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1.
PLoS One ; 15(9): e0238723, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32916693

RESUMO

The aim of this study was to examine the risk of falls associated with the use of non-gamma amino butyric acid (GABA) sleep medications, suvorexant and ramelteon. This case-control and case-crossover study was performed at the Kudanzaka Hospital, Chiyoda Ward, Tokyo. A total of 325 patients who had falls and 1295 controls matched by sex and age were included. The inclusion criteria for the case group were hospitalized patients who had their first fall and that for the control were patients who were hospitalized and did not have a fall, between January 2016 and November 2018. The internal sleep medications administered were classified as suvorexant, ramelteon, non-benzodiazepines, benzodiazepines, or kampo. In the case-control study, age, sex, clinical department, the fall down risk score, and hospitalized duration were adjusted in the logistic regression model. In the case-control study, multivariable logistic regression showed that the use of suvorexant (odds ratio [OR]: 2.61, 95% confidence interval [CI]: 1.29-5.28), nonbenzodiazepines (OR: 2.49, 95% CI: 1.73-3.59), and benzodiazepines (OR: 1.65, 95% CI: 1.16-2.34) was significantly associated with an increased OR of falls. However, the use of ramelteon (OR: 1.40, 95% CI: 0.60-3.16) and kampo (OR: 1.55, 95% CI: 0.75-3.19) was not significantly associated with an increased OR of falls. In the case-crossover study, the use of suvorexant (OR: 1.78, 95% CI: 1.05-3.00) and nonbenzodiazepines (OR: 1.63, 95% CI: 1.17-2.27) was significantly associated with an increased OR of falls. Similar patterns were observed in several sensitivity analyses. It was suggested that suvorexant increases the OR of falls. This result is robust in various analyses. This study showed that the risk of falls also exists for non-GABA sleep medication, suvorexant, and thus it is necessary to carefully prescribe hypnotic drugs under appropriate assessment.


Assuntos
Acidentes por Quedas , Azepinas/efeitos adversos , Indenos/efeitos adversos , Medicamentos Indutores do Sono/efeitos adversos , Triazóis/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Azepinas/administração & dosagem , Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Estudos Cross-Over , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Indenos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sono/efeitos dos fármacos , Sono/fisiologia , Triazóis/administração & dosagem
2.
Medicine (Baltimore) ; 99(30): e21043, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791676

RESUMO

BACKGROUND: Delirium is a frequently encountered complication, which is associated with increased mortality. Suvorexant, an approved agent for the treatment of insomnia, is recently suggested to be also effective for prevention of delirium by some authors. However, a consensus has yet to be reached. The goal of this study was to perform a meta-analysis to overall estimate the effectiveness of suvorexant in preventing delirium and its related consequences. METHODS: Eligible studies were identified by searching online databases of PubMed, EMBASE, and Cochrane Library. The pooled OR was calculated for binary outcomes (e.g., the incidence of delirium, mortality, or adverse events), while standardized mean difference (SMD) were expressed for continuous outcomes (e.g., time to delirium onset, length of stay in hospital and ICU, time on ventilation). RESULTS: Seven studies which comprised 402 suvorexant treatment patients and 487 patients with control treatment were included in this meta-analysis. Overall, pooled analysis indicated the incidence of delirium could be significantly reduced (OR, 0.30; P < .001) and time to delirium onset was significantly lengthened (SMD, 0.44; P = .006) in patients undergoing suvorexant treatment compared with controls. Suvorexant had no beneficial effects on the secondary outcomes [length of stay in hospital (SMD, -0.65; P = .161) and ICU (SMD, 0.34; P = .297), time on ventilation (SMD, 1.09; P = .318), drug-related adverse events (OR, drug-related adverse events (OR, 1.66; P = .319) and mortality (OR, 2.21; P = .261)]. Subgroup analysis also confirmed the benefit of suvorexant on the development of delirium, which was significant in any subgroup. CONCLUSION: Suvorexant should be recommended for the prevention of delirium in clinic.


Assuntos
Azepinas/uso terapêutico , Delírio/prevenção & controle , Medicamentos Indutores do Sono/uso terapêutico , Triazóis/uso terapêutico , Azepinas/efeitos adversos , Humanos , Tempo de Internação , Mortalidade , Respiração Artificial , Medicamentos Indutores do Sono/efeitos adversos , Fatores de Tempo , Triazóis/efeitos adversos
3.
Ann Hematol ; 99(9): 2193-2195, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621180
5.
Am J Trop Med Hyg ; 103(1): 378-393, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32314694

RESUMO

Malaria volunteer infection studies (VISs) accelerate new drug and vaccine development. In the induced blood-stage malaria (IBSM) model, volunteers are inoculated with erythrocytes infected with Plasmodium falciparum. Observations of elevated liver enzymes in the IBSM model with new chemical entities (NCEs) promoted an analysis of available data. Data were reviewed from eight IBSM studies of seven different NCEs, plus two studies with the registered antimalarial piperaquine conducted between June 2013 and January 2017 at QIMR Berghofer, Brisbane, Australia. Alanine aminotransferase (ALT) was elevated (> 2.5 times the upper limit of normal [×ULN]) in 20/114 (17.5%) participants. Of these, 8.9% (10/114) had moderate increases (> 2.5-5 × ULN), noted in seven studies of six different NCEs ± piperaquine or piperaquine alone, and 8.9% (10/114) had severe elevations (> 5 × ULN), occurring in six studies of six different NCEs ± piperaquine. Aspartate aminotransferase (AST) was elevated (> 2.5 × ULN) in 11.4% (13/114) of participants, across six of the 10 studies. Bilirubin was > 2 × ULN in one participant. Published data from other VIS models, using sporozoite inoculation by systemic administration or mosquito feeding, also showed moderate/severe liver enzyme elevations. In conclusion, liver enzyme elevations in IBSM studies are most likely multifactorial and could be caused by the model conditions, that is, malaria infection/parasite density and/or effective parasite clearance, or by participant-specific risk factors, acetaminophen administration, or direct hepatotoxicity of the test drug. We make recommendations that may mitigate the risk of liver enzyme elevations in future VISs and propose measures to assist their interpretation, should they occur.


Assuntos
Alanina Transaminase/metabolismo , Antimaláricos/efeitos adversos , Aspartato Aminotransferases/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Voluntários Saudáveis , Malária Falciparum/tratamento farmacológico , Parasitemia/tratamento farmacológico , Acrilamidas/efeitos adversos , Adamantano/efeitos adversos , Adamantano/análogos & derivados , Adulto , Aminopiridinas/efeitos adversos , Aminoquinolinas/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Transfusão de Eritrócitos , Eritrócitos/parasitologia , Feminino , Compostos Ferrosos/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Indóis/efeitos adversos , Isoquinolinas/efeitos adversos , Masculino , Metalocenos/efeitos adversos , Peróxidos/efeitos adversos , Piperazinas/efeitos adversos , Plasmodium falciparum , Primaquina/efeitos adversos , Pirimidinas/efeitos adversos , Quinolinas/efeitos adversos , Compostos de Espiro/efeitos adversos , Sulfonas/efeitos adversos , Triazóis/efeitos adversos , Adulto Jovem
6.
Int J Clin Pharmacol Ther ; 58(6): 293-298, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32301699

RESUMO

OBJECTIVES: We assessed the relative efficacy and safety of once-daily administration of 100 and 200 mg filgotinib (a JAK1-selective inhibitor) in patients with active rheumatoid arthritis (RA). MATERIALS AND METHODS: We conducted a Bayesian network meta-analysis combining the direct and indirect evidence from randomized controlled trials (RCTs) that examined the efficacy and safety of filgotinib in patients with active RA. RESULTS: Five RCTs involving 3,920 patients met the inclusion criteria. There were 15 pairwise comparisons, including 8 direct comparisons and 7 interventions. The ACR20 response rate was significantly higher in the filgotinib 200 mg + methotrexate (MTX) group than in the placebo or placebo + MTX group (odds ratio (OR): 12.39, 95% credible interval (CrI): 3.36 - 45.98.10; OR: 2.68, 95% CrI: 1.80 - 4.39). Compared to the placebo group, the filgotinib 100 mg, adalimumab 40 mg + MTX, filgotinib 200 mg, and placebo + MTX groups showed a significantly higher ACR20 response rate. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated filgotinib 200 mg + MTX was likely to achieve the best ACR20 response rate (SUCRA = 0.902), followed by filgotinib 100 mg + MTX (SUCRA = 0.694), filgotinib 100 mg (SUCRA = 0.675), adalimumab 40 mg + MTX (SUCRA = 0.661), filgotinib 200 mg (SUCRA = 0.305), placebo + MTX (SUCRA = 0.259), and placebo (SUCRA = 0.005). The safety based on the number of serious adverse events (SAEs) did not differ significantly among 6 six interventions. CONCLUSION: Filgotinib 100 and 200 mg administration once daily in combination with MTX was the most efficacious intervention for active RA, with no significant risk of SAEs.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Piridinas/administração & dosagem , Triazóis/administração & dosagem , Antirreumáticos/efeitos adversos , Teorema de Bayes , Quimioterapia Combinada , Humanos , Janus Quinase 1/antagonistas & inibidores , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Metanálise em Rede , Piridinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Triazóis/efeitos adversos
7.
Neurology ; 94(21): e2222-e2232, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32341187

RESUMO

OBJECTIVE: To assess the dose-response of daridorexant, a new dual orexin receptor antagonist, on wake after sleep onset (WASO). METHODS: Elderly (≥65 years) participants (n = 58) with insomnia were randomly allocated (Latin square design) to receive 5 treatments (5, 10, 25, and 50 mg daridorexant and placebo) during 5 treatment periods, each consisting of 2 treatment nights followed by a 5- to 12-day washout period. Main efficacy endpoints were the absolute change from baseline in WASO (primary) and latency to persistent sleep (LPS; secondary) to days 1 and 2 (mean of 2 treatment nights assessed by polysomnography) in each period. Safety and tolerability were also assessed. RESULTS: Of 58 participants included, 67% were female, and the median age was 69 years (range 65-85 years). WASO and LPS were dose-dependently reduced from baseline to days 1 and 2 after daridorexant administration (multiple comparison procedure modeling, p < 0.0001 and p = 0.004, respectively); reductions were statistically significant for doses ≥10 mg compared with placebo (WASO: -32.0, -45.1, -61.4 minutes; LPS: -44.9, -43.8, -45.4 minutes for 10, 25, and 50 mg, respectively, p ≤ 0.025). Treatment-emergent adverse events were similar for daridorexant and placebo; the most frequent were fatigue, nasopharyngitis, gait disturbance, and headache (≤7% in any group). CONCLUSIONS: Daridorexant was well tolerated. Dose-dependent improvements in WASO and LPS were statistically significant (dose range 10-50 mg) in elderly people with insomnia disorder. CLINICALTRIALSGOV IDENTIFIER: NCT02841709. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for elderly people with insomnia, daridorexant reduced WASO.


Assuntos
Benzimidazóis/uso terapêutico , Pirrolidinas/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Benzimidazóis/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Antagonistas dos Receptores de Orexina/uso terapêutico , Polissonografia , Pirrolidinas/efeitos adversos , Resultado do Tratamento , Triazóis/efeitos adversos
8.
J Pediatr Hematol Oncol ; 42(4): 261-265, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32218096

RESUMO

PURPOSE: Primary objective is to evaluate safety of isavuconazonium sulfate (ISA) in pediatrics below 18 years old. Exploratory endpoint includes mortality due to probable and proven invasive fungal infection (IFI) and overall morality in this population. PATIENTS AND METHODS: Retrospective review of patients below 18 years receiving ISA for ≥7 days for possible, probable, or proven IFI or prophylaxis between June 2015 and March 2018. Descriptive analysis performed to calculate median, frequency, and percentages. RESULTS: Safety analysis included 18 patients and a subgroup of 11/18 patients were assessed for efficacy. Median age 12.5 years (4 to 17 y), median weight 50.25 kg (19 to 118 kg), 50% male, 77% acute leukemias, 94% hematopoietic cell transplant recipients, 50% matched unrelated donors and 78% in remission. Elevated alanine aminotransferase 3 times baseline within 30 days of ISA occurred in 22% (4/18). No patients had elevated bilirubin or increase in serum creatinine. All-cause mortality at 90 days was 22% (4/18) and 27% (3/11) in patients with probable or proven IFI. Clinical response rates: 14-day: 45% (5/11) partial, 27% (3/11) stable; 30-day: 45% (5/11) partial, 36% (4/11) stable; 90-day: 54% (6/11) had either partial (n=3) or complete (n=3) response to ISA. CONCLUSIONS: ISA is safe in pediatric patients for the treatment of IFI. Prospective, randomized controlled trials are warranted to determine efficacy and safety of ISA in pediatric patients with hematologic malignancies and hematopoietic cell transplant.


Assuntos
Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Infecções Fúngicas Invasivas , Nitrilos/administração & dosagem , Piridinas/administração & dosagem , Triazóis/administração & dosagem , Adolescente , Criança , Pré-Escolar , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/terapia , Humanos , Infecções Fúngicas Invasivas/sangue , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/etiologia , Masculino , Nitrilos/efeitos adversos , Piridinas/efeitos adversos , Estudos Retrospectivos , Triazóis/efeitos adversos
9.
Leukemia ; 34(9): 2430-2440, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32094461

RESUMO

Selinexor is an oral, small molecule inhibitor of the nuclear export protein exportin 1 with demonstrated activity in hematologic and solid malignancies. Side effects associated with selinexor include nausea, vomiting, fatigue, diarrhea, decreased appetite, weight loss, thrombocytopenia, neutropenia, and hyponatremia. We reviewed 437 patients with multiple myeloma treated with selinexor and assessed the kinetics of adverse events and impact of supportive care measures. Selinexor reduced both platelets and neutrophils over the first cycle of treatment and reached a nadir between 28 and 42 days. Platelet transfusions and thrombopoietin receptor agonists were effective at treating thrombocytopenia, and granulocyte colony stimulating factors were effective at resolving neutropenia. The onset of gastrointestinal side effects (nausea, vomiting, and diarrhea) was most common during the first 1-2 weeks of treatment. Nausea could be mitigated with 5-HT3 antagonists and either neurokinin 1 receptor antagonists, olanzapine, or cannbainoids. Loperamide and bismuth subsalicylate ameliorated diarrhea. The primary constitutional side effects of fatigue and decreased appetite could be managed with methylphenidate, megestrol, cannabinoids or olanzapine, respectively. Hyponatremia was highly responsive to sodium replacement. Selinexor has well-established adverse effects that mainly occur within the first 8 weeks of treatment, are reversible, and respond to supportive care.


Assuntos
Antineoplásicos/efeitos adversos , Ensaios Clínicos como Assunto , Hidrazinas/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Triazóis/efeitos adversos , Idoso , Antineoplásicos/uso terapêutico , Apetite/efeitos dos fármacos , Diarreia/induzido quimicamente , Fadiga/induzido quimicamente , Fadiga/tratamento farmacológico , Feminino , Humanos , Hidrazinas/uso terapêutico , Hiponatremia/induzido quimicamente , Hiponatremia/terapia , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Trombocitopenia/induzido quimicamente , Triazóis/uso terapêutico
10.
Gastroenterology ; 158(6): 1554-1573.e12, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31926171

RESUMO

BACKGROUND & AIMS: Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis. METHODS: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990, through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events. RESULTS: We identified 973 studies; of these, 82 were included in the final analysis, comprising 66,159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared with patients given placebo or active comparator (relative risk 0.72; 95% confidence interval 0.40-1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% confidence interval 1.04-2.37). CONCLUSIONS: In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Herpes Zoster/epidemiologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Inibidores de Janus Quinases/efeitos adversos , Psoríase/tratamento farmacológico , Espondilite Anquilosante/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Reumatoide/mortalidade , Azetidinas/efeitos adversos , Herpes Zoster/induzido quimicamente , Herpes Zoster/imunologia , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Incidência , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/mortalidade , Inibidores de Janus Quinases/administração & dosagem , Janus Quinases/antagonistas & inibidores , Janus Quinases/imunologia , Janus Quinases/metabolismo , Piperidinas/efeitos adversos , Placebos/administração & dosagem , Placebos/efeitos adversos , Psoríase/imunologia , Psoríase/mortalidade , Piridinas/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/mortalidade , Sulfonamidas/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Triazóis/efeitos adversos
11.
Ann Neurol ; 87(3): 347-356, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31953863

RESUMO

OBJECTIVE: To evaluate the dose-response relationship of daridorexant, a new dual orexin receptor antagonist, on sleep variables in subjects with insomnia disorder. METHODS: Adults (≤64 years) with insomnia disorder were randomized (1:1:1:1:1:1) to receive daily oral placebo, daridorexant (5, 10, 25, or 50mg), or 10mg zolpidem for 30 days. The primary efficacy outcome was the change in wake time after sleep onset from baseline to days 1 and 2. Secondary outcome measures were change in latency to persistent sleep from baseline to days 1 and 2, change in subjective wake time after sleep onset, and subjective latency to sleep onset from baseline to week 4. Safety was also assessed. RESULTS: Of 1,005 subjects screened, 359 (64% female) were randomized and received ≥1 dose. A significant dose-response relationship (multiple comparison procedure-modeling, 2-sided p < 0.001) was found in the reduction of wake after sleep onset and latency to persistent sleep from baseline to days 1 and 2 with daridorexant. These reductions were sustained through to days 28 and 29 (p = 0.050 and p = 0.042, respectively). Similar dose-dependent relationships were observed for subjective wake after sleep onset and subjective latency to sleep onset. The incidence of treatment-emergent adverse events was 35%, 38%, 38%, and 34% in subjects treated with 5, 10, 25, and 50mg daridorexant, respectively, compared with 30% for placebo, and 40% for 10mg zolpidem. There were no clinically relevant treatment-related serious adverse events. Four subjects withdrew due to adverse events. INTERPRETATION: Daridorexant induced a dose-dependent reduction in wake time after sleep onset in subjects with insomnia disorder (Clinicaltrials.gov NCT02839200). Ann Neurol 2020;87:347-356.


Assuntos
Benzimidazóis/administração & dosagem , Pirrolidinas/administração & dosagem , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/administração & dosagem , Adulto , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Pessoa de Meia-Idade , Antagonistas dos Receptores de Orexina/efeitos adversos , Antagonistas dos Receptores de Orexina/uso terapêutico , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Resultado do Tratamento , Triazóis/efeitos adversos , Triazóis/uso terapêutico , Zolpidem/uso terapêutico
12.
J Steroid Biochem Mol Biol ; 199: 105605, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31982514

RESUMO

Recent reports described cases of severe hypertension and hypokalemia accompanied by low renin and aldosterone levels during antifungal therapy with posaconazole and itraconazole. These conditions represent characteristics of secondary endocrine hypertension caused by mineralocorticoid excess. Different mechanisms can cause mineralocorticoid excess, including inhibition of the adrenal steroidogenic enzymes CYP17A1 and CYP11B1, inhibition of the peripheral cortisol oxidizing enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) or direct activation of the mineralocorticoid receptor (MR). Compared to previous experiments revealing a threefold more potent inhibition of 11ß-HSD2 by itraconazole than with posaconazole, the current study found sevenfold stronger CYP11B1 inhibition by posaconazole over itraconazole. Both compounds most potently inhibited CYP11B2. The major pharmacologically active itraconazole metabolite hydroxyitraconazole (OHI) resembled the effects of itraconazole but was considerably less active. Molecular modeling calculations assessed the binding of posaconazole, itraconazole and OHI to 11ß-HSD2 and the relevant CYP enzymes, and predicted important interactions not formed by the other systemically used azole antifungals, thus providing an initial explanation for the observed inhibitory activities. Together with available clinical observations, the presented data suggest that itraconazole primarily causes pseudohyperaldosteronism through cortisol-induced MR activation due to 11ß-HSD2 inhibition, and posaconazole by CYP11B1 inhibition and accumulation of the mineralocorticoids 11-deoxycorticosterone and 11-deoxycortisol because of hypothalamus-pituitary-adrenal axis (HPA) feedback activation. Therapeutic drug monitoring and introduction of upper plasma target levels may help preventing the occurrence of drug-induced hypertension and hypokalemia. Furthermore, the systemically used azole antifungals voriconazole, isavuconazole and fluconazole did not affect any of the mineralocorticoid excess targets, offering alternative therapeutic options.


Assuntos
Hiperaldosteronismo/genética , Hipertensão/genética , Esteroide 11-beta-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/genética , Aldosterona/metabolismo , Animais , Antifúngicos/efeitos adversos , Antifúngicos/farmacologia , Azóis/efeitos adversos , Azóis/metabolismo , Cricetinae , Modelos Animais de Doenças , Monitoramento de Medicamentos , Células HEK293 , Humanos , Hidrocortisona/biossíntese , Hidrocortisona/metabolismo , Hiperaldosteronismo/induzido quimicamente , Hiperaldosteronismo/metabolismo , Hiperaldosteronismo/patologia , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/patologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Itraconazol/efeitos adversos , Itraconazol/farmacologia , Mineralocorticoides/farmacologia , Triazóis/efeitos adversos , Triazóis/farmacologia
14.
Expert Opin Pharmacother ; 21(4): 399-408, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31957504

RESUMO

Introduction: Despite unprecedented advances in the treatment of multiple myeloma (MM), almost all patients develop a disease that is resistant to the five most commonly used and active anti-MM agents. The prognosis for this patient population is particularly poor resulting in an unmet need for additional therapeutic options. Exportin-1 (XPO-1) is a major nuclear export protein of macromolecular cargo frequently overexpressed in MM. Selinexor is a first-in-class, oral Selective-Inhibitor-of-Nuclear-Export (SINE) compound that impedes XPO-1. Based on results of the STORM-trial, selinexor in combination with dexamethasone was granted accelerated FDA approval for patients with penta-refractory MM in July 2019.Areas covered: This article summarizes our up-to-date knowledge on the pathophysiologic role of XPO-1 in MM. Furthermore, it reviews the most recent clinical data on selinexor in combination with dexamethasone and other anti-MM agents; and discusses its safety profile, management strategies; and potential future developments.Expert opinion: Selinexor represents a next-generation-novel agent with an innovative mechanism of action that marks a significant advance in the treatment of heavily pretreated MM patients. Ongoing studies investigate its therapeutic potential also in earlier lines of therapy. Additional data is needed to confirm that selinexor and other SINE compounds are a valuable addition to our current therapeutic armamentarium.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hidrazinas/uso terapêutico , Carioferinas/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/uso terapêutico , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Ensaios Clínicos como Assunto , Dexametasona/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/efeitos adversos , Hidrazinas/farmacocinética , Carioferinas/genética , Mieloma Múltiplo/metabolismo , Prognóstico , Receptores Citoplasmáticos e Nucleares/genética , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Triazóis/farmacocinética
15.
Gynecol Oncol ; 156(2): 308-314, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31822399

RESUMO

BACKGROUND: Selinexor is an oral inhibitor of the nuclear export protein Exportin 1 (XPO1) with demonstrated antitumor activity in solid and hematological malignancies. We evaluated the efficacy and safety of selinexor in heavily pretreated, recurrent gynecological malignancies. METHODS: In this phase 2 trial, patients received selinexor (35 or 50 mg/m2 twice-weekly [BIW] or 50 mg/m2 once-weekly [QW]) in 4-week cycles. Primary endpoint was disease control rate (DCR) including complete response (CR), partial response (PR) or stable disease (SD) ≥12 weeks. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. RESULTS: 114 patients with ovarian (N = 66), endometrial (N = 23) or cervical (N = 25) cancer were enrolled. Median number of prior regimens for ovarian, endometrial and cervical cancer was 6 (1-11), 2 (1-5), and 3 (1-6) respectively. DCR was 30% (ovarian 30%; endometrial 35%; cervical 24%), which included confirmed PRs in 8%, 9%, and 4% of patients with ovarian, endometrial, and cervical cancer respectively. Median PFS and OS for patients with ovarian, endometrial and cervical cancer were 2.6, 2.8 and 1.4 months, and 7.3, 7.0, and 5.0 months, respectively. Common Grade 3/4 adverse events (AEs) were thrombocytopenia (17%), fatigue (14%), anemia (10%), nausea (9%) and hyponatremia (9%). Patients with ovarian cancer receiving 50 mg/m2 QW had fewer high-grade AEs with similar efficacy as BIW treatment. CONCLUSIONS: Selinexor demonstrated single-agent activity and disease control in patients with heavily pretreated ovarian and endometrial cancers. Side effects were a function of dose level and treatment frequency, similar to previous reports, reversible and mitigated with supportive care.


Assuntos
Neoplasias dos Genitais Femininos/tratamento farmacológico , Hidrazinas/administração & dosagem , Carioferinas/antagonistas & inibidores , Recidiva Local de Neoplasia/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Neoplasias dos Genitais Femininos/metabolismo , Neoplasias dos Genitais Femininos/patologia , Humanos , Hidrazinas/efeitos adversos , Carioferinas/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Receptores Citoplasmáticos e Nucleares/metabolismo , Triazóis/efeitos adversos
16.
Mycoses ; 63(1): 89-94, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31610064

RESUMO

BACKGROUND: Posaconazole is used to prevent invasive fungal infections (IFIs) in patients with haematologic malignancy. In this study, we compared plasma posaconazole concentrations (PPCs) and the incidence of breakthrough IFIs between patients with haematologic malignancy receiving posaconazole oral suspension vs tablet. METHODS: We retrospectively collected data on adult patients with haematologic malignancies who received posaconazole prophylaxis during chemotherapy from April 2014 through May 2018. A total of 242 cases with PPCs, 88 in the oral suspension group and 154 in the tablet group, were included in this study. RESULTS: Patients receiving tablets achieved a significantly higher mean PPC than did those on oral suspension (1.631 ± 0.878 µg/mL in the tablet group vs. 0.879 ± 0.585 µg/mL in the oral suspension group). One hundred and thirty-seven of 154 patients (89.0%) receiving tablets had PPCs of 0.7 µg/mL or more, while only 41 of 88 patients (46.6%) receiving oral suspension attained an optimal level (P < .001). The incidence of breakthrough IFIs was significantly higher in the oral suspension group compared with in the tablet group (14.8% of oral suspension vs. 4.5% of tablet; P = .005). In the analysis including patients receiving posaconazole tablets, hypoalbuminemia (< 3.5 g/dL) was found to be a risk factor associated with suboptimal levels (odds ratio: 8.872; 95% confidence interval: 3.011 - 26.141; P < .001). CONCLUSIONS: Suboptimal PPCs in the tablet group were less common than those in the oral suspension group. Therapeutic drug monitoring may be still necessary even in patients receiving posaconazole tablets, especially in those with hypoalbuminemia.


Assuntos
Neoplasias Hematológicas/microbiologia , Infecções Fúngicas Invasivas , Triazóis , Administração Oral , Adulto , Antifúngicos/uso terapêutico , Monitoramento de Medicamentos , Feminino , Neoplasias Hematológicas/complicações , Humanos , Hipoalbuminemia/sangue , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/prevenção & controle , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Suspensões/farmacologia , Comprimidos/farmacologia , Resultado do Tratamento , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Triazóis/sangue , Triazóis/uso terapêutico
18.
Ann Pharmacother ; 54(1): 64-74, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31416335

RESUMO

Objective: To compare and contrast doravirine (DOR) with other agents in the nonnucleoside reverse transcriptase inhibitor (NNRTI) class, review safety and efficacy data from both completed and ongoing clinical trials, and outline the potential place in therapy of DOR. Data Sources: A literature search using the PubMed database (inception to June 2019) was conducted using the search terms HIV, doravirine, non-nucleoside reverse transcriptase inhibitor, NNRTI, and MK-1439. Study Selection and Data Extraction: Clinical data were limited to those published in the English language from phase 2 or 3 clinical trials. Ongoing trials were identified through ClinicalTrials.gov. Data Synthesis: DOR was approved by the US Food and Drug Administration on the strength of 2 phase 3 randomized, double-blind, noninferiority clinical trials with additional studies currently underway examining its utility in other clinical scenarios. Relevance to Patient Care and Clinical Practice: The role of NNRTIs as part of antiretroviral (ARV) therapy has diminished in recent years given the introduction of more tolerable individual ARV agents and regimens. Despite this, new agents are still needed in the therapeutic arena because treatment failure as well as intolerance can still occur with many first-line therapies. The optimal place in therapy of DOR remains to be defined. Conclusions: DOR is a new NNRTI that represents a potential treatment option for treatment-naïve patients, without many of the previously described untoward effects of the NNRTI class.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Piridonas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Triazóis/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Humanos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Resultado do Tratamento , Triazóis/administração & dosagem , Triazóis/efeitos adversos
19.
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
20.
Pediatr Infect Dis J ; 38(10): 1035-1037, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31568141

RESUMO

Isavuconazole is a new azole approved for adults with invasive aspergillosis and mucormycosis, with a favorable hepatic tolerability reported in Phase III trials. Here, we report on a case of drug-induced liver failure related to isavuconazole in a pediatric patient treated for invasive aspergillosis after bone marrow transplant.


Assuntos
Antifúngicos/efeitos adversos , Aspergilose Pulmonar Invasiva/complicações , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/patologia , Nitrilos/efeitos adversos , Piridinas/efeitos adversos , Triazóis/efeitos adversos , Adolescente , Antifúngicos/administração & dosagem , Transplante de Medula Óssea/efeitos adversos , Humanos , Masculino , Nitrilos/administração & dosagem , Piridinas/administração & dosagem , Triazóis/administração & dosagem
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