuricemia/complicações , Hiperuricemia/tratamento farmacológico , Masculino , Tioglicolatos/efeitos adversos , Tioglicolatos/uso terapêutico , Resultado do Tratamento , Triazóis/efeitos adversos , Triazóis/uso terapêutico
12.
Future Microbiol ; 14: 477-488, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30874453

RESUMO

Aim: Posaconazole (POS) is an extended-spectrum triazole approved for treatment of refractory invasive fungal disease. Outcome analysis of POS salvage therapy is of great clinical significance. Methods: We retrospectively reviewed data for 113 patients who received POS oral suspension as salvage therapy between December 2013 and May 2018. Results: Cumulative success rate at 12 weeks was 53.1% (60/113) with a rapid increase within the first 3-4 weeks and a plateau at 6 weeks after POS initiation. Multivariate logistic regression analysis showed that disseminated infection, prolonged neutropenia, severe graft-versus-host disease and high-dose steroid use were independent risk factors of response. Conclusion: POS oral suspension is effective as a salvage therapy for invasive fungal disease.


Assuntos
Antifúngicos/uso terapêutico , Doenças Hematológicas/complicações , Infecções Fúngicas Invasivas/complicações , Infecções Fúngicas Invasivas/tratamento farmacológico , Terapia de Salvação , Triazóis/uso terapêutico , Adolescente , Adulto , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento , Triazóis/efeitos adversos , Adulto Jovem
13.
Mycoses ; 62(6): 534-541, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30851214

RESUMO

BACKGROUND: Isavuconazole use in the real-world setting has not been extensively described. Subgroups of patients with particular prognostic significance, such as previous triazole prophylaxis or treatment and the important subgroup treated empirically for invasive fungal infection, have beforehand been excluded from trials. OBJECTIVES: We aimed to determine treatment response and safety in these patients at a large US transplant and cancer centre. PATIENTS/METHODS: We conducted a retrospective cohort study of all adult inpatients administered ≥3 doses of isavuconazole between June 2015 and October 2017. RESULTS: Ninety-one adults were identified. Six (7%) received primary prophylaxis, 10 (11%) treatment then secondary prophylaxis and 75 (82%) treatment only. Overall treatment response was 62%. Six-week mortality was 24%. Sixty-three per cent of 32 patients treated with isavuconaozle following prophylaxis with another antifungal agent exhibited a treatment response. Among 49 patients switched from treatment with another agent, 53% had a treatment response. Thirty-four patients received isavuconazole empirically, and 65% demonstrated a treatment response. Individuals given isavuconazole prophylaxis developed no breakthrough invasive fungal infections. One patient discontinued isavuconazole due to hepatotoxicity. CONCLUSIONS: Real-world isavuconazole use appears safe and is associated with treatment responses in varied patients including critically important subgroups previously unreported.


Assuntos
Antifúngicos/uso terapêutico , Quimioprevenção/métodos , Micoses/tratamento farmacológico , Micoses/prevenção & controle , Nitrilos/uso terapêutico , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Centros Médicos Acadêmicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/efeitos adversos , Substituição de Medicamentos/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilos/efeitos adversos , Piridinas/efeitos adversos , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Triazóis/efeitos adversos , Estados Unidos
14.
Mycoses ; 62(6): 526-533, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30864238

RESUMO

BACKGROUND: Posaconazole (PCZ) is used mainly for the prevention of invasive fungal infection (IFI). METHODS: A multicentre retrospective, investigational study using a non-randomized, single-arm design carried out in six tertiary hospitals in Spain to evaluate the use of PCZ in different forms of administration in the (non-prophylactic) treatment of IFI. RESULTS: Over an eight-year-period, 67 patients were included in this study. PCZ was administered as salvage therapy (intolerant or refractory to a previous antifungal agent) in 65/67 (97%); of these, it was used against Aspergillosis (68.6%), Zygomycosis (13.4%), other moulds (8.9%) and yeast (10.5%). The median duration of PCZ therapy was 75 days. The oral solution was associated with low serum levels (<0.7 mg/L) in 63% of available patients. Clinical response at 3 and 12 months of PCZ therapy were for aspergillosis: 47.8% and 41.3%; for zygomycosis: 55.5% and 55.5%; and for other mycoses: 69.2% and 69.2%, respectively. Suspension by toxicity was only observed in 6% and 7.5% of patients at 3 and 12 months, respectively, mainly with grade III/IV elevations of liver function test (LFTs). CONCLUSIONS: Posaconazole salvage therapy, especially oral tablets, can be an effective alternative option for patients with IFI who cannot tolerate or do not respond to other antifungal therapies.


Assuntos
Antifúngicos/administração & dosagem , Micoses/tratamento farmacológico , Terapia de Salvação/métodos , Triazóis/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/efeitos adversos , Antifúngicos/farmacocinética , Análise Química do Sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Espanha , Centros de Atenção Terciária , Resultado do Tratamento , Triazóis/efeitos adversos , Triazóis/farmacocinética , Suspensão de Tratamento/estatística & dados numéricos
15.
Transpl Infect Dis ; 21(3): e13067, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30866168

RESUMO

BACKGROUND: Lung transplant recipients are prone to invasive fungal infections prompting many transplant centers to use prolonged triazole antifungal prophylaxis. From a practical standpoint, it is unclear if lung transplant recipients are able to continue prolonged or lifelong prophylaxis without premature discontinuation from side effects, drug interactions, development of fungal disease, or medication cost. We examined the number of patients that are able to reach a prophylactic endpoint and understand the reasons for early termination. METHODS: We conducted a retrospective chart review of all lung and heart-lung transplant patients at Mayo Clinic Rochester from May 1, 2002 to December 31, 2017. Type, duration, and reason for discontinuation of triazole prophylaxis were examined. RESULTS: During the study period, 193 patients underwent lung or heart-lung transplantation. Itraconazole, voriconazole, and posaconazole were given to 180, 73, and 60 post-transplant patients, respectively. Providers switched itraconazole to another prophylactic antifungal medication for reasons other than prophylactic completion in 61.8% (126 out of 204) of exposure episodes; this was similar with voriconazole (68.8%, 53 out of 77, P = 0.41). Posaconazole was actively discontinued significantly less often (18.3%, 11 out of 60, P < 0.05). The most common reasons for discontinuing itraconazole were malabsorption (15.5% of exposure episodes) and concern for breakthrough fungal infection (10.2%). In comparison, the most common reason for voriconazole discontinuation was side effect or intolerance (54.5% of VR exposure episodes vs 9.8% of IT exposure episodes, P < 0.05). CONCLUSIONS: Itraconazole and posaconazole appeared to have fewer side effects prompting discontinuation than voriconazole, but itraconazole was discontinued more often because of malabsorption and clinical suspicion of fungal infections.


Assuntos
Antifúngicos/efeitos adversos , Transplante de Pulmão/efeitos adversos , Adesão à Medicação/estatística & dados numéricos , Micoses/prevenção & controle , Triazóis/efeitos adversos , Triazóis/uso terapêutico , Adulto , Idoso , Antifúngicos/uso terapêutico , Interações de Medicamentos , Feminino , Humanos , Infecções Fúngicas Invasivas/prevenção & controle , Itraconazol/efeitos adversos , Itraconazol/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Voriconazol/efeitos adversos , Voriconazol/uso terapêutico
16.
Int J Clin Pract ; 73(5): e13333, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30810253

RESUMO

OBJECTIVES: Solithromycin is a new monotherapy option for community-acquired bacterial pneumonia (CABP) patients. However, the efficacy and safety of solithromycin monotherapy for the treatment of CABP remains controversial. The aim of this meta-analysis was to evaluate the role that solithromycin played in the treatment of CABP. METHODS: We systematically retrieved randomised controlled trials (RCTs) compared solithromycin with other antibiotics in the treatment of CABP, which were published on PubMed, ScienceDirect, Cochrane libary and the Clinical Trials.gov before July 2018. Ultimately, a meta-analysis of all RCTs eligible for inclusion criteria was performed. RESULTS: Three RCTs, comprising 1855 patients, were included in the meta-analysis. There were no statistically significant differences between patients given solithromycin and those given other antibiotics with regard to early clinical response (ECR) [1855 patients, odds ratio (OR) = 1.00, 95% confidence interval (CI) 0.80 to 1.24, P = 0.99] and clinical success rates at short-term follow-up (SFU) (1855 patients, OR = 0.78, 95% CI 0.60 to 1.01, P = 0.06) in the intention-to-treat (ITT) population, as were the ECR (787 patients, OR = 0.90, 95% CI 0.64 to 1.27, P = 0.55) and clinical success rates at SFU (358 patients, OR = 0.73, 95% CI 0.41 to 1.31, P = 0.30) in microbiological intention-to-treat population (mITT). Similarly, with regard to the occurrence of treatment-emergent adverse events (TEAEs), drug-related adverse events (AEs), serious AEs, serious drug-related AEs and mortality, no statistically significant difference between patients given solithromycin and those given other antibiotics was observed. CONCLUSION: In the treatment of CABP, solithromycin monotherapy is an effective and safe antibiotic regimen. Other advantages (ie anti-inflammatory effect, potent activity against expected pathogens of CABP and convenient clinical use) of solithromycin may make it a more fascinating option compared with the currently used regimens.


Assuntos
Antibacterianos/administração & dosagem , Infecções Comunitárias Adquiridas/tratamento farmacológico , Macrolídeos/administração & dosagem , Pneumonia Bacteriana/tratamento farmacológico , Triazóis/administração & dosagem , Antibacterianos/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Macrolídeos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Triazóis/efeitos adversos
17.
Am J Med ; 132(4): 457-467, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30611833

RESUMO

In observational studies, high serum urate levels are associated with adverse outcomes, including mortality. However, the hypothesis that urate-lowering may improve nongout outcomes has not been confirmed by placebo-controlled clinical trials. On the contrary, 7 recent placebo-controlled trials of urate-lowering drugs with different mechanisms of action (uricosuric: lesinurad; xanthine oxidase inhibition: febuxostat; uricase: pegloticase) have observed higher mortality or trends to higher mortality in gout patients, with the largest decreases in serum urate. Because all urate-lowering mechanisms were implicated, this raises safety concerns about urate-lowering itself. Far from unexpected, the higher mortality associated with more intense urate-lowering is in line with the U-shaped association of urate with mortality in some observational studies. Urate accounts for most of the antioxidant capacity of plasma, and strategies to increase urate are undergoing clinical trials in neurological disease. Post hoc analysis of recent trials should explore whether the magnitude of urate-lowering is associated with adverse outcomes, and safety trials are needed before guidelines recommend lowering serum urate below certain thresholds.


Assuntos
Supressores da Gota/efeitos adversos , Ácido Úrico/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Humanos , Estresse Oxidativo , Polietilenoglicóis/efeitos adversos , Tioglicolatos/efeitos adversos , Triazóis/efeitos adversos , Urato Oxidase/efeitos adversos , Xantina Oxidase/antagonistas & inibidores
18.
J Oncol Pharm Pract ; 25(7): 1758-1761, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30259783

RESUMO

Drug-drug interactions between digoxin and the triazole antifungal agents, mediated via various cytochrome P450 isozymes, have been described in the literature. Posaconazole is not extensively metabolized by these isozymes but is both a p-glycoprotein (P-gp) substrate and inhibitor. To our knowledge, there have been no published cases of clinically significant posaconazole-digoxin drug-drug interactions. We report an interaction between posaconazole (300 mg by mouth daily) and digoxin (0.25 mg by mouth daily, Monday through Friday) resulting in atrial fibrillation with slow ventricular response and degenerating into polymorphic ventricular tachycardia.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Digoxina/efeitos adversos , Triazóis/efeitos adversos , Idoso , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Fibrilação Atrial/induzido quimicamente , Digoxina/administração & dosagem , Interações de Medicamentos , Feminino , Humanos , Triazóis/administração & dosagem
19.
Mycoses ; 62(1): 81-86, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30230043

RESUMO

BACKGROUND: Posaconazole (PCZ) is widely used for prophylaxis or treatment of invasive fungal infections (IFIs) in leukaemia patients. However, issues with PCZ tolerability can result in treatment interruption. Isavuconazole (ISA) has a similar broad spectrum of activity to PCZ; however, real-world data regarding the tolerability of ISA after PCZ toxicity are lacking. OBJECTIVES: To describe the tolerability of ISA after PCZ toxicity in leukaemia patients. PATIENTS/METHODS: We retrospectively assessed tolerability of ISA after PCZ toxicity in adult leukaemia patients (March 2015 to November 2017). We included all patients who received ≥7 days of ISA within 48 hours of PCZ discontinuation. Laboratory markers for liver toxicity were collected at three time points: prior to PCZ, at switch to ISA and after ISA therapy. RESULTS: We identified 23 such patients. Increased liver function tests (LFTs) were noted in 20 patients on PCZ, while three patients had Grade 3/4 QTc prolongation. No patient discontinued subsequent ISA due to toxicity. Grade 3/4 elevations in LFTs were decreased after changing to ISA (30% after PCZ vs 5% after ISA). No patient had significant QTc prolongation after switching to ISA. CONCLUSIONS: Isavuconazole was well-tolerated in patients discontinuing PCZ due to toxicity, with no patient discontinuing ISA due to toxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Leucemia/complicações , Micoses/tratamento farmacológico , Micoses/prevenção & controle , Nitrilos/efeitos adversos , Piridinas/efeitos adversos , Triazóis/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Nitrilos/administração & dosagem , Piridinas/administração & dosagem , Estudos Retrospectivos , Triazóis/administração & dosagem , Adulto Jovem
20.
Mycoses ; 62(3): 214-216, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30474309

RESUMO

Liver function test (LFT) abnormalities are a common occurrence in haematology patients receiving antifungal therapies. The cause of elevated LFTs is often multifactorial. Posaconazole is associated with elevated LFTs in approximately 5%-10% of patients. Recently, DiPippo, et al demonstrated that switching to isavuconazole in such cases leads to a reduction in LFTs in the majority of patients. However, the LFTs in such patients may have declined with time while continuing on posaconazole therapy. We retrospectively assessed LFT kinetics in 157 AML patients receiving posaconazole for antifungal prophylaxis and found that in 27 patients who developed grade 2 or higher CTCAE hepatotoxicity, 85% (23/27) had lower LFTs at the end of posaconazole therapy, despite continuation in the setting of hepatotoxicity, and this change from maximum LFTs was statistically significant (P < 0.0001). Thus, the development of LFT abnormalities while on posaconazole therapy may not warrant a switch to an alternative, potentially less effective antifungal, as hepatotoxicity is often multifactorial and generally resolves with time in the majority of patients.


Assuntos
Antifúngicos/efeitos adversos , Quimioprevenção/efeitos adversos , Leucemia Mieloide Aguda/complicações , Hepatopatias/epidemiologia , Micoses/prevenção & controle , Triazóis/efeitos adversos , Adulto , Idoso , Antifúngicos/administração & dosagem , Quimioprevenção/métodos , Substituição de Medicamentos , Feminino , Humanos , Hepatopatias/diagnóstico , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Triazóis/administração & dosagem , Adulto Jovem
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