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1.
Medicine (Baltimore) ; 100(6): e24630, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578579

RESUMO

RATIONALE: Mucormycosis is a rare fungal infection that typically occurs in immunosuppressed patients following chemotherapy or hematopoietic stem cell transplantation. PATIENT CONCERNS: An 11-year-old child with newly developed acute lymphoblastic leukemia suffered from the paroxysmal left chest pain, fever, and hemoptysis. DIAGNOSES: We made a histopathologic diagnosis aided by bronchoscopy techniques, which indicated invasive fungal hyphae that are characteristic of mucormycosis. INTERVENTIONS: The patient was treated with oral posaconazole and repeated bronchoscopy interventions for 4 months. OUTCOMES: The patient's clinical signs and symptoms and signs were no longer present. The prior lung lesions were also no longer observable using radiologic methods, and a 3-month follow-up with the patient showed no signs of mucormycosis recurrence. Finally, the patient was cured, when the cancer chemotherapy was stopped. Close follow-up for another 2 years showed no evidence of recurrence. LESSONS: Mucormycosis diagnosis is difficult as clinical and imaging findings vary. This case demonstrates that posaconazole monotherapy combined with bronchoscopy interventions may be a safe and effective treatment option for pediatric pulmonary mucormycosis.


Assuntos
Hospedeiro Imunocomprometido , Pneumopatias Fúngicas/diagnóstico , Mucormicose/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras , Administração Oral , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Criança , Diagnóstico Diferencial , Febre/etiologia , Humanos , Pneumopatias Fúngicas/complicações , Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/patologia , Masculino , Mucormicose/complicações , Mucormicose/tratamento farmacológico , Mucormicose/patologia , Triazóis/administração & dosagem , Triazóis/uso terapêutico
2.
Int J Nanomedicine ; 16: 119-132, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33447031

RESUMO

Purpose: This manuscript aimed at encapsulating an antifungal terconazole (TCZ) into innovative novasomes for improving its penetration into the skin and clinically modulating its therapeutic efficacy. Methods: Novasomes containing free fatty acid (FFA) as a penetration enhancer were formulated using ethanol injection technique based on 24 full factorial design to explore the impact of various formulation variables on novasomes characteristics regarding entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). The optimum formulation was chosen using Design-Expert® software and utilized for further explorations. Results: The chosen formulation (N15; including 100 mg lipid components and Span 80 to oleic acid in a ratio of 2:1 (w/w)) exhibited an EE% = 99.45 ± 0.78%, PS = 623.00 ± 2.97 nm, PDI = 0.40 ± 0.04, and ZP = -73.85 ± 0.64 mV. N15 showed spherical vesicles with a higher deformability index (DI) (9.62 ± 0.15 g) compared to traditional niosomal formulation (0.92 ± 0.12 g). Further, N15 showed superior inhibition of Candida albicans growth relative to TCZ suspension using XTT (2,3-bis-(2-methyloxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) reduction assay. Moreover, in vivo skin deposition tests revealed a superior TCZ deposition inside the skin from N15 in comparison to traditional niosomal formulation and TCZ suspension. Furthermore, histopathological examination for rats assured the safety of N15 for topical use. A clinical study conducted on infants suffering from napkin candidiasis proved the superiority of N15 to placebo in providing a complete cure of such fungal infections. Conclusion: Concisely, the obtained outcomes confirmed the pronounced efficacy of N15 to successfully treat skin fungal infections.


Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Triazóis/administração & dosagem , Administração Tópica , Animais , Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Análise Fatorial , Humanos , Lactente , Lipossomos , Masculino , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Ratos , Ratos Wistar , Pele/efeitos dos fármacos , Pele/microbiologia , Pele/patologia , Absorção Cutânea/efeitos dos fármacos , Eletricidade Estática , Suspensões , Triazóis/farmacologia , Triazóis/uso terapêutico
3.
Medicina (Kaunas) ; 57(1)2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33435164

RESUMO

This article aims to critically review the evidence on the available therapeutic strategies for the treatment of hyperuricemia. For this reason, several papers were reviewed. Xanthine oxidase inhibitors are the safest and most effective uric acid lowering drugs for the management of chronic hyperuricemia, while the efficacy of uricosuric agents is strongly modulated by pharmacogenetics. Emergent drugs (lesinurad, peglotidase) were found to be more effective for the acute management of refractory hyperuricemia, but their use is supported by a relatively small number of clinical trials so that further well-designed clinical research is needed to deepen their efficacy and safety profile.


Assuntos
Hiperuricemia/tratamento farmacológico , Uricosúricos/uso terapêutico , Xantina Oxidase/antagonistas & inibidores , Acetamidas/uso terapêutico , Alopurinol/uso terapêutico , Benzobromarona/uso terapêutico , Doença Crônica , Medicina Baseada em Evidências , Febuxostat/uso terapêutico , Supressores da Gota/uso terapêutico , Humanos , Naftalenos/uso terapêutico , Nitrilos/uso terapêutico , Fenilacetatos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Probenecid/uso terapêutico , Propionatos/uso terapêutico , Piridinas/uso terapêutico , Tioglicolatos/uso terapêutico , Triazóis/uso terapêutico , Urato Oxidase/uso terapêutico
4.
BMC Infect Dis ; 21(1): 82, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33461505

RESUMO

BACKGROUND: Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole. CASE PRESENTATION: We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement. CONCLUSIONS: Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.


Assuntos
Úlcera da Córnea/diagnóstico , Infecções Oculares Fúngicas/diagnóstico , Sordariales/isolamento & purificação , Idoso , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Úlcera da Córnea/tratamento farmacológico , Úlcera da Córnea/microbiologia , Diagnóstico Diferencial , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Humanos , Masculino , Nitrilos/administração & dosagem , Nitrilos/uso terapêutico , Soluções Oftálmicas , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Triazóis/administração & dosagem , Triazóis/uso terapêutico
5.
J Med Chem ; 64(1): 890-904, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33372782

RESUMO

The sigma 1 receptor (S1R) is a molecular chaperone protein located in the endoplasmic reticulum and plasma membranes and has been shown to play important roles in various pathological disorders including pain and, as recently discovered, COVID-19. Employing structure- and QSAR-based drug design strategies, we rationally designed, synthesized, and biologically evaluated a series of novel triazole-based S1R antagonists. Compound 10 exhibited potent binding affinity for S1R, high selectivity over S2R and 87 other human targets, acceptable in vitro metabolic stability, slow clearance in liver microsomes, and excellent blood-brain barrier permeability in rats. Further in vivo studies in rats showed that 10 exhibited negligible acute toxicity in the rotarod test and statistically significant analgesic effects in the formalin test for acute inflammatory pain and paclitaxel-induced neuropathic pain models during cancer chemotherapy. These encouraging results promote further development of our triazole-based S1R antagonists as novel treatments for pain of different etiologies.


Assuntos
Manejo da Dor/métodos , Receptores sigma/antagonistas & inibidores , Triazóis/química , Animais , Sítios de Ligação , Barreira Hematoencefálica/metabolismo , Desenho de Fármacos , Cobaias , Meia-Vida , Humanos , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Estrutura Terciária de Proteína , Relação Quantitativa Estrutura-Atividade , Ratos , Receptores sigma/metabolismo , Triazóis/metabolismo , Triazóis/uso terapêutico
6.
AIDS ; 35(1): 91-99, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33048879

RESUMO

OBJECTIVE: To evaluate changes in weight and BMI in adults with HIV-1 at 1 and 2 years after starting an antiretroviral regimen that included doravirine, ritonavir-boosted darunavir, or efavirenz. DESIGN: Post-hoc analysis of pooled data from three randomized controlled trials. METHODS: We evaluated weight change from baseline, weight gain at least 10%, and increase in BMI after 48 and 96 weeks of treatment with doravirine, ritonavir-boosted darunavir, or efavirenz-based regimens. Risk factors for weight gain and metabolic outcomes associated with weight gain were also examined. RESULTS: Mean (and median) weight changes were similar for doravirine [1.7 (1.0) kg] and ritonavir-boosted darunavir [1.4 (0.6) kg] and were lower for efavirenz [0.6 (0.0) kg] at week 48 but were similar across all treatment groups at week 96 [2.4 (1.5), 1.8 (0.7), and 1.6 (1.0) kg, respectively]. No significant differences between treatment groups were found in the proportion of participants with at least 10% weight gain or the proportion with BMI class increase at either time point. Low CD4 T-cell count and high HIV-1 RNA at baseline were associated with at least 10% weight gain and BMI class increase at both timepoints, but treatment group, age, sex, and race were not. CONCLUSION: Weight gains over 96 weeks were low in all treatment groups and were similar to the average yearly change in adults without HIV-1. Significant weight gain and BMI class increase were similar across the treatment groups and were predicted by low baseline CD4 T-cell count and high baseline HIV-1 RNA.


Assuntos
Fármacos Anti-HIV , Índice de Massa Corporal , Infecções por HIV , Piridonas/uso terapêutico , Triazóis/uso terapêutico , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Darunavir/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Piridonas/efeitos adversos , Ritonavir/uso terapêutico , Resultado do Tratamento , Triazóis/efeitos adversos , Carga Viral
7.
BMC Infect Dis ; 20(1): 755, 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33054720

RESUMO

BACKGROUND: Saksenaea species (spp.) are uncommon causes of mucormycosis but are emerging pathogens mostly associated with trauma and soil contamination often in immunocompetent hosts. Due to lack of sporulation in the laboratory, diagnosis and susceptibility testing is difficult so optimal treatment regimens are unknown. CASE PRESENTATION: A 67 year-old man from the Northern Territory in Australia, with a history of eosinophilic granulomatosis with polyangiitis, developed disseminated Saksenaea infection after initially presenting with symptoms consistent with bacterial pyelonephritis. Despite a delay in diagnosis; with aggressive surgical management and dual therapy with amphotericin B and posaconazole, he survived. CONCLUSIONS: We describe an unusual case of disseminated infection with a favourable outcome to date.


Assuntos
Mucormicose/diagnóstico , Mucormicose/etiologia , Idoso , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Granulomatose com Poliangiite/etiologia , Humanos , Hospedeiro Imunocomprometido , Masculino , Mucormicose/tratamento farmacológico , Mucormicose/cirurgia , Northern Territory , Triazóis/uso terapêutico
8.
J Pharmacol Sci ; 144(4): 229-236, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070842

RESUMO

The kidneys are the major organs for erythropoietin (EPO) production in adults, and thus, kidney damage results in reduced EPO levels and anemia. Inhibitors of Hypoxia-inducible factor-prolyl hydroxylase domain-containing protein (HIF-PHD) are awaited as new therapeutic options for renal anemia. It can be predicted that most patients who receive HIF-PHD inhibitors have renal dysfunction as a cause of anemia. Therefore, in the present study, we investigated the effects of the HIF-PHD inhibitor molidustat on anemia and renal dysfunction when initiated after the onset of renal anemia. Male C57BL/6J mice received adenine orally to induce nephropathy. After the onset of nephropathy, the mice were treated with either vehicle or molidustat. After 4 weeks of administration, vehicle-treated mice displayed significant anemia, and molidustat ameliorated this anemia. Vehicle-treated mice exhibited reduced creatinine clearance and body weight, increased blood urea nitrogen levels, histopathological changes, immune cell infiltration, and dehydration. Molidustat reversed immune cell infiltration, dehydration, and renal fibrosis without improving renal functional parameters. In conclusion, molidustat treatment initiated after the onset of nephropathy and renal anemia reversed anemia in mice. Molidustat improved some parameters of renal abnormality, but it did not restore renal function.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/complicações , Adenina/efeitos adversos , Anemia/tratamento farmacológico , Anemia/etiologia , Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Inibidores de Prolil-Hidrolase , Pirazóis/uso terapêutico , Triazóis/uso terapêutico , Lesão Renal Aguda/metabolismo , Animais , Modelos Animais de Doenças , Eritropoetina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Triazóis/administração & dosagem , Triazóis/farmacologia
9.
Lancet Haematol ; 7(8): e566-e574, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32735836

RESUMO

BACKGROUND: The median overall survival of patients with high-risk myelodysplastic syndromes refractory to hypomethylating agents is less than 6 months. Currently, no standard therapy for such patients exists. Preclinical studies have shown that inhibition of the nuclear export protein exportin 1 (XPO1) causes nuclear accumulation of p53 and disruption of NF-κB signalling, both relevant targets for myelodysplastic syndromes. We therefore aimed to assess the safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents. METHODS: We did a single-centre, single-arm, phase 2 trial at the Memorial Sloan Kettering Cancer Center in the USA. We included patients 18 years or older with high-risk myelodysplastic syndromes or oligoblastic acute myeloid leukaemia (defined as blasts ≥20% but ≤30%) refractory to hypomethylating agents and with an Eastern Cooperative Oncology Group performance status score of 0-2. Eligible patients received 3-week long cycles of oral selinexor (60 mg twice per week for 2 weeks, followed by 1 week off). The primary outcome was overall response rate. Complete remission, partial remission, marrow complete remission, or haematological improvement were included in the response categories for assessing the primary endpoint. The activity analysis included all patients who completed at least one full-scheduled post-treatment disease assessment. All patients who were given selinexor were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT02228525. FINDINGS: Between Sept 23, 2014, and March 13, 2018, 25 patients were enrolled on this study. The median follow-up was 8·5 months (IQR 3·1-12·2). Two patients did not meet the full eligibility criteria after baseline assessment; therefore, 23 patients were evaluable for activity assessment. In the 23 evaluable patients, overall response rate was 26% (95% CI 10-48) in six patients with marrow complete remission, with an additional 12 patients (52%, 95% CI 31-73) achieving stable disease. The most common grade 3 or 4 adverse events were thrombocytopenia (eight [32%] of 25 patients) and hyponatraemia (five [20%]). There were no drug-related serious adverse events and no treatment-related deaths. INTERPRETATION: Selinexor showed responses in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents. Adverse events were manageable with supportive care implementation. Further studies are needed to compare selinexor with supportive care alone, and to identify patient subgroups that might benefit the most from selinexor treatment. FUNDING: Karyopharm Therapeutics.


Assuntos
Azacitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Hidrazinas/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Triazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/farmacologia , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Síndromes Mielodisplásicas/patologia , Segurança do Paciente , Prognóstico , Taxa de Sobrevida
10.
PLoS Negl Trop Dis ; 14(8): e0008529, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804966

RESUMO

Chagas disease is a neglected disease that remains a public health threat, particularly in Latin America. The most important treatment options are nitroimidazole derivatives, such as nifurtimox and benznidazole (BZN). Some studies suggest that for adults seropositive to T. cruzi but without clinically evident chronic Chagas cardiomyopathy (CCC), a simple fixed-dose scheme of BZN could be equivalent to a weight-adjusted dose. We compared the efficacy and safety of a fixed dose of BZN with an adjusted dose for T. cruzi seropositive adults without CCC. We used the Cochrane methods, and reported according to the PRISMA statement. We included randomized controlled trials (RCTs) allocating participants to fixed and/or adjusted doses of BZN for T. cruzi seropositive adults without CCC. We searched (December 2019) Cochrane, MEDLINE, EMBASE, LILACS, Clinicaltrials.gov, and International Clinical Trials Registry Platform (ICTRP), and contacted Chagas experts. Selection, data extraction, and risk of bias assessment, using the Cochrane tool, were performed independently by pairs of reviewers. Discrepancies were solved by consensus within the team. Primary outcomes were parasite-related outcomes and efficacy or patient-related safety outcomes. We conducted a meta-analysis using RevMan 5.3 software and used GRADE summary of finding tables to present the certainty of evidence by outcome. We identified 655 records through our search strategy and 10 studies (four of them ongoing) met our inclusion criteria. We did not find any study directly comparing fixed vs adjusted doses of BZN, however, some outcomes allowed subgroup comparisons between fixed and adjusted doses of BZN against placebo. Moderate-certainty evidence suggests no important subgroup differences for positive PCR at one year and for three safety outcomes (drug discontinuation, peripheral neuropathy, and mild rash). The same effect was observed for any serious adverse events (low-certainty evidence). All subgroups showed similar effects (I2 0% for all these subgroup comparisons but 32% for peripheral neuropathy), supporting the equivalence of BZN schemes. We conclude that there is no direct evidence comparing fixed and adjusted doses of BZN. Based on low to very low certainty of evidence for critical clinical outcomes and moderate certainty of evidence for important outcomes, fixed and adjusted doses may be equivalent in terms of safety and efficacy. An individual patient data network meta-analysis could better address this issue.


Assuntos
Cardiomiopatias , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/administração & dosagem , Nitroimidazóis/uso terapêutico , Adulto , Bases de Dados Factuais , Humanos , Nifurtimox/uso terapêutico , Segurança do Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Triazóis/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos
11.
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
12.
Curr Opin Infect Dis ; 33(4): 290-297, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32657965

RESUMO

PURPOSE OF REVIEW: Although clinical outcomes in the treatment of aspergillosis have markedly improved with the availability of newer triazoles, the development of resistance to these antifungals, especially in Aspergillus fumigatus, is a growing concern. The purpose of this review is to provide an update on azole resistance mechanisms and their epidemiology in A. fumigatus, the clinical implications of azole resistance, and to discuss future treatment options against azole-resistant aspergillosis. RECENT FINDINGS: Resistance may develop through either patient or environmental azole exposure. Environmental exposure is the most prevalent means of resistance development, and these isolates can cause disease in various at-risk groups, which now include those with influenza, and potentially COVID-19. Although current treatment options are limited, newer therapies are in clinical development. These include agents with novel mechanisms of action which have in vitro and in vivo activity against azole-resistant A. fumigatus. SUMMARY: Azole-resistant A. fumigatus is an emerging threat that hampers our ability to successfully treat patients with aspergillosis. Certain geographic regions and patient populations appear to be at increased risk for this pathogen. As new patient groups are increasingly recognized to be at increased risk for invasive aspergillosis, studies to define the epidemiology and management of azole-resistant A. fumigatus are critically needed. While treatment options are currently limited, new agents under clinical development may offer hope.


Assuntos
Antifúngicos/farmacologia , Aspergilose/imunologia , Aspergillus fumigatus/imunologia , Infecções por Coronavirus/imunologia , Farmacorresistência Fúngica Múltipla/imunologia , Pneumonia Viral/imunologia , Triazóis/farmacologia , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergilose/microbiologia , Aspergillus fumigatus/efeitos dos fármacos , Betacoronavirus/imunologia , Exposição Ambiental , Humanos , Hospedeiro Imunocomprometido/imunologia , Testes de Sensibilidade Microbiana , Pandemias , Triazóis/uso terapêutico
13.
BMC Infect Dis ; 20(1): 527, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32698804

RESUMO

BACKGROUND: Conidiobolus spp. (mainly C. coronatus) are the causal agents of rhino-facial conidiobolomycosis, a limited soft tissue infection, which is essentially observed in immunocompetent individuals from tropical areas. Rare cases of invasive conidiobolomycosis due to C. coronatus or other species (C.incongruus, C.lamprauges) have been reported in immunocompromised patients. We report here the first case of invasive pulmonary fungal infection due to Conidiobolus pachyzygosporus in a Swiss patient with onco-haematologic malignancy. CASE PRESENTATION: A 71 year-old female was admitted in a Swiss hospital for induction chemotherapy of acute myeloid leukemia. A chest CT performed during the neutropenic phase identified three well-circumscribed lung lesions consistent with invasive fungal infection, along with a positive 1,3-beta-d-glucan assay in serum. A transbronchial biopsy of the lung lesions revealed large occasionally septate hyphae. A Conidiobolus spp. was detected by direct 18S rDNA in the tissue biopsy and subsequently identified at species level as C. pachyzygosporus by 28S rDNA sequencing. The infection was cured after isavuconazole therapy, recovery of the immune system and surgical resection of lung lesions. CONCLUSIONS: This is the first description of C. pachyzygosporus as human pathogen and second case report of invasive conidiobolomycosis from a European country.


Assuntos
Conidiobolus/genética , Leucemia Mieloide Aguda/complicações , Pneumopatias Fúngicas/complicações , Pneumopatias Fúngicas/diagnóstico , Zigomicose/complicações , Zigomicose/diagnóstico , Idoso , Antifúngicos/uso terapêutico , Biópsia , Conidiobolus/isolamento & purificação , DNA Fúngico/genética , DNA Ribossômico/genética , Feminino , Humanos , Hifas/isolamento & purificação , Hospedeiro Imunocomprometido , Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/patologia , Nitrilos/uso terapêutico , Piridinas/uso terapêutico , Suíça , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Triazóis/uso terapêutico , Zigomicose/tratamento farmacológico , Zigomicose/patologia
14.
Ann Hematol ; 99(7): 1429-1440, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32514626

RESUMO

With the advent of new targeted drugs in hematology and oncology patient prognosis is improved. Combination with antifungal prophylaxis challenges clinicians due to pharmacological profiles prone to drug-drug interactions (DDI). Midostaurin is a novel agent for FLT3-TKD/-ITDmut-acute myeloid leukemia (AML) and metabolized via cytochrome P450 3A4 (CYP3A4). Posaconazole is a standard of care antifungal agent used for prophylaxis during induction treatment of AML and a strong CYP3A4 inhibitor. Concomitant administration of both drugs leads to elevated midostaurin exposure. Both drugs improve overall survival at low numbers needed to treat. The impact of CYP3A4-related DDI remains to be determined. Severe adverse events have been observed; however, it remains unclear if they can be directly linked to DDI. The lack of prospective clinical studies assessing incidence of invasive fungal infections and clinical impact of DDI contributes to neglecting live-saving antifungal prophylaxis. Management strategies to combine both drugs have been proposed, but evidence on which approach to use is scarce. In this review, we discuss several approaches in the specific clinical setting of concomitant administration of midostaurin and posaconazole and give examples from everyday clinical practice. Therapeutic drug monitoring will become increasingly important to individualize and personalize antineoplastic concomitant and antifungal treatment in the context of DDI. Pharmaceutical companies addressing the issue in clinical trials may take a pioneer role in this field. Other recently developed and approved drugs for the treatment of AML likely inhere potential of DDI marking a foreseeable issue in future treatment of this life-threatening disease.


Assuntos
Antifúngicos/uso terapêutico , Quimioprevenção/tendências , Infecções Fúngicas Invasivas/prevenção & controle , Leucemia Mieloide Aguda/tratamento farmacológico , Estaurosporina/análogos & derivados , Triazóis/uso terapêutico , Antifúngicos/classificação , Quimioprevenção/métodos , Interações Medicamentosas , Drogas em Investigação/uso terapêutico , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/microbiologia , Leucemia Mieloide Aguda/mortalidade , Prognóstico , Estaurosporina/uso terapêutico
15.
JAMA Netw Open ; 3(6): e206614, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32484552

RESUMO

Importance: Many shift workers have difficulty sleeping during the daytime owing to an inappropriately timed circadian drive for wakefulness. Objective: To determine whether a dual hypocretin receptor antagonist would enable shift workers to have more daytime sleep. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial included 2 weeks of baseline data and 3 weeks of intervention data, from March 2016 to December 2018. Individuals were recruited through poster advertisements in the broader San Francisco Bay area in California. From an initial voluntary recruitment cohort of 38 shift workers, 19 individuals with self-reported difficulty sleeping during the daytime following night work shift were included. Data were analyzed from Janaury to March 2019. Interventions: 1 week of 10 mg suvorexant or placebo, titrated upward to 20 mg suvorexant or placebo for 2 additional weeks. Main Outcomes and Measures: Objective (ie, actigraphy) and subjective (ie, sleep logs) measures of sleep. Results: Among 19 participants who completed the study (mean [SD] age, 37.7 [11.1] years; 13 [68%] men), 8 participants (42%) were assigned to the suvorexant group and 11 participants (58%) were assigned to the placebo group. Compared with individuals in the placebo group, individuals in the suvorexant group increased their objective total sleep time by a mean (SE) of 1.04 (0.53) hours (P = .05) at the end of 1 week of 10-mg doses and by 2.16 (0.75) hours (P = .004) by the end of the 2 weeks of 20-mg doses. Subjective sleep was similarly improved as, compared with the placebo group, individuals in the suvorexant group increased their subjective total sleep time by a mean (SE) of 2.08 (0.47) hours (P < .001) at the end of 1 week of 10-mg doses and by 2.97 (0.56) hours (P < .001) by the end of the 2 weeks of 20-mg doses. Physician ratings of daytime sleep aligned with these measures, as there was no change in the placebo group and a much improved change in the suvorexant group. No adverse events were reported in the suvorexant group. Conclusions and Relevance: This pilot study found that the use of a dual hypocretin receptor antagonist in shift workers under real-world conditions resulted in more than 2 extra hours of daytime sleep per episode. Future research should confirm this pilot finding in a larger sample size and examine whether, over the long term, use of this medication has a concomitant improvement in medical and psychiatric health as well as workplace performance and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02491788.


Assuntos
Azepinas/uso terapêutico , Antagonistas dos Receptores de Orexina/uso terapêutico , Transtornos do Sono do Ritmo Circadiano/tratamento farmacológico , Sono/efeitos dos fármacos , Triazóis/uso terapêutico , Actigrafia/métodos , Adulto , California/epidemiologia , Estudos de Casos e Controles , Ritmo Circadiano/fisiologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Transtornos do Sono do Ritmo Circadiano/epidemiologia , Transtornos do Sono do Ritmo Circadiano/fisiopatologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/fisiopatologia
16.
Psychosomatics ; 61(5): 544-550, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32591212

Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Antipsicóticos/uso terapêutico , Infecções por Coronavirus/terapia , Delírio/tratamento farmacológico , Hipnóticos e Sedativos/efeitos adversos , Pneumonia Viral/terapia , Agitação Psicomotora/tratamento farmacológico , Medicamentos Indutores do Sono/uso terapêutico , Idoso , Analgésicos Opioides/efeitos adversos , Azepinas/uso terapêutico , Betacoronavirus , Depressores do Sistema Nervoso Central/uso terapêutico , Clordiazepóxido/efeitos adversos , Infecções por Coronavirus/complicações , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/psicologia , Delírio/etiologia , Delírio/fisiopatologia , Delírio/psicologia , Dexmedetomidina/efeitos adversos , Feminino , Guanfacina/uso terapêutico , Haloperidol/uso terapêutico , Humanos , Hidromorfona/efeitos adversos , Unidades de Terapia Intensiva , Ketamina/efeitos adversos , Melatonina/uso terapêutico , Midazolam/efeitos adversos , Oxicodona/efeitos adversos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologia , Pneumonia Viral/psicologia , Propofol/efeitos adversos , Agitação Psicomotora/etiologia , Agitação Psicomotora/fisiopatologia , Agitação Psicomotora/psicologia , Respiração Artificial , Transtornos do Sono do Ritmo Circadiano/tratamento farmacológico , Transtornos do Sono do Ritmo Circadiano/etiologia , Transtornos do Sono do Ritmo Circadiano/fisiopatologia , Traqueostomia , Triazóis/uso terapêutico , Ácido Valproico/uso terapêutico
17.
Epilepsia ; 61(7): e79-e84, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32562438

RESUMO

The assay of saliva samples provides a valuable alternative to the use of blood samples for therapeutic drug monitoring (TDM), at least for certain categories of patients. To determine the feasibility of using saliva sampling for the TDM of rufinamide, we compared rufinamide concentrations in paired samples of saliva and plasma collected from 26 patients with epilepsy at steady state. Within-patient relationships between plasma rufinamide concentrations and dose, and the influence of comedication were also investigated. Assay results in the two tested fluids showed a good correlation (r2  = .78, P < .0001), but concentrations in saliva were moderately lower than those in plasma (mean saliva to plasma ratio = 0.7 ± 0.2). In eight patients evaluated at three different dose levels, plasma rufinamide concentrations increased linearly with increasing dose. Patients receiving valproic acid comedication had higher dose-normalized plasma rufinamide levels than patients comedicated with drugs devoid of strong enzyme-inducing or enzyme-inhibiting activity. Overall, these findings indicate that use of saliva represents a feasible option for the application of TDM in patients treated with rufinamide. Because rufinamide concentrations are lower in saliva than in plasma, a correction factor is needed if measurements made in saliva are used as a surrogate for plasma concentrations.


Assuntos
Anticonvulsivantes/metabolismo , Monitoramento de Medicamentos/métodos , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Saliva/metabolismo , Triazóis/metabolismo , Adolescente , Adulto , Anticonvulsivantes/sangue , Anticonvulsivantes/uso terapêutico , Criança , Epilepsia/sangue , Feminino , Humanos , Masculino , Triazóis/sangue , Triazóis/uso terapêutico , Adulto Jovem
18.
Lancet Haematol ; 7(7): e511-e522, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32589977

RESUMO

BACKGROUND: Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. METHODS: SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling). FINDINGS: Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7-37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3-4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor. INTERPRETATION: Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting. FUNDING: Karyopharm Therapeutics Inc.


Assuntos
Antineoplásicos/uso terapêutico , Hidrazinas/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Triazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Carioferinas/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores
19.
Sleep Med Clin ; 15(2): 133-145, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32386689

RESUMO

The scope of this article is to review the effects on sleep of prescription drugs that are commonly prescribed for chronic insomnia in adults. The following groups are discussed: benzodiazepines and its receptor agonists, the dual orexin receptor antagonist suvorexant, melatonin and its receptor agonists, sedating antidepressants, and antipsychotics. Together with the neurobiologic and pharmacologic properties of these drugs, clinical effects are described, including subjective and objective effects on sleep duration, continuity, and architecture. Medical prescription information is given when available. Recently published American and European guidelines for the treatment of insomnia serve as reference frame.


Assuntos
Benzodiazepinas/uso terapêutico , Melatonina/uso terapêutico , Medicamentos Indutores do Sono/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Sono/efeitos dos fármacos , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Azepinas/farmacologia , Azepinas/uso terapêutico , Benzodiazepinas/farmacologia , Humanos , Melatonina/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Antagonistas dos Receptores de Orexina/uso terapêutico , Medicamentos sob Prescrição/farmacologia , Medicamentos sob Prescrição/uso terapêutico , Medicamentos Indutores do Sono/farmacologia , Triazóis/farmacologia , Triazóis/uso terapêutico
20.
FASEB J ; 34(6): 7253-7264, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32367579

RESUMO

Drug repurposing is potentially the fastest available option in the race to identify safe and efficacious drugs that can be used to prevent and/or treat COVID-19. By describing the life cycle of the newly emergent coronavirus, SARS-CoV-2, in light of emerging data on the therapeutic efficacy of various repurposed antimicrobials undergoing testing against the virus, we highlight in this review a possible mechanistic convergence between some of these tested compounds. Specifically, we propose that the lysosomotropic effects of hydroxychloroquine and several other drugs undergoing testing may be responsible for their demonstrated in vitro antiviral activities against COVID-19. Moreover, we propose that Niemann-Pick disease type C (NPC), a lysosomal storage disorder, may provide new insights into potential future therapeutic targets for SARS-CoV-2, by highlighting key established features of the disorder that together result in an "unfavorable" host cellular environment that may interfere with viral propagation. Our reasoning evolves from previous biochemical and cell biology findings related to NPC, coupled with the rapidly evolving data on COVID-19. Our overall aim is to suggest that pharmacological interventions targeting lysosomal function in general, and those particularly capable of reversibly inducing transient NPC-like cellular and biochemical phenotypes, constitute plausible mechanisms that could be used to therapeutically target COVID-19.


Assuntos
Antivirais/farmacocinética , Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Endossomos/virologia , Hidroxicloroquina/farmacologia , Lisossomos/virologia , Doença de Niemann-Pick Tipo C/patologia , Pneumonia Viral/tratamento farmacológico , Proteína ADAM17/fisiologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Benzilisoquinolinas/farmacologia , Benzilisoquinolinas/uso terapêutico , Transporte Biológico , Catepsina L/fisiologia , Endocitose , Endossomos/efeitos dos fármacos , Endossomos/fisiologia , Glicopeptídeos/farmacologia , Glicopeptídeos/uso terapêutico , Humanos , Hidroxicloroquina/farmacocinética , Hidroxicloroquina/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Lipídeos de Membrana/metabolismo , Microdomínios da Membrana/fisiologia , Doença de Niemann-Pick Tipo C/metabolismo , Oxisteróis/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Receptores Virais/metabolismo , Serina Endopeptidases/fisiologia , Triazóis/farmacologia , Triazóis/uso terapêutico , Internalização do Vírus/efeitos dos fármacos
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