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1.
Viruses ; 13(3)2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33803811

RESUMEN

COVID-19 has become a global pandemic of the highest priority. Multiple treatment protocols have been proposed worldwide with no definitive answer for acure. A prior retrospective study showed association between bitter taste receptor 38 (T2R38) phenotypes and the severity of COVID-19. Based on this, we proposed assessing the different T2R38 phenotypes response towards a targeted treatment protocol. Starting July 2020 till December 2020, we tested subjects for T2R38 phenotypic expression (supertasters, tasters, and nontasters). Subjects who were subsequently infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (diagnosed via PCR) were included. Based on their taster status, supertasters were given dexamethasone for 4 days; tasters were given azithromycin and dexamethasone +/- hydroxychloroquine for 7 days; and nontasters were given azithromycin and dexamethasone for 12 days. Subjects were followed prospectively and their outcomes were documented. Seven hundred forty-seven COVID-19 patients were included, with 184 (24.7%) supertasters, 371 (49.6%) tasters, and192 (25.7%) nontasters. The average duration of symptoms with the treatment protocol was 5 days for supertasters, 8.1 days for tasters, and 16.2 days for nontasters. Only three subjects (0.4%) required hospitalization (3/3 nontasters). Targeted treatment protocol showed significant correlation (p < 0.05) based on patients' T2R38 phenotypic expression. Assessing treatment protocols for COVID-19 patients according to their T2R38 phenotype could provide insight into the inconsistent results obtained from the different studies worldwide. Further study is warranted on the categorization of patients based on their T2R38 phenotype.


Asunto(s)
/tratamiento farmacológico , Protocolos Clínicos , Receptores Acoplados a Proteínas G/metabolismo , /fisiología , Adulto , Azitromicina/administración & dosificación , /metabolismo , Dexametasona/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Estudios Prospectivos , Receptores Acoplados a Proteínas G/genética , Estudios Retrospectivos , Gusto
2.
Am J Case Rep ; 22: e930733, 2021 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-33907174

RESUMEN

BACKGROUND Intravenous (IV) dexamethasone is widely used in critical illness, chemotherapy, or severe COVID-19. Although glucocorticoid-induced hyperglycemia (GCIH) is well-known, there is no report describing the glycemic profile following a single dose of IV dexamethasone as captured on continuous glucose monitoring (CGM) in a patient with diabetes treated with insulin. CASE REPORT A 70-year-old woman with diabetes and pancreatic adenocarcinoma was treated with chemotherapy containing dexamethasone every other week. CGM data of 23 cycles revealed a reproducible triphasic glycemic pattern consisting of a constant hyperglycemia period, followed by a transient improvement, and ending with another hyperglycemic plateau. Given this recurrent pattern, basal insulin and correction insulin were adjusted with subsequent GCIH attenuation. CONCLUSIONS This is the first report of CGM glycemic profile following recurring doses of IV dexamethasone in a patient with diabetes treated with basal-bolus insulin. The understanding of triphasic glycemic pattern allows optimal glycemic management.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos Hormonales/efectos adversos , Automonitorización de la Glucosa Sanguínea/efectos adversos , Dexametasona/administración & dosificación , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hiperglucemia/inducido químicamente , Insulina/efectos adversos , Neoplasias Pancreáticas/tratamiento farmacológico , Administración Intravenosa , Anciano , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/uso terapéutico , Glucemia , Dexametasona/efectos adversos , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Humanos , Hipoglucemiantes/efectos adversos , Insulina/administración & dosificación , Recurrencia Local de Neoplasia , Neoplasias Pancreáticas/patología
3.
Lancet Haematol ; 8(4): e289-e298, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33770484

RESUMEN

BACKGROUND: Primary immune thrombocytopenia is an autoimmune bleeding disorder. Preclinical reports suggest that the sialidase inhibitor oseltamivir induces a platelet response in the treatment of immune thrombocytopenia. This study investigated the activity and safety of dexamethasone plus oseltamivir versus dexamethasone alone as initial treatment in adult patients with primary immune thrombocytopenia. METHODS: This multicentre, randomised, open-label, parallel group, phase 2 trial was done in five tertiary medical hospitals in China. Eligible patients were aged 18 years or older with newly diagnosed, treatment-naive primary immune thrombocytopenia. Participants were randomly assigned (1:1), using block randomisation, to receive either dexamethasone (orally at 40 mg per day for 4 days) plus oseltamivir (orally at 75 mg twice a day for 10 days) or dexamethasone monotherapy (orally at 40 mg a day for 4 days). Patients who did not respond to treatment (platelet counts remained <30 × 109 cells per L or showed bleeding symptoms by day 10) were given an additional cycle of dexamethasone for 4 days in each group. Patients in the dexamethasone plus oseltamivir group who relapsed (platelet counts reduced again to <30 × 109 cells per L) after an initial response were allowed a supplemental course of oseltamivir (75 mg twice a day for 10 days). The coprimary endpoints were 14-day initial overall response and 6-month overall response. Complete response was defined as a platelet count at or above 100 × 109 cells per L and an absence of bleeding. Partial response was defined as a platelet count at or above 30 × 109 cells per L but less than 100 × 109 cells per L and at least a doubling of the baseline platelet count and an absence of bleeding. A response lasting for at least 6 months without any additional primary immune thrombocytopenia-specific intervention was defined as sustained response. All patients who were randomly assigned and received the allocated intervention were included in the modified intention-to-treat population analysis. This study has been completed and is registered with ClinicalTrials.gov, number NCT01965626. FINDINGS: From Feb 1, 2016, to May 1, 2019, 120 patients were screened for eligibility, of whom 24 were ineligible and excluded, 96 were enrolled and randomly assigned to receive dexamethasone plus oseltamivir (n=47) or dexamethasone (n=49), and 90 were included in the modified intention-to-treat analysis. Six patients did not receive the allocated intervention. Patients in the dexamethasone plus oseltamivir group had a significantly higher initial response rate (37 [86%] of 43 patients) than did those in the dexamethasone group (31 [66%] of 47 patients; odds ratio [OR] 3·18; 95 CI% 1·13-9·23; p=0·030) at day 14. The 6-month sustained response rate in the dexamethasone plus oseltamivir group was also significantly higher than that in the dexamethasone group (23 [53%] vs 14 [30%]; OR 2·17; 95 CI% 1·16-6·13; p=0·032). During the median follow-up of 8 months (IQR 5-14), two of 90 patients discontinued treatment due to serious adverse events (grade 3); one (2%) patient with general oedema in the dexamethasone plus oseltamivir group and one (2%) patient with fever in the dexamethasone group. The most frequently observed adverse events of any grade were fatigue (five [12%] of 43 in the dexamethasone plus oseltamivir group vs eight [17%] of 47 in the dexamethasone group), gastrointestinal reactions (eight [19%] vs three [6%]), insomnia (seven [16%] vs four [9%]), and anxiety (five [12%] vs three [6%]). There were no grade 4 or 5 adverse events and no treatment-related deaths. INTERPRETATION: Dexamethasone plus oseltamivir offers a readily available combination therapy in the management of newly diagnosed primary immune thrombocytopenia. The preliminary activity of this combination warrants further investigation. Multiple cycles of oseltamivir, as a modification of current first-line treatment, might be more effective in maintaining the platelet response. FUNDING: National Natural Science Foundation of China.


Asunto(s)
Dexametasona/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Glucocorticoides/uso terapéutico , Oseltamivir/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Administración Oral , Adulto , China/epidemiología , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/métodos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Femenino , Estudios de Seguimiento , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Hemorragia/epidemiología , Humanos , Análisis de Intención de Tratar/métodos , Masculino , Persona de Mediana Edad , Oseltamivir/administración & dosificación , Oseltamivir/efectos adversos , Recuento de Plaquetas/estadística & datos numéricos , Recuento de Plaquetas/tendencias , Púrpura Trombocitopénica Idiopática/inmunología , Seguridad , Resultado del Tratamiento
4.
Lancet Haematol ; 8(4): e299-e304, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33770485

RESUMEN

To our knowledge, no study has evaluated the quality of control groups in randomised controlled trials of multiple myeloma. We aimed to do a systematic review of randomised controlled trials of multiple myeloma to ascertain the quality of the control groups used. PubMed (MEDLINE), Embase, Cochrane Controlled Register of Trials, and CinicalTrials.gov were searched for articles of randomised controlled trials of multiple myeloma based in the USA that initiated participant enrolment between Jan 1, 2010, and June 30, 2020. A control group regimen was considered to be inferior if a previous randomised controlled trial had shown an improved progression-free survival versus the control group before enrolment. Of 49 identified randomised controlled trials, seven (14%) began enrolling patients into inferior control groups after an existing superior regimen to the control had already been published. Nine (18%) of the 49 trials continued enrolment on substandard control groups after data emerged during the study enrolment period. The median time that newer data emerged regarding inferiority of the control group from the time a trial first enrolled a patient was 13 months (IQR 8-29 months). 12 (75%) of these 16 randomised controlled trials are published, and nine (75%) of the 12 published trials had overlapping investigators with trials that had previously shown the inferiority of the control group being used. Greater scrutiny on the quality of control groups in randomised controlled trials of multiple myeloma is needed.


Asunto(s)
Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/uso terapéutico , Bortezomib/administración & dosificación , Bortezomib/uso terapéutico , Grupos Control , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/uso terapéutico , Lenalidomida/administración & dosificación , Lenalidomida/uso terapéutico , Mieloma Múltiple/epidemiología , Supervivencia sin Progresión , Control de Calidad , Inducción de Remisión/métodos , Estados Unidos/epidemiología
5.
Medicine (Baltimore) ; 100(11): e25161, 2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33726001

RESUMEN

RATIONALE: An intravitreal dexamethasone (IV-DEX) implant is safe and effective for the treatment of macular edemas; however, the efficacy of IV-DEX implants in silicone oil (SO)-filled eyes remains controversial. There is no previous study comparing an IV-DEX implant in the same eye with and without intravitreal SO. PATIENT CONCERNS: A 72-year-old man with proliferative diabetic retinopathy, macular edema, and rhegmatogenous retinal detachment, treated with pars plana vitrectomy with SO tamponade had refractory macular edema. DIAGNOSIS: Refractory macular edema. INTERVENTION: Subtenon triamcinolone injection, intravitreal anti-vascular endothelial growth factor injection, and IV-DEX implantation were performed; this was followed by intravitreal SO removal combined with IV-DEX implantation. OUTCOMES: The macular edema did not decrease significantly with posterior subtenon triamcinolone injection, intravitreal anti-vascular endothelial growth factor injection, and IV-DEX implantation; however, the edema was relieved after SO removal and a new IV-DEX implantation. LESSONS: IV-DEX implant may be less efficacious in the treatment of macular edema in an SO-filled eye than that in a normal vitreous cavity.


Asunto(s)
Dexametasona/administración & dosificación , Retinopatía Diabética/tratamiento farmacológico , Edema Macular/tratamiento farmacológico , Desprendimiento de Retina/tratamiento farmacológico , Aceites de Silicona/administración & dosificación , Anciano , Remoción de Dispositivos , Implantes de Medicamentos/administración & dosificación , Humanos , Inyecciones Intravítreas , Masculino , Triamcinolona/administración & dosificación , Factores de Crecimiento Endotelial Vascular/administración & dosificación , Vitrectomía/métodos
6.
Medicine (Baltimore) ; 100(11): e25188, 2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33726009

RESUMEN

RATIONALE: The HLH-94 protocol is a standard induction treatment for hemophagocytic lymphohistiocytosis. However, about 30% of patients may not respond. Ruxolitinib has been clinically proven to be an effective treatment for hemophagocytic lymphohistiocytosis (HLH). PATIENT CONCERNS: A previously healthy 14-year-old girl presented to the local hospital with a 4-day history of persistent fever and sore throat. DIAGNOSIS: Clinical and laboratory tests revealed fever >38.5°C, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, and an elevated interleukin-2 receptor level. INTERVENTION: This patient was treated with ruxolitinib and the HLH-94 protocol. OUTCOMES: The patient's clinical and some laboratory indices improved. Unfortunately, vital signs such as respiratory function and consciousness did not improve. LESSONS: This case report highlights the effect of using ruxolitinib in conjunction with the HLH-94 protocol. However, safety evaluation of this regimen was not performed because critically ill patient died too fast.


Asunto(s)
Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Herpesvirus Humano 4 , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Pirazoles/administración & dosificación , Adolescente , Protocolos Clínicos , Dexametasona/administración & dosificación , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Quimioterapia Combinada , Infecciones por Virus de Epstein-Barr/complicaciones , Etopósido/administración & dosificación , Resultado Fatal , Femenino , Humanos , Quimioterapia de Inducción , Unidades de Cuidados Intensivos , Linfohistiocitosis Hemofagocítica/virología , Metilprednisolona/administración & dosificación , Polietilenglicoles/administración & dosificación , Resultado del Tratamiento
7.
AAPS PharmSciTech ; 22(3): 103, 2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33712964

RESUMEN

The topical use of rosmarinic acid (RA) in skin inflammatory pathologies is restricted due to its poor water solubility, poor permeability, and chemical instability. In this study, RA-loaded transethosomes-in-Carbopol® formulations have been developed to evaluate its anti-inflammatory activity on imiquimod-induced psoriasis-like skin inflammation in mice. In vitro release profiles demonstrated sustained behavior due to the retentive action of gel and the entrapment of RA into the vesicles. However, the low viscosity of the combined formulation increased the drug release rate. Animal evaluation of anti-inflammatory activity demonstrated that transethosomes-in-gel containing dexamethasone (Dex-TE-Gel), as positive control, showed effect in all the pro-inflammatory parameters evaluated, evidencing that these drug-loaded nanocarriers have been effectively reached the site of action. In addition, transethosomes-in-gel containing RA (RA-TE-Gel) formulations produced a great reduction in the punch edema (P < 0.001) and in TNF-α and IL-6 (P < 0.05). However, non-significant differences were obtained for IL-1ß, IL17, and MPO. Despite the protecting effect of Carbopol® and transethosomes on oxidation index and antioxidant activity of RA over the 7 days of treatment, however, a degradation process of this antioxidant to caffeic acid may be the cause of these in vivo results. We have also checked that the pH existing into the intercellular space of damaged cells (pH 6.8) may be affecting. Therefore, our results suggest that RA-TE-Gel could act as an effective RA formulation for skin delivery; further studies will help to understand the loss of activity at the cellular level.


Asunto(s)
Cinamatos/administración & dosificación , Cinamatos/uso terapéutico , Depsidos/administración & dosificación , Depsidos/uso terapéutico , Psoriasis/tratamiento farmacológico , Administración Cutánea , Animales , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Portadores de Fármacos , Composición de Medicamentos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Femenino , Geles , Ratones , Ratones Endogámicos BALB C , Viscosidad
8.
Trials ; 22(1): 172, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33648568

RESUMEN

OBJECTIVES: The primary objective of this study is to test the hypothesis that administration of dexamethasone 20 mg is superior to a 6 mg dose in adult patients with moderate or severe ARDS due to confirmed COVID-19. The secondary objective is to investigate the efficacy and safety of dexamethasone 20 mg versus dexamethasone 6 mg. The exploratory objective of this study is to assess long-term consequences on mortality and quality of life at 180 and 360 days. TRIAL DESIGN: REMED is a prospective, phase II, open-label, randomised controlled trial testing superiority of dexamethasone 20 mg vs 6 mg. The trial aims to be pragmatic, i.e. designed to evaluate the effectiveness of the intervention in conditions that are close to real-life routine clinical practice. PARTICIPANTS: The study is multi-centre and will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. INCLUSION CRITERIA: Subjects will be eligible for the trial if they meet all of the following criteria: 1. Adult (≥18 years of age) at time of enrolment; 2. Present COVID-19 (infection confirmed by RT-PCR or antigen testing); 3. Intubation/mechanical ventilation or ongoing high-flow nasal cannula (HFNC) oxygen therapy; 4. Moderate or severe ARDS according to Berlin criteria: • Moderate - PaO2/FiO2 100-200 mmHg; • Severe - PaO2/FiO2 < 100 mmHg; 5. Admission to ICU in the last 24 hours. EXCLUSION CRITERIA: Subjects will not be eligible for the trial if they meet any of the following criteria: 1. Known allergy/hypersensitivity to dexamethasone or excipients of the investigational medicinal product (e.g. parabens, benzyl alcohol); 2. Fulfilled criteria for ARDS for ≥14 days at enrolment; 3. Pregnancy or breastfeeding; 4. Unwillingness to comply with contraception measurements from enrolment until at least 1 week after the last dose of dexamethasone (sexual abstinence is considered an adequate contraception method); 5. End-of-life decision or patient is expected to die within next 24 hours; 6. Decision not to intubate or ceilings of care in place; 7. Immunosuppression and/or immunosuppressive drugs in medical history: a) Systemic immunosuppressive drugs or chemotherapy in the past 30 days; b) Systemic corticosteroid use before hospitalization; c) Any dose of dexamethasone during the present hospital stay for COVID-19 for ≥5 days before enrolment; d) Systemic corticosteroids during present hospital stay for conditions other than COVID-19 (e.g. septic shock); 8. Current haematological or generalized solid malignancy; 9. Any contraindication for corticosteroid administration, e.g. • intractable hyperglycaemia; • active gastrointestinal bleeding; • adrenal gland disorders; • presence of superinfection diagnosed with locally established clinical and laboratory criteria without adequate antimicrobial treatment; 10. Cardiac arrest before ICU admission; 11. Participation in another interventional trial in the last 30 days. INTERVENTION AND COMPARATOR: Dexamethasone solution for injection/infusion is the investigational medicinal product as well as the comparator. The trial will assess two doses, 20 mg (investigational) vs 6 mg (comparator). Patients in the intervention group will receive dexamethasone 20 mg intravenously once daily on day 1-5, followed by dexamethasone 10 mg intravenously once daily on day 6-10. Patients in the control group will receive dexamethasone 6 mg day 1-10. All authorized medicinal products containing dexamethasone in the form of solution for i.v. injection/infusion can be used. MAIN OUTCOMES: Primary endpoint: Number of ventilator-free days (VFDs) at 28 days after randomisation, defined as being alive and free from mechanical ventilation. SECONDARY ENDPOINTS: a) Mortality from any cause at 60 days after randomisation; b) Dynamics of inflammatory marker (C-Reactive Protein, CRP) change from Day 1 to Day 14; c) WHO Clinical Progression Scale at Day 14; d) Adverse events related to corticosteroids (new infections, new thrombotic complications) until Day 28 or hospital discharge; e) Independence at 90 days after randomisation assessed by Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days through telephone structured interviews using the Barthel Index. RANDOMISATION: Randomisation will be carried out within the electronic case report form (eCRF) by the stratified permuted block randomisation method. Allocation sequences will be prepared by a statistician independent of the study team. Allocation to the treatment arm of an individual patient will not be available to the investigators before completion of the whole randomisation process. The following stratification factors will be applied: • Age <65 and ≥ 65; • Charlson Comorbidity index (CCI) <3 and ≥3; • CRP <150 mg/L and ≥150 mg/L • Trial centre. Patients will be randomised in a 1 : 1 ratio into one of the two treatment arms. Randomisation through the eCRF will be available 24 hours every day. BLINDING (MASKING): This is an open-label trial in which the participants and the study staff will be aware of the allocated intervention. Blinded pre-planned statistical analysis will be performed. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size is calculated to detect the difference of 3 VFDs at 28 days (primary efficacy endpoint) between the two treatment arms with a two-sided type I error of 0.05 and power of 80%. Based on data from a multi-centre randomised controlled trial in COVID-19 ARDS patients in Brazil and a multi-centre observational study from French and Belgian ICUs regarding moderate to severe ARDS related to COVID-19, investigators assumed a standard deviation of VFD at 28 days as 9. Using these assumptions, a total of 142 patients per treatment arm would be needed. After adjustment for a drop-out rate, 150 per treatment arm (300 patients per study) will be enrolled. TRIAL STATUS: This is protocol version 1.1, 15.01.2021. The trial is due to start on 2 February 2021 and recruitment is expected to be completed by December 2021. TRIAL REGISTRATION: The study protocol was registered on EudraCT No.:2020-005887-70, and on December 11, 2020 on ClinicalTrials.gov (Title: Effect of Two Different Doses of Dexamethasone in Patients With ARDS and COVID-19 (REMED)) Identifier: NCT04663555 with a last update posted on February 1, 2021. FULL PROTOCOL: The full protocol (version 1.1) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the standard formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Asunto(s)
/terapia , Dexametasona/administración & dosificación , Glucocorticoides/administración & dosificación , Respiración Artificial , /terapia , /complicaciones , Ensayos Clínicos Fase II como Asunto , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Estudios de Equivalencia como Asunto , Humanos , Tiempo de Internación , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , /etiología
9.
Signal Transduct Target Ther ; 6(1): 107, 2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-33658482

RESUMEN

Synthetic glucocorticoid dexamethasone is the first trial-proven drug that reduces COVID-19 mortality by suppressing immune system. In contrast, interferons are a crucial component of host antiviral immunity and can be directly suppressed by glucocorticoids. To investigate whether therapeutic interferons can compensate glucocorticoids-induced loss of antiviral immunity, we retrospectively analyzed a cohort of 387 PCR-confirmed COVID-19 patients with quasi-random exposure to interferons and conditional exposure to glucocorticoids. Among patients receiving glucocorticoids, early interferon therapy was associated with earlier hospital discharge (adjusted HR 1.68, 95% CI 1.19-2.37) and symptom relief (adjusted HR 1.48, 95% CI 1.06-2.08), while these associations were insignificant among glucocorticoids nonusers. Early interferon therapy was also associated with lower prevalence of prolonged viral shedding (adjusted OR 0.24, 95% CI 0.10-0.57) only among glucocorticoids users. Additionally, these associations were glucocorticoid cumulative dose- and timing-dependent. These findings reveal potential therapeutic synergy between interferons and glucocorticoids in COVID-19 that warrants further investigation.


Asunto(s)
/tratamiento farmacológico , Dexametasona/administración & dosificación , Interferones/administración & dosificación , Adulto , /mortalidad , Dexametasona/agonistas , Sinergismo Farmacológico , Femenino , Humanos , Interferones/agonistas , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
10.
Ann Hematol ; 100(4): 995-1002, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33651193

RESUMEN

Waldenstrom macroglobulinemia (WM) is a rare type of non-Hodgkin lymphoma with great heterogeneity, and the data of peripheral blood T-lymphocyte subsets in WM are limited. This study aimed to investigate the clinical correlation and distribution of circulating T-lymphocyte subsets in newly diagnosed WM patients. We retrospectively searched medical records for 86 newly diagnosed WM patients. Comparisons of the absolute CD3+ T-lymphocyte count (ACD3C), CD4+ T-lymphocyte count (ACD4C), CD8+ T-lymphocyte count (ACD8C), and CD4+/CD8+ T-lymphocyte ratio (CD4+/CD8+) as continuous parameters in different groups were calculated. Univariate and multivariate analyses were used to assess prognostic factors for overall survival (OS) and progression-free survival (PFS). Young patients (<65 years) had lower ACD8C levels and a higher CD4+/CD8+ ratio. And the lower level of ß2-microglobulin (<3 mg/L) was associated with a higher CD4+/CD8+ ratio. With a median follow-up of 25 months, the univariate survival analysis showed that CD4+/CD8+ ratio inversion (CD4+/CD8+<1.5) was associated with shorter OS and PFS, and multivariate analysis confirmed that inverted CD4+/CD8+ ratio could be an independent adverse prognostic factor for OS and PFS. Additionally, initial treatment with rituximab or bortezomib significantly improved the PFS and OS of CD4+/CD8+ inversion patients but did not affect normal CD4+/CD8+ patients. We show that low circulating CD4+/CD8+ ratio at diagnosis is an adverse prognostic factor in WM patients and that first-line therapy which included rituximab or bortezomib significantly improved PFS and OS for patients with CD4+/CD8+ ratio less than 1.5.


Asunto(s)
Relación CD4-CD8 , Macroglobulinemia de Waldenström/sangre , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/administración & dosificación , Antineoplásicos Alquilantes/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/administración & dosificación , Dexametasona/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Estudios Retrospectivos , Rituximab/administración & dosificación , Tasa de Supervivencia , Resultado del Tratamiento , Macroglobulinemia de Waldenström/tratamiento farmacológico , Macroglobulinemia de Waldenström/genética , Macroglobulinemia de Waldenström/mortalidad , Microglobulina beta-2/análisis
11.
Nat Med ; 27(3): 491-503, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33619369

RESUMEN

Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination. The primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate, progression-free survival and overall survival. Treatment was safe and well tolerated; deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary refractory and early relapsed patients, with 11 healthy subjects and 15 newly diagnosed MM patients, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR-Cas9 deletion of PPIA or inhibition of PPIA with a small molecule inhibitor (ciclosporin) significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Análisis de la Célula Individual/métodos , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Estudios de Casos y Controles , Dexametasona/administración & dosificación , Resistencia a Antineoplásicos , Femenino , Humanos , Lenalidomida/administración & dosificación , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Oligopéptidos/administración & dosificación , Resultado del Tratamiento
12.
Acta Anaesthesiol Scand ; 65(5): 702-710, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33583027

RESUMEN

BACKGROUND: Coronavirus disease 2019 (COVID-19) can lead to severe hypoxic respiratory failure and death. Corticosteroids decrease mortality in severely or critically ill patients with COVID-19. However, the optimal dose remains unresolved. The ongoing randomised COVID STEROID 2 trial investigates the effects of higher vs lower doses of dexamethasone (12 vs 6 mg intravenously daily for up to 10 days) in 1,000 adult patients with COVID-19 and severe hypoxia. METHODS: This protocol outlines the rationale and statistical methods for a secondary, pre-planned Bayesian analysis of the primary outcome (days alive without life support at day 28) and all secondary outcomes registered up to day 90. We will use hurdle-negative binomial models to estimate the mean number of days alive without life support in each group and present results as mean differences and incidence rate ratios with 95% credibility intervals (CrIs). Additional count outcomes will be analysed similarly and binary outcomes will be analysed using logistic regression models with results presented as probabilities, relative risks and risk differences with 95% CrIs. We will present probabilities of any benefit/harm, clinically important benefit/harm and probabilities of effects smaller than pre-defined clinically minimally important differences for all outcomes analysed. Analyses will be adjusted for stratification variables and conducted using weakly informative priors supplemented by sensitivity analyses using sceptic priors. DISCUSSION: This secondary, pre-planned Bayesian analysis will supplement the primary, conventional analysis and may help clinicians, researchers and policymakers interpret the results of the COVID STEROID 2 trial while avoiding arbitrarily dichotomised interpretations of the results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04509973; EudraCT: 2020-003363-25.


Asunto(s)
/tratamiento farmacológico , Dexametasona/administración & dosificación , Hipoxia/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Teorema de Bayes , Humanos
14.
Eur J Pharmacol ; 897: 173947, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33607104

RESUMEN

The aim of this study was to evaluate the clinical effects of dexamethasone administration in patients with mild to moderate acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19). The study included 50 patients who were randomly assigned to the dexamethasone group or control group. Dexamethasone was administered at a dose of 20 mg/day from day 1-5 and then at 10 mg/day from day 6-10. The need for invasive mechanical ventilation, death rate, duration of clinical improvement, length of hospital stay, and radiological changes in the computed tomography scan were assessed. The results revealed that 92% and 96% of patients in the dexamethasone and control groups, respectively, required noninvasive ventilation (P = 0.500). Among them, 52% and 44% of patients in the dexamethasone and control groups, respectively, required invasive mechanical ventilation (P = 0.389). At the end of the study, 64% of patients in the dexamethasone group and 60% of patients in the control group died (P = 0.500); the remaining patients were discharged from the hospital during the 28-day follow-up period. The median length of hospital stay was 11 days in the dexamethasone group and 6 days in the control group (P = 0.036) and the median length of hospital stay was 7 days in the dexamethasone group and 3 days in the control group (P < 0.001). No significant differences were observed in the other outcomes. This study showed that corticosteroid administration had no clinical benefit in patients with COVID-19-induced mild to moderate ARDS.


Asunto(s)
Antiinflamatorios/uso terapéutico , /tratamiento farmacológico , Dexametasona/uso terapéutico , /etiología , Adulto , Anciano , Antiinflamatorios/administración & dosificación , Dexametasona/administración & dosificación , Femenino , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Resultados Negativos , Respiración Artificial , Tomografía Computarizada por Rayos X , Insuficiencia del Tratamiento
16.
Ann Hematol ; 100(4): 1039-1047, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33634350

RESUMEN

Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a type of rare and distinct entity of non-Hodgkin lymphoma with poor prognosis. It is important to evaluate the early treatment response accurately to decide further treatment strategy. 18F-FDG PET/CT plays an important role in response evaluation and prognostic prediction in some kinds of lymphomas. However, data available regarding patients with ENKTL are limited. Thus, in this prospective study, we analyzed the prognostic value of 18F-FDG PET/CT in ENKTL. Thirty-four patients with newly diagnosed ENKTL were enrolled in this phase 2 study (NCT02825147, July 7, 2016). The patients received pre-, mid-, and end-treatment 18F-FDG PET/CT scans. Deauville score (DS), maximal standardized uptake values (SUVmax), and the change in SUVmax (ΔSUVmax) were recorded for response assessment. The median follow-up period was 42.2 months. The 2-year overall survival (OS) and progression-free survival (PFS) were 82.4% and 73.5%, respectively. Univariate analysis revealed that Ann Arbor stage (P < 0.002), mid-treatment DS (P = 0.005), mid-SUVmax (P = 0.001), mid-∆SUVmax (P = 0.004), end-treatment DS (P < 0.001), and end-SUVmax (P = 0.014) were prognostic factors for OS. Ann Arbor stage (P = 0.001), mid-treatment DS (P = 0.008), mid-SUVmax (P = 0.029), mid-∆SUVmax (P < 0.001), and end-treatment DS (P =0.021) were of prognostic significance for PFS. Multivariate analysis showed that mid-SUVmax (P = 0.042) and DS at the middle (P = 0.050) and end (P = 0.044) of treatment were significant independent predictors of PFS. 18F-FDG PET/CT is useful for predicting the prognosis of ENKTL.


Asunto(s)
Linfoma Extranodal de Células NK-T/diagnóstico por imagen , Cavidad Nasal , Tomografía Computarizada por Tomografía de Emisión de Positrones , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Asparaginasa/administración & dosificación , Dexametasona/administración & dosificación , Etopósido/administración & dosificación , Femenino , Radioisótopos de Flúor , Fluorodesoxiglucosa F18 , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Linfoma Extranodal de Células NK-T/tratamiento farmacológico , Linfoma Extranodal de Células NK-T/mortalidad , Linfoma Extranodal de Células NK-T/radioterapia , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Radiofármacos , Radioterapia de Alta Energía , Sensibilidad y Especificidad , Adulto Joven
17.
J Clin Neurosci ; 84: 38-41, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33485596

RESUMEN

Reversible cerebral vasoconstriction syndrome (RCVS) is an uncommon disorder characterised by thunderclap headache and self-resolving angiographic vasospasm in the presence or absence of neurological deficit. We present the first case of RCVS likely precipitated by a complex array of confounding factors including a hyperosmolar hyperglycaemic state (HHS), induction chemotherapy with cyclophosphamide, non-Hodgkin's lymphoma, pancytopenia and previous blood transfusions. However, the clinical presentation in this case of altered conscious state followed by thunderclap headache was highly suggestive of HHS being the crucial inciting factor. This report of RCVS associated with HHS lends unique insight into key underlying pathophysiological mechanisms, and warns of the need to maintain a high index of suspicion for this elusive condition given the dynamic and transient nature of its clinical and radiological features.


Asunto(s)
Coma Hiperglucémico Hiperosmolar no Cetósico/complicaciones , Vasoespasmo Intracraneal/etiología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Cefaleas Primarias/etiología , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Quimioterapia de Inducción/métodos , Persona de Mediana Edad , Vincristina/administración & dosificación
18.
Am J Hematol ; 96(4): E114-E117, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33476436
19.
Int J Mol Sci ; 22(2)2021 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-33440880

RESUMEN

Osteoarthritis (OA) remains one of the common degenerative joint diseases and a major cause of pain and disability in older adult individuals. Oral administration of non-steroidal anti-inflammatory drugs (NSAIDs) (such as diclofenac, DIC) or intra-articular injected gluco-corticosteroids (such as dexamethasone, DEX) were the conventional treatment strategies for OA to reduce joint pain. Current limitations for both drugs including severe adverse effects with risks of toxicity were noted. The aim of the present study was to generate a novel OA treatment formulation hyaluronic acid (HA)-Liposomal (Lipo)-DIC/DEX to combat joint pain. The formulation was prepared by constructing DIC with DEX-loaded nanostructured lipid carriers Lipo-DIC/DEX mixed with hyaluronic acid (HA) for prolonged OA application. The prepared Lipo-DIC/DEX nanoparticles revealed the size as 103.6 ± 0.3 nm on average, zeta potential as -22.3 ± 4.6 mV, the entrapment efficiency of 90.5 ± 5.6%, and the DIC and DEX content was 22.5 ± 4.1 and 2.5 ± 0.6%, respectively. Evidence indicated that HA-Lipo-DIC/DEX could reach the effective working concentration in 4 h and sustained the drug-releasing time for at least 168 h. No significant toxicities but increased cell numbers were observed when HA-Lipo-DIC/DEX co-cultured with articular chondrocytes cells. Using live-animal In vivo imaging system (IVIS), intra-articular injection of each HA-Lipo-DIC/DEX sufficed to reduce knee joint inflammation in OA mice over a time span of four weeks. Single-dose injection could reduce the inflammation volume down to 77.5 ± 5.1% from initial over that time span. Our results provided the novel drug-releasing formulation with safety and efficiency which could be a promising system for osteoarthritis pain control.


Asunto(s)
Dexametasona/administración & dosificación , Diclofenaco/química , Ácido Hialurónico/química , Liposomas , Nanopartículas/química , Animales , Portadores de Fármacos/química , Liberación de Fármacos , Humanos , Cinética , Elastasa de Leucocito/metabolismo , Ratones , Estructura Molecular , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo
20.
Ann Hematol ; 100(3): 725-734, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33432438

RESUMEN

Multiple myeloma (MM) is an incurable disease, and patients usually receive multiple lines of therapy. Due to the abundance of novel treatments for MM, we conducted a network meta-analysis to identify combinations that could fare better than others in relapsed/refractory MM, in the setting of novel drugs. We searched PubMed and Cochrane databases for phase III trials in previously treated MM that had lenalidomide or bortezomib in the control arm. The primary endpoint was progression-free survival (PFS), extracted as hazard-ratio. We used the P score to rank treatments. Thirteen studies were included. All but two studies compared one novel agent against two, with or without dexamethasone. Based on the P score, daratumumab and pegylated liposomal doxorubicin had a higher probability of achieving better PFS, followed by isatuximab, carfilzomib, pomalidomide, and panobinostat. Although most overall survival data were not mature enough, the addition of a second or third novel agent to either immunomodulatory (IMID) or proteasome inhibitor (PI) backbone seemed to improve survival (HR = 0.84, 95CI 0.77-0.92). Severe adverse events were more frequent with isatuximab, panobinostat, and pomalidomide. In summary, in the absence of trials directly comparing two novel agents-based therapies, we provide a tool that indirectly compares these newer therapies and that can help physicians to prioritize some regimens over others.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/administración & dosificación , Resistencia a Antineoplásicos , Lenalidomida/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Bortezomib/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Resistencia a Antineoplásicos/efectos de los fármacos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Humanos , Lenalidomida/efectos adversos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/epidemiología , Mieloma Múltiple/patología , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Metaanálisis en Red , Supervivencia sin Progresión , Recurrencia
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