RESUMEN
A 10 yr old spayed female ragdoll cat presented with sudden onset of sneezing, nasal discharge, and stertor. There was no improvement in clinical signs despite treatment with antibiotics, feline interferon, and nebulization. A computed tomography (CT) scan revealed findings consistent with chronic rhinitis, and a tissue biopsy obtained by rhinoscopy led to a histopathologic diagnosis of sinonasal aspergillosis. Polymerase chain reaction amplification identified the causative agent as Aspergillus udagawae. Oral itraconazole therapy was initiated. However, the cat's clinical signs progressed to include left exophthalmos, nictitating membrane protrusion, and lacrimation. A second CT scan revealed a soft-tissue attenuating structure extending into the left retrobulbar space, confirming progression to sino-orbital aspergillosis (SOA). The oral medication was changed to posaconazole and continued for 5 mo, resulting in resolution of the clinical signs. The cat has remained asymptomatic over 24 mo since initial diagnosis. This case represents the first successful treatment of feline SOA caused by A udagawae infection with posaconazole. A udagawae is the second most common cause of SOA and is known to be intractable because of its low susceptibility to antifungal agents and poor response to topical clotrimazole. Posaconazole may be a valuable treatment option for SOA caused by A udagawae.
Asunto(s)
Antifúngicos , Aspergilosis , Aspergillus , Enfermedades de los Gatos , Triazoles , Gatos , Enfermedades de los Gatos/tratamiento farmacológico , Enfermedades de los Gatos/microbiología , Animales , Femenino , Aspergilosis/veterinaria , Aspergilosis/tratamiento farmacológico , Antifúngicos/uso terapéutico , Triazoles/uso terapéutico , Triazoles/administración & dosificación , Aspergillus/efectos de los fármacos , Aspergillus/aislamiento & purificación , Administración Oral , Enfermedades Orbitales/veterinaria , Enfermedades Orbitales/tratamiento farmacológicoRESUMEN
Insomnia is highly comorbid in patients with psychiatric disorders, including depression, bipolar disorder, and substance use disorders, and should be treated as an independent condition. Dual orexin receptor antagonists (DORAs) have been investigated as a treatment for chronic insomnia. The objective of this systematic review was to examine evidence for two DORAs, lemborexant and suvorexant, as treatments for insomnia comorbid with a psychiatric disorder. We searched PubMed, Cochrane, and Embase from their inception until January and April 2023, and included studies examining suvorexant and lemborexant for treating insomnia comorbid with psychiatric disorders. We also manually searched clinical trial registries ( https://clinicaltrials.gov and https://www.umin.ac.jp/ctr ). Randomized clinical trials and observational/cohort studies were included. We identified 18 studies from PubMed, Cochrane, and Embase and three studies from clinicaltrials.gov and UMIN. Of the 21 reports, four were completed/terminated randomized clinical trials, eight were ongoing clinical trials, and nine were observational studies. We identified evidence for switching from benzodiazepine receptor agonists to a DORA, or using a DORA as add-on therapy and, therefore, discuss this topic as well. Two studies examined switching to or adding on a DORA in patients being treated with a benzodiazepine receptor agonist. DORAs may be as effective and safe for treating psychiatric comorbid insomnia (for most psychiatric conditions) as they are for treating primary insomnia. However, the evidence is limited to a few small studies. Further investigation of DORAs for the treatment of comorbid insomnia in those with coexisting psychiatric conditions is warranted.
Asunto(s)
Antagonistas de los Receptores de Orexina , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Trastornos del Inicio y del Mantenimiento del Sueño/complicaciones , Antagonistas de los Receptores de Orexina/uso terapéutico , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/complicaciones , Azepinas/uso terapéutico , Comorbilidad , Triazoles/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Chronic pulmonary aspergillosis (CPA) represents a spectrum of lung disorders caused by local proliferation of Aspergillus hyphae in individuals with non-systemic or mildly systemic immunodepression or altered pulmonary integrity due to underlying disease. While long-term systemic antifungal treatment is still the mainstay for management, surgery is considered mainly in rarer invasive disease manifestations such as sinusitis and osteomyelitis. Optimal application of existing antifungal agents with suitable pharmacokinetic properties is important for the treatment of diseases such as CPA, which requires long-term use. Appropriate management of side effects by therapeutic drug monitoring, maintenance of adherence, and assessment of drug resistance to Aspergillus can provide safe and effective treatment in the future. Most available antifungal agents for the management of mycoses in humans have disadvantages that can limit their use in clinical practice. By contrast, second generation antifungals such as triazoles have advantages of extended antifungal spectrum and availability in both oral and intravenous formulations. Isavuconazole, a new extended spectrum triazole, has been shown to be effective against Aspergillus. The safety profile and excellent pharmacokinetic characteristics of isavuconazole make it an attractive option for treatment of invasive fungal infections including CPA. With this drug now available in Japan, new evidence is expected to expand treatment options. This review focuses on the selection of antifungal agents based on national and international guidelines and the characteristics of each agent for their appropriate use in CPA.
Asunto(s)
Antifúngicos , Aspergilosis Pulmonar , Triazoles , Humanos , Antifúngicos/farmacocinética , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Aspergilosis Pulmonar/tratamiento farmacológico , Enfermedad Crónica , Triazoles/farmacocinética , Triazoles/administración & dosificación , Triazoles/uso terapéutico , Aspergillus/efectos de los fármacos , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Piridinas/farmacocinética , Nitrilos/uso terapéutico , Nitrilos/administración & dosificación , Nitrilos/farmacocinética , Farmacorresistencia FúngicaRESUMEN
BACKGROUND: Trilaciclib, in comparison to placebo plus carboplatin, etoposide, ± atezolizumab (PEA), has shown significant reductions in incidence of severe neutropenia (SN) among patients with extensive-stage small cell lung cancer (ES-SCLC). Despite these findings, real-world utility remains limited. METHODS: A single-center quasi-experimental study compared trilaciclib + PEA (PEAT) versus PEA in ES-SCLC patients. The study period ranged from April 1, 2021 to July 31, 2022, for the PEAT recipients and February 1, 2020, to February 28, 2021, for PEA recipients. The primary endpoint evaluated was incidence of SN after cycle 1 and during the treatment period. Secondary endpoints included measures related to myelopreservation and patient outcomes. RESULTS: Among 34 PEAT and 44 PEA patients, baseline characteristics were similar, except for a higher median age (69 vs 64 years) and more males (64.7% vs 38.6%) in the PEAT cohort. The PEAT cohort exhibited a lower SN rate (3%) versus the PEA cohort (18%), with statistical significance demonstrated on multivariate analysis (p = 0.015). Additionally, the PEAT cohort also demonstrated significant reductions in red blood cell transfusion requirements (3% vs 23%; p = 0.02), grade 3-4 anemia (6% vs 25%; p = 0.03), and grade 3-4 thrombocytopenia (0% vs 11%, p = 0.045). CONCLUSION: Trilaciclib, in combination with PEA, demonstrated an improvement in the safety profile without compromising survival outcomes in ES-SCLC patients. These findings underscore the potential benefits of incorporating trilaciclib in real-world clinical settings for enhanced patient care.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Masculino , Femenino , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Persona de Mediana Edad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Triazoles/administración & dosificación , Triazoles/uso terapéutico , Neutropenia/inducido químicamente , Neutropenia/epidemiología , Estadificación de Neoplasias , Pirimidinas , PirrolesRESUMEN
BACKGROUND: Filgotinib, an oral, once-daily, Janus kinase 1 preferential inhibitor, is an approved treatment for moderately to severely active ulcerative colitis. AIMS: The aim of this study is to assess the safety and efficacy of continued filgotinib therapy over ~4 years in the long-term extension of the phase 2b/3 SELECTION trial (SELECTIONLTE; NCT02914535). METHODS: In this interim analysis of SELECTIONLTE, SELECTION completers (week 10 responders to filgotinib who completed the maintenance study) continued their assigned treatment (double-blind filgotinib 200 mg [FIL200] or filgotinib 100 mg) and SELECTION week 10 non-responders received open-label FIL200. We assessed safety by adverse events (AEs), and efficacy by partial Mayo Clinic Score (pMCS), inflammatory biomarkers and health-related quality of life (HRQoL). We compared safety and efficacy between achievers and non-achievers of a multi-component endpoint, comprehensive disease control (CDC), comprising symptomatic, endoscopic, inflammatory biomarker and HRQoL improvements. RESULTS: Data for completers (n = 250) and non-responders (n = 372) were reported for ≤202 weeks. AE occurrences were low and consistent with previous analyses. The as-observed proportion of FIL200-treated patients in pMCS, biomarker and HRQoL remission during SELECTIONLTE remained high among completers (week 144: 80.0%, 86.4% and 86.0%, respectively) and increased among non-responders (week 192: 62.1%, 76.7% and 59.3%, respectively). Significantly higher proportions of CDC achievers at SELECTION week 58 achieved pMCS, IBDQ and corticosteroid-free pMCS remission than non-achievers, up to LTE week 96. CONCLUSIONS: Filgotinib induced and maintained symptomatic remission and improved HRQoL over 4 years. Safety results showed a proven long-term benefit-risk profile. FIL200-treated CDC achievers had better long-term outcomes than non-achievers.
Asunto(s)
Colitis Ulcerosa , Calidad de Vida , Índice de Severidad de la Enfermedad , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Método Doble Ciego , Resultado del Tratamiento , Estudios de Seguimiento , Triazoles/uso terapéutico , Triazoles/efectos adversos , Triazoles/administración & dosificación , Piridinas/uso terapéutico , Piridinas/efectos adversos , Piridinas/administración & dosificación , Adulto JovenRESUMEN
Importance: Delirium is common among older hospitalized adults. In addition to presenting immediate management issues, delirium can increase the long-term risk of dementia, institutionalization, and mortality. Delirium is associated with disrupted sleep, and prior studies suggest that some specific sleep-promoting agents may reduce delirium. Objective: To evaluate the orexin receptor antagonist suvorexant for reducing delirium in older adults at high risk for delirium after hospitalization. Design, Setting, and Participants: This double-blind, placebo-controlled, phase 3 randomized clinical trial was conducted at 50 hospitals in Japan between October 22, 2020, and December 23, 2022. The study population included Japanese adults aged 65 to 90 years who were at high risk for delirium (mild cognitive impairment or mild dementia, history of delirium at prior hospitalization, or both) and had been hospitalized for acute disease or elective surgery. Data analysis was performed between January 23 and March 13, 2023. Intervention: Participants were randomized 1:1 to suvorexant (15 mg) or placebo taken at bedtime for up to 7 days while in the hospital. Main Outcomes and Measures: Delirium, the primary end point, was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria while participants were hospitalized. The treatment difference in the proportion of participants with delirium was analyzed. Results: This study included 203 participants: 101 were treated with suvorexant (mean [SD] age, 81.5 [4.5]; years; 52 men [51.5%] and 49 women [48.5%]) and 102 received placebo (mean [SD] age, 82.0 [4.9] years; 45 men [44.1%] and 57 women [55.9%]). There were 17 participants with delirium (16.8%) in the suvorexant group compared with 27 (26.5%) in the placebo group (difference, -8.7% [95% CI, -20.1% to 2.6%]; P = .13). Adverse events were similar between the 2 groups. Conclusions and Relevance: In this randomized clinical trial of suvorexant in older adults at high risk for delirium after hospitalization, fewer participants taking suvorexant had delirium compared with placebo, but the difference was not statistically significant. Further studies are needed to determine whether suvorexant may be useful for reducing delirium, particularly delirium with a hyperactive component, in this population. Trial Registration: ClinicalTrials.gov Identifier: NCT04571944.
Asunto(s)
Azepinas , Delirio , Hospitalización , Triazoles , Humanos , Anciano , Masculino , Femenino , Delirio/tratamiento farmacológico , Delirio/prevención & control , Anciano de 80 o más Años , Método Doble Ciego , Hospitalización/estadística & datos numéricos , Triazoles/uso terapéutico , Azepinas/uso terapéutico , Antagonistas de los Receptores de Orexina/uso terapéutico , Japón , Fármacos Inductores del Sueño/uso terapéuticoRESUMEN
INTRODUCTION: New diagnostic methods and antifungal strategies may improve prognosis of mucormycosis. We describe the diagnostic value of metagenomic nextâgeneration sequencing (mNGS) and identify the prognostic factors of mucormycosis. METHODS: We conducted a retrospective study of hematologic patients suffered from mucormycosis and treated with monotherapy [amphotericin B (AmB) or posaconazole] or combination therapy (AmB and posaconazole). The primary outcome was 84-day all-cause mortality after diagnosis. RESULTS: Ninety-five patients were included, with "proven" (n = 27), "probable" (n = 16) mucormycosis confirmed by traditional diagnostic methods, and "possible" (n = 52) mucormycosis with positive mNGS results. The mortality rate at 84 days was 44.2%. Possible + mNGS patients and probable patients had similar diagnosis processes, overall survival rates (44.2% vs 50.0%, p = 0.685) and overall response rates to effective drugs (44.0% vs 37.5%, p = 0.647). Furthermore, the median diagnostic time was shorter in possible + mNGS patients than proven and probable patients (14 vs 26 days, p < 0.001). Combination therapy was associated with better survival compared to monotherapy at six weeks after treatment (78.8% vs 53.1%, p = 0.0075). Multivariate analysis showed that combination therapy was the protective factor (HR = 0.338, 95% CI: 0.162-0.703, p = 0.004), though diabetes (HR = 3.864, 95% CI: 1.897-7.874, p < 0.001) and hypoxemia (HR = 3.536, 95% CI: 1.874-6.673, p < 0.001) were risk factors for mortality. CONCLUSIONS: Mucormycosis is a life-threatening infection. Early management of diabetes and hypoxemia may improve the prognosis. Exploring effective diagnostic and treatment methods is important, and combination antifungal therapy seems to hold potential benefits.
Asunto(s)
Anfotericina B , Antifúngicos , Enfermedades Hematológicas , Secuenciación de Nucleótidos de Alto Rendimiento , Mucormicosis , Humanos , Mucormicosis/diagnóstico , Mucormicosis/tratamiento farmacológico , Mucormicosis/mortalidad , Mucormicosis/microbiología , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Pronóstico , Antifúngicos/uso terapéutico , Adulto , Anciano , Enfermedades Hematológicas/complicaciones , Anfotericina B/uso terapéutico , Metagenómica/métodos , Triazoles/uso terapéutico , Adulto Joven , Quimioterapia Combinada , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Tyrosine kinase inhibitors (TKIs) and triazole antifungals are the first-line drugs for treating chronic myeloid leukemia (CML) and fungal infections, respectively, but both suffer from large exposure differences and narrow therapeutic windows. Moreover, these two types of drugs are commonly used together in CML patients with fungal infections. Multiple studies and guidelines have suggested the importance of therapeutic drug monitoring (TDM) of TKIs and triazoles. Currently, methods for the simultaneous determination of both types of drugs are limited. We developed a simple, rapid, and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of three commonly used TKIs (imatinib, dasatinib, and nilotinib) and three commonly used triazoles (voriconazole, itraconazole, and posaconazole) in human plasma. The analytes were eluted on a Welch XB-C18 analytical column (50 × 2.1 mm, 5 µm) at 0.7 mL/min, using a gradient elution of 10 mM ammonium formate (A) and methanol-acetonitrile-isopropanol (80:10:10, v/v/v) containing 0.2 % formic acid (B) with a total analysis time of 3.5 min. The calibration curves were linear over the range from 20 to 4000 ng/mL for imatinib and nilotinib, from 2 to 400 ng/mL for dasatinib, and from 50 to 10,000 ng/mL for voriconazole, itraconazole, and posaconazole. Selectivity, accuracy, precision, recovery, matrix effect, and stability all met the validation requirements. The method was successfully used for TDM in CML patients who co-treated with both TKIs and triazoles. Drug-drug interaction analysis between TKIs and triazoles showed that a significant positive correlation was observed between imatinib and voriconazole, as well as dasatinib and voriconazole. Therefore, this method can be well applied in clinical TDM for patients receiving TKIs, triazoles, or both simultaneously.
Asunto(s)
Interacciones Farmacológicas , Monitoreo de Drogas , Inhibidores de Proteínas Quinasas , Espectrometría de Masas en Tándem , Triazoles , Humanos , Espectrometría de Masas en Tándem/métodos , Triazoles/sangre , Triazoles/uso terapéutico , Monitoreo de Drogas/métodos , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/química , Reproducibilidad de los Resultados , Cromatografía Liquida/métodos , Modelos Lineales , Límite de Detección , Cromatografía Líquida con Espectrometría de MasasRESUMEN
Exportin-1 (XPO1) is a major transporter for hundreds of proteins. Selinexor is the first generation XPO1 inhibitor. At present, selinexor has gained more attention in the application of multiple myeloma (MM). Meanwhile, the latest clinical trials have confirmed that whether it is a single agent or combined with other chemotherapy regimens, selinexor can also achieve good therapeutic effects in patients with leukemia and lymphoma. This review summarizes the results of preclinical studies and clinical trials of selinexor in treatment of non-MM hematological malignancies, aiming to explore how to choose single agent or in combination with other regimens as induction chemotherapy.
Asunto(s)
Neoplasias Hematológicas , Hidrazinas , Mieloma Múltiple , Triazoles , Humanos , Proteína Exportina 1/antagonistas & inhibidores , Neoplasias Hematológicas/tratamiento farmacológico , Hidrazinas/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Triazoles/uso terapéuticoRESUMEN
Global epidemiological data show that the incidence of invasive fungal disease (IFD) has increased in recent decades, with the rising frequency of infections caused by Aspergillus and Mucorales order species. The number and variety of patients at risk of IFD has also expanded, owing in part to advances in the treatment of hematologic malignancies and other serious diseases, including hematopoietic stem cell transplantation (HCT) and other therapies causing immune suppression. Isavuconazonium sulfate (active moiety: isavuconazole) is an advanced-generation triazole antifungal approved for the treatment of invasive aspergillosis and mucormycosis that has demonstrated activity against a variety of yeasts, moulds, and dimorphic fungi. While real-world clinical experience with isavuconazole is sparse in some geographic regions, it has been shown to be effective and well tolerated in diverse patient populations, including those with multiple comorbidities who may have failed to respond to prior triazole antifungal therapy. Isavuconazole may be suitable for patients with IFD receiving concurrent QTc-prolonging therapy, as well as those on venetoclax or ruxolitinib. Data from clinical trials are not available to support the use of isavuconazole prophylactically for the prevention of IFD or for the treatment of endemic IFD, such as those caused by Histoplasma spp., but real-world evidence from case studies suggests that it has clinical utility in these settings. Isavuconazole is an option for patients at risk of IFD, particularly when the use of alternative antifungal therapies is not possible because of toxicities, pharmacokinetics, or drug interactions.
This article summarizes the epidemiology and risk factors for IFD, before focusing on the effectiveness and safety of the antifungal agent isavuconazole for treatment of invasive aspergillosis and mucormycosis, and its potential to prevent IFD in specific patient populations.
Asunto(s)
Antifúngicos , Infecciones Fúngicas Invasoras , Nitrilos , Piridinas , Triazoles , Humanos , Nitrilos/uso terapéutico , Nitrilos/farmacología , Nitrilos/efectos adversos , Triazoles/uso terapéutico , Piridinas/uso terapéutico , Piridinas/efectos adversos , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/prevención & control , Infecciones Fúngicas Invasoras/epidemiología , Antifúngicos/uso terapéutico , Antifúngicos/farmacología , Mucormicosis/tratamiento farmacológico , Mucormicosis/epidemiología , Salud Global , Aspergilosis/tratamiento farmacológico , Aspergilosis/epidemiología , Aspergillus/efectos de los fármacos , Mucorales/efectos de los fármacosRESUMEN
BACKGROUND: Currently, real-world data on doravirine are scarce. In a national prospective cohort, we assessed the effectiveness and tolerability of switching to doravirine-based antiretroviral therapy (ART) in people with HIV. METHODS: We did a nationwide, matched, prospective cohort study of people with HIV without previous virological failure and stable for at least 12 months on non-doravirine-containing triple or dual ART switching to doravirine before Sept 1, 2020 (exposed group). Participants in the exposed group were matched 1:2 to individuals continuing stable non-doravirine-containing ART, on age, sex, HIV acquisition category, time since ART initiation, calendar time, pre-ART CD4-count, pre-ART plasma viral load (PVL) and anchor drug class before switching. The primary outcome was protocol-defined virological failure (PDVF; PVL of ≥200 copies per mL) in the intention-to-treat (ITT) population at week 104, with participants modifying their regimen or becoming lost to follow-up considered as PDVF (non-inferiority margin +5%). In contrast, in the on-treatment population, those who modified their regimen or became lost to follow-up were censored from that moment onwards. Tolerability was a secondary outcome. FINDINGS: In total, 590 participants in the exposed group and 1180 participants in the unexposed group (of whom 55·3% used integrase strand transfer inhibitor-based regimens) were included. In the ITT analysis, PDVF occurred in 135 (22·9%) exposed participants and in 295 (25·0%) unexposed participants (risk difference -2·12%, upper limit of the one-sided 95% CI +1·40%). In the on-treatment analysis, 10 (2·2%) of 455 non-censored exposed participants and 26 (2·9%) of 885 non-censored unexposed participants had PDVF (risk difference -0·70%, upper limit of the one-sided 95% CI +0·73%). All exposed participants with a PVL of 200 copies or more per mL resuppressed without regimen modification: no confirmed virological failure (two consecutive PVLs of ≥200 copies per mL) was observed. 104 (17·6%) exposed participants and 211 (17·9%) unexposed participants modified their regimen. 73 (12.4%) exposed participants discontinued doravirine due to adverse events: abnormal dreams (1·7%) and insomnia (1·5%) were most common. INTERPRETATION: Switching to doravirine in well suppressed people with HIV without previous virological failure was non-inferior compared with continuing non-doravirine-containing regimens after 2 years in a real-world setting. FUNDING: None.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Piridonas , Carga Viral , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Masculino , Femenino , Estudios Prospectivos , Adulto , Carga Viral/efectos de los fármacos , Persona de Mediana Edad , Piridonas/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/efectos adversos , Triazoles/uso terapéutico , Triazoles/efectos adversos , Sustitución de Medicamentos , Resultado del Tratamiento , Recuento de Linfocito CD4RESUMEN
Primary cutaneous mucormycosis is caused by environmental fungi and may complicate leg ulcers or traumatic wounds even in immunocompetent individuals. This case report highlights recurrent lower limb ulcers and cellulitis in a patient with type two diabetes mellitus, which was unresponsive to conventional antibiotic treatment. Histopathology revealed the diagnosis of cutaneous mucormycosis, and fungal cultures identified Rhizopus variabilis as the causative organism. Initial courses of oral azole antifungals yielded only partial response and he eventually required more aggressive treatment with i.v. amphotericin B and oral posaconazole. Good treatment outcomes for this condition require a high index of clinical suspicion, early histopathological and microbiological diagnosis, targeted systemic antifungal therapy, and surgical debridement if necessary.
Asunto(s)
Antifúngicos , Celulitis (Flemón) , Dermatomicosis , Diabetes Mellitus Tipo 2 , Úlcera de la Pierna , Mucormicosis , Humanos , Mucormicosis/diagnóstico , Mucormicosis/complicaciones , Celulitis (Flemón)/microbiología , Celulitis (Flemón)/tratamiento farmacológico , Masculino , Diabetes Mellitus Tipo 2/complicaciones , Antifúngicos/uso terapéutico , Úlcera de la Pierna/microbiología , Dermatomicosis/diagnóstico , Dermatomicosis/tratamiento farmacológico , Dermatomicosis/patología , Rhizomucor/aislamiento & purificación , Anfotericina B/uso terapéutico , Recurrencia , Persona de Mediana Edad , Triazoles/uso terapéutico , Rhizopus/aislamiento & purificaciónRESUMEN
Patients with rheumatoid arthritis (RA) who receive immunosuppressive medications have a heightened risk of infection. The goal of our study was to calculate the pooled cumulative incidence and risk of infection in patients with RA treated with Janus kinase inhibitors (JAKi). The PubMed and EMBASE databases were queried for randomized controlled trials comparing patients with RA treated with JAKi (upadacitinib, baricitinib, tofacitinib, peficitinib, or filgotinib), defined as the treatment group, compared with control subjects, defined as participants receiving placebo or treatment regimen that was similar to that of participants in the treatment group, with the exception of JAKi. The primary study endpoint was the relative risk (RR) of any-grade and severe infection. The secondary endpoints were RR and cumulative incidence of opportunistic infections, herpes zoster, and pneumonia. The Stata v17 software was used for all data analysis. Results showed that treatment with baricitinib was associated with an increased risk of any-grade (RR 1.34; 95% CI: 1.19-1.52) and opportunistic (RR 2.69; 95% CI: 1.22-5.94) infection, whereas treatment with filgotinib (RR 1.21; 95% CI: 1.05-1.39), peficitinib (RR 1.40; 95% CI: 1.05-1.86) and upadacitinib (RR 1.30; 95% CI: 1.09-1.56) was associated with increased risk of any-grade infection only. Analysis based on type of infection showed a pooled cumulative incidence of 32.44% for any-grade infections, 2.02% for severe infections, 1.74% for opportunistic infections, 1.56% for herpes zoster, and 0.49% for pneumonia in patients treated with any JAKi during the follow-up period. Treatment with specific JAKi in patients with RA is associated with an increased risk of any-grade and opportunistic infections but not severe infection. Close clinical monitoring of patients with RA treated with JAKi is required to establish the long-term infection risk profile of these agents.
Asunto(s)
Artritis Reumatoide , Azetidinas , Inhibidores de las Cinasas Janus , Piperidinas , Purinas , Pirazoles , Pirimidinas , Sulfonamidas , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/complicaciones , Humanos , Inhibidores de las Cinasas Janus/efectos adversos , Inhibidores de las Cinasas Janus/uso terapéutico , Azetidinas/efectos adversos , Azetidinas/uso terapéutico , Incidencia , Purinas/efectos adversos , Purinas/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/uso terapéutico , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Piperidinas/efectos adversos , Piperidinas/uso terapéutico , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico , Herpes Zóster/epidemiología , Herpes Zóster/inducido químicamente , Infecciones Oportunistas/epidemiología , Infecciones Oportunistas/inducido químicamente , Pirroles/efectos adversos , Pirroles/uso terapéutico , Niacinamida/análogos & derivados , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Infecciones/epidemiología , Infecciones/inducido químicamente , Ensayos Clínicos Controlados Aleatorios como Asunto , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Antirreumáticos/efectos adversos , Antirreumáticos/uso terapéutico , Triazoles/efectos adversos , Triazoles/uso terapéutico , Adamantano/análogos & derivados , PiridinasAsunto(s)
Aromatasa , Ginecomastia , Humanos , Ginecomastia/genética , Masculino , Niño , Aromatasa/genética , Anastrozol , Secuenciación del Exoma , Nitrilos , Triazoles/uso terapéutico , Fenotipo , Mutación , Mama/anomalías , Mama/patología , LinajeRESUMEN
BACKGROUND: Janus kinase (JAK) inhibitors (JAKis) are effective therapeutic agents against rheumatoid arthritis (RA). However, patients having RA with particular risk factors may have a higher incidence of adverse effects (AEs), including major cardiovascular events (MACE) and infections. In this multicenter cohort study, we aimed to clarify the risk factors affecting the drug retention of JAKis in patients with RA. METHODS: We retrospectively evaluated patients with RA who received their first JAKi (tofacitinib, baricitinib, upadacitinib, or filgotinib) at our institute. The clinical outcomes, including AEs, were recorded, particularly MACE and serious infections. The drug retention rates were analyzed using the Kaplan-Meier method, and risk factors affecting drug retention rates were determined using a multivariable Cox regression hazards model. RESULTS: Overall 184 patients with RA receiving their first use of baricitinib (57.6%), tofacitinib (23.9%), upadacitinib (12.0%), or filgotinib (6.5%) were included in this study. Fifty-six (30.4%) patients discontinued JAKi treatment owing to ineffectiveness (9.2%) or AEs, including infections (21.2%). The overall drug retention rates were significantly lower in patients treated with pan-JAKi than in those treated with JAK1 inhibitors (p = 0.03). In the Cox regression model, the presence of baseline high RA disease activity, use of glucocorticoid and treatments with pan-JAKis were associated with reduced drug retention rates of JAKis (p < 0.001, p = 0.01 and 0.04, respectively). Pan-JAKi treated patients with high disease activity had significantly lower drug retention rates (p < 0.001). CONCLUSIONS: In a real-world setting, the drug retention rates of JAKis were reduced mainly by treatment discontinuation owing to AEs. Treatment with pan-JAKis and high baseline RA disease activity were identified as predictive factors for the discontinuation of JAKis. Lower drug retention rates were found in patients receiving pan-JAKis with high disease activity than in those without high disease activity.
Asunto(s)
Artritis Reumatoide , Azetidinas , Inhibidores de las Cinasas Janus , Piperidinas , Purinas , Pirazoles , Sulfonamidas , Humanos , Artritis Reumatoide/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/efectos adversos , Azetidinas/uso terapéutico , Azetidinas/efectos adversos , Estudios Retrospectivos , Anciano , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Purinas/uso terapéutico , Purinas/efectos adversos , Sulfonamidas/uso terapéutico , Sulfonamidas/efectos adversos , Piperidinas/uso terapéutico , Piperidinas/efectos adversos , Pirimidinas/uso terapéutico , Pirimidinas/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversos , Triazoles/uso terapéutico , Triazoles/efectos adversos , Factores de Riesgo , Adulto , PiridinasRESUMEN
Purpose: Ocular melanoma is a common primary malignant ocular tumor in adults with limited effective treatments. Epigenetic regulation plays an important role in tumor development. The switching/sucrose nonfermentation (SWI/SNF) chromatin remodeling complex and bromodomain and extraterminal domain family proteins are epigenetic regulators involved in several cancers. We aimed to screen a candidate small molecule inhibitor targeting these regulators and investigate its effect and mechanism in ocular melanoma. Methods: We observed phenotypes caused by knockdown of the corresponding gene and synergistic effects with BRD inhibitor treatment and SWI/SNF complex knockdown. The effect of JQ-1 on ocular melanoma cell cycle and apoptosis was analyzed with flow cytometry. Via RNA sequencing, we also explored the mechanism of BRD4. Results: The best tumor inhibitory effect was observed for the BRD4 inhibitor (JQ-1), although there were no statistically obvious changes in the shBRD4 and shBRD9 groups. Interestingly, the inhibitory effect of JQ-1 was decrease in the shBRD4 group. JQ-1 inhibits the growth of melanoma in various cell lines and in tumor-bearing mice. We found 17 of these 28 common differentially expressed genes were downregulated after MEL270 and MEL290 cells treated with JQ-1. Four of these 17 genes, TP53I11, SH2D5, SEMA5A, and MDGA1, were positively correlated with BRD4. In TCGA database, low expression of TP53I11, SH2D5, SEMA5A, and MDGA1 improved the overall survival rate of patients. Furthermore, the disease-free survival rate was increased in the groups with low expression of TP53I11, SH2D5, and SEMA5A. Conclusions: JQ-1 may act downstream of BRD4 and suppress ocular melanoma growth by inducing G1 cell cycle arrest.
Asunto(s)
Apoptosis , Azepinas , Puntos de Control del Ciclo Celular , Proteínas de Ciclo Celular , Melanoma , Factores de Transcripción , Triazoles , Animales , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Melanoma/metabolismo , Ratones , Humanos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Azepinas/farmacología , Triazoles/farmacología , Triazoles/uso terapéutico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Úvea/tratamiento farmacológico , Neoplasias de la Úvea/genética , Neoplasias de la Úvea/patología , Neoplasias de la Úvea/metabolismo , Citometría de Flujo , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Desnudos , Proteínas que Contienen BromodominioRESUMEN
The molecular pathogenesis of exocrine pancreatic cancer involves mutations K-RAS, TP53, CDKN2A, and SMAD4. The KRAS oncogene leads to constitutively active tumor cell proliferation and is present in 90% of unresectable or metastatic pancreatic adenocarcinomas. Of these, the G12C variant of K-RAS genes accounts for 1-2% of mutations. A 65-year-old woman initially diagnosed with T3N0M0 pancreatic adenocarcinoma, underwent six cycles of neoadjuvant chemotherapy with mFOLFIRINOX followed by Whipple procedure. Her pathological stage was T4N2. She then received adjuvant mFOLFIRINOX but unfortunately her disease progressed through multiple lines of chemotherapy. Molecular analysis by Next Generation Sequence(NGS) panel revealed KRAS G12C mutation. Based on this mutational status, she was started on Sotorasib to which she had clinical response lasting for about 11 months prior to disease progression. Off-label use of Sotorasib as fourth-line treatment in our patient with KRAS G12C mutated pancreatic cancer was efficacious and relatively well tolerated.
Asunto(s)
Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Femenino , Anciano , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patología , Triazoles/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genética , Pirimidinas/uso terapéutico , Mutación , Antineoplásicos/uso terapéutico , Irinotecán/uso terapéutico , Oxaliplatino/uso terapéutico , Fluorouracilo/uso terapéutico , Leucovorina/uso terapéutico , Uso Fuera de lo Indicado , Piperazinas , PiridinasRESUMEN
OBJECTIVE: To report long-term efficacy and safety of selinexor maintenance therapy in adults with TP53 wild-type (TP53wt) stage IV or recurrent endometrial cancer (EC) who achieved partial remission (PR) or complete remission (CR) following chemotherapy. METHODS: Analysis of the prespecified, exploratory subgroup of patients with TP53wt EC from the phase 3 SIENDO study was performed. Progression-free survival (PFS) benefit in patients with TP53wt EC and across other patient subgroups were exploratory endpoints. Safety and tolerability were also assessed. RESULTS: Of the 263 patients enrolled in the SIENDO trial, 113 patients had TP53wt EC; 70/113 (61.9%) had TP53wt/proficient mismatch repair (pMMR) EC, and 29/113 (25.7%) had TP53wt/deficient mismatch repair (dMMR) EC. As of April 1, 2024, the median PFS (mPFS) for TP53wt patients who received selinexor compared with placebo was 28.4 versus 5.2â¯months (36.8-month follow-up, HR 0.44; 95% CI 0.27-0.73). A benefit in mPFS was seen with selinexor versus placebo regardless of MMR status (patients with TP53wt/pMMR EC: 39.5 vs 4.9â¯months, HR 0.36; 95% CI 0.19-0.71; patients with TP53wt/dMMR EC: 13.1 vs 3.7â¯months, HR 0.49; 95% CI 0.18-1.34). Selinexor treatment was generally manageable, with no new safety signals identified. CONCLUSION: In the phase 3 SIENDO study, selinexor maintenance therapy showed a promising efficacy signal and a manageable safety profile in the prespecified subgroup of patients with TP53wt EC who achieved a PR or CR following chemotherapy. These results are being further evaluated in an ongoing randomized phase 3 trial (NCT05611931).
Asunto(s)
Neoplasias Endometriales , Hidrazinas , Recurrencia Local de Neoplasia , Triazoles , Proteína p53 Supresora de Tumor , Humanos , Femenino , Triazoles/administración & dosificación , Triazoles/efectos adversos , Triazoles/uso terapéutico , Persona de Mediana Edad , Hidrazinas/efectos adversos , Hidrazinas/administración & dosificación , Hidrazinas/uso terapéutico , Anciano , Proteína p53 Supresora de Tumor/genética , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Estudios de Seguimiento , Supervivencia sin Progresión , Anciano de 80 o más Años , Quimioterapia de Mantención/métodos , Estadificación de NeoplasiasRESUMEN
Mucormycosis is an uncommon infection but is increasing in prevalence. Cutaneous disease is associated with burns and traumatic injuries. Cutaneous mucormycosis is the least deadly form but mortality is still approximately 36%. Burn superinfection with mucormycosis is increasingly common and can be an insidious process that may not present until the disease disseminates. We present the case of a 30-year-old male who presented to the emergency department for a rash. A rash with yellow crusting was noted to involve his scalp, face, ear, right shoulder, and parts of both feet. He had been placed on antibiotics by an urgent care a few days prior to presenting. He denied systemic symptoms, chemical exposure, change in detergent, autoimmune diseases, or travel. The patient has a history of intravenous opioid and dissociative abuse and had multiple episodes of syncope-including at his work in a factory where there were hot metals, refrigerants, and numerous corrosive chemicals. Surgical debridement revealed mucormycosis on pathology. The patient was treated with isavuconazole, surgical debridement, and skin grafting. He experienced complete recovery.