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1.
Hematology ; 26(1): 652-655, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34474661

RESUMO

OBJECTIVES: Myeloma relapse remains challenging. Daratumumab (dara) with immunomodulatory agents (IMiD) and dexamethasone (dex) was proven highly effective in relapsed or refractory multiple myeloma (RRMM) in randomized controlled trials. The recommended schedule of dara is weekly for eight doses, followed by 2-weekly for eight doses, and then every 4-weekly thereafter. However, the cost of daratumumab is daunting, precluding widespread and prolonged use in some countries. In this study, we aimed to evaluate the efficacy of using a 3-weekly daratumumab regimen in RRMM. METHODS: Thirteen RRMM patients were treated with dara-IMiD-dex till maximal response, followed by single-agent IMiD maintenance until disease progression. Dara (every 6 weekly) would be added upon significant biochemical disease progression. RESULTS: After a median of four daratumumab infusions (range: 3-10), the best responses included complete response (CR) in seven patients (53.8%), very good partial response (VGPR) in four patients (30.8%), and partial response (PR) in two patients (15.4%). The median time to VGPR was four weeks. At 10 months, the overall survival was 90%, and progression-free survival was 54.7%. Two of three patients tested achieved MRD-ve CR. Another patient, who had PET-CT reassessment, showed PET-ve CR. DISCUSSION: Despite less frequent daratumumab use, we reported rapid responses with a median time to VGPR of only four weeks, and a response rate of 100% including CR rate of 54%. Despite less frequent daratumumab use, grade ¾ neutropenia remained common with a frequency comparable to that observed in Pollux. CONCLUSION: This 3-weekly dara-IMiD-dex regimen preserves a high efficacy with rapid, deep responses including MRD-ve and PET-ve CR, hence a cost-effective regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Lenalidomida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Recidiva , Taxa de Sobrevida , Talidomida/administração & dosagem , Talidomida/análogos & derivados
2.
Medicine (Baltimore) ; 100(34): e27064, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449500

RESUMO

BACKGROUND: Dexmedetomidine (Dexm), a selective alpha-2 adrenoceptor agonist, and dexamethasone (Dexa), a very potent and highly selective glucocorticoid, have both been proven effectively to prolong the duration of local anesthetics (LA) in regional anesthesia. However, data comparing the efficacy of Dexm and Dexa as perineural adjuvants are inconsistent. Therefore, this systematic review and meta-analysis of randomized and quasi-randomized controlled trials (RCTs) was conducted to compare the effects of Dexm and Dexa when used as LA adjuvants on peripheral nerve block (PNB). METHODS: We systematically searched PubMed, Cochrane Library, EMBASE, Web of Science, and ScienceDirect databases up to October, 2020. The primary outcome was the duration of analgesia. Secondary outcomes included incidence of rescue analgesia, cumulative opioid consumption, time required for onset of sensory and motor blockades, duration of sensory and motor blockades, incidence of postoperative nausea and vomiting (PONV), and side effect-associated outcomes (e.g., bradycardia, sedation, hypotension, rates of infection, and neurological complications). The study was registered on PROSPERO, number CRD42020188796. RESULTS: After screening of full-text relevant articles, 13 RCTs that met the inclusion criteria were retrieved for this systematic review. It was revealed that perineural Dexm provided equivalent analgesic duration to perineural Dexa. Besides, the intake of Dexm increased the incidence of rescue analgesia in limbs surgery, as well as the cumulative opioid consumption, and decreased the time required for onset of sensory and motor blockades for long-acting LA (all P < .05). Other analysis revealed insignificant difference between the 2 groups in terms of the incidence of PONV (P > .05). Additionally, 2 studies demonstrated that Dexm possesses more sedative properties than Dexa (P < .05). CONCLUSIONS: This meta-analysis indicated that the analgesic duration of Dexm and Dexa as LA adjuvants in PNB is the same. Meanwhile, the effects of perineural Dexm and Dexa on some secondary outcomes, including the incidence of rescue analgesia, cumulative opioid consumption, and time required for onset of sensory and motor blockades, are associated with the surgical site and type of LA.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Anestesia Local/métodos , Dexametasona/uso terapêutico , Dexmedetomidina/uso terapêutico , Glucocorticoides/uso terapêutico , Bloqueio Nervoso/métodos , Adjuvantes Anestésicos , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Dexametasona/administração & dosagem , Dexmedetomidina/administração & dosagem , Glucocorticoides/administração & dosagem , Humanos , Nervos Periféricos , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
S Afr Med J ; 111(6): 550-553, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-34382564

RESUMO

BACKGROUND: The hyperinflammation seen as part of a dysregulated immune response to SARS-CoV-2 in its most severe form leads to acute respiratory distress syndrome (ARDS), multiorgan failure and death. Corticosteroid therapy targets this hyperinflammation, otherwise known as a cytokine storm. It is the only therapeutic agent to date with a mortality benefit, with clear guidelines from national and international health authorities guiding its use. Objectives. To compare severity-of-illness indices, survival, length of intensive care unit (ICU) stay and potential ICU complications in patients treated with different corticosteroid regimens (high-dose hydrocortisone, high-dose methylprednisolone and lower-dose dexamethasone). Methods. In this single-centre descriptive retrospective observational study of a cohort of patients with severe COVID-19 admitted to a COVID-dedicated ICU, we compared patients treated with the three different corticosteroid regimens. Results. In 242 cases we could not demonstrate any statistically or clinically significant difference in the outcome of patients with critical COVID-19 treated with high-dose intravenous hydrocortisone (n=88) or methylprednisolone (n=46) compared with a relatively lower dose of dexamethasone (n=108). The survival rates were 38.6%, 39.1% and 33.3%, respectively (p=0.68). Patients treated with methylprednisolone tended to have a shorter length of ICU stay (median (interquartile range) 6 (4 - 10), 4 (2 - 8) and 5 (2 - 8) days; p=0.015) and fewer episodes of nosocomial sepsis (47.7%, 32.6% and 48.1%; p=0.01). Conclusions. Hydrocortisone or methylprednisolone can be given as an alternative to dexamethasone in the management of critical COVID-19, and this is a feasible alternative, especially in resource-constrained settings.


Assuntos
COVID-19/tratamento farmacológico , Dexametasona/administração & dosagem , Glucocorticoides/administração & dosagem , Hidrocortisona/administração & dosagem , Metilprednisolona/administração & dosagem , Adulto , COVID-19/complicações , COVID-19/mortalidade , Estudos de Coortes , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Unidades de Terapia Intensiva , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Taxa de Sobrevida
4.
Medicine (Baltimore) ; 100(29): e26705, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34398044

RESUMO

ABSTRACT: Cytokine release syndrome (CRS) or cytokine storm is thought to be the cause of inflammatory lung damage, worsening pneumonia and death in patients with COVID-19. Steroids (Methylprednislone or Dexamethasone) and Tocilizumab (TCZ), an interleukin-6 receptor antagonist, are approved for treatment of CRS in India. The aim of this study was to evaluate the efficacy and safety of combination therapy of TCZ and steroid in COVID-19 associated CRS.This retrospective cohort study was conducted at Noble hospital and Research Centre (NHRC), Pune, India between April 2 and November 2, 2020. All patients administered TCZ and steroids during this period were included. The primary endpoint was incidence of all cause mortality. Secondary outcomes studied were need for mechanical ventilation and incidence of systemic and infectious complications. Baseline and time dependent risk factors significantly associated with death were identified by Relative risk estimation.Out of 2831 admitted patients, 515 (24.3% females) were administered TCZ and steroids. There were 135 deaths (26.2%), while 380 patients (73.8%) had clinical improvement. Mechanical ventilation was required in 242 (47%) patients. Of these, 44.2% (107/242) recovered and were weaned off the ventilator. Thirty seven percent patients were managed in wards and did not need intensive care unit (ICU) admission. Infectious complications like hospital acquired pneumonia, blood stream bacterial and fungal infections were observed in 2.13%, 2.13% and 0.06% patients respectively. Age ≥ 60 years (P = .014), presence of co-morbidities like hypertension (P = .011), IL-6 ≥ 100 pg/ml (P = .002), D-dimer ≥ 1000 ng/ml (P < .0001), CT severity index ≥ 18 (P < .0001) and systemic complications like lung fibrosis (P = .019), cardiac arrhythmia (P < .0001), hypotension (P < .0001) and encephalopathy (P < .0001) were associated with increased risk of death.Combination therapy of TCZ and steroids is likely to be safe and effective in management of COVID-19 associated cytokine release syndrome. Efficacy of this anti-inflammatory combination therapy needs to be validated in randomized controlled trials.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Dexametasona/uso terapêutico , Metilprednisolona/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , COVID-19/complicações , COVID-19/mortalidade , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/mortalidade , Dexametasona/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Índia , Unidades de Terapia Intensiva/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
5.
J Korean Med Sci ; 36(29): e203, 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34313036

RESUMO

Coronavirus disease 2019 (COVID-19) is generally milder in children than in adults, and a substantial proportion of children with the disease have asymptomatic infections. Remdesivir is recommended for severe COVID-19. To date, there are little data on the outcomes of remdesivir treatment in children. We report a case of severe COVID-19 in a previously healthy but obese (body mass index, 27.6; 99.8th percentile of the age) 9-year-old boy treated with remdesivir and dexamethasone. The patient had pneumonia at the time of diagnosis and required supplemental oxygen due to hypoxia one day after diagnosis. The patient developed respiratory distress as his pneumonia progressed rapidly. Therefore, remdesivir with dexamethasone therapy was initiated on hospital day 2. Supplemental oxygen was gradually weaned on hospital day 6 and stopped on hospital day 9. Significant improvement in pneumonic consolidations on chest X-ray was noted on hospital day 8. The patient was discharged on hospital day 21. We did not observe any adverse effects of remdesivir therapy and successfully treated a 9-year-old child with severe COVID-19.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , COVID-19/tratamento farmacológico , Dexametasona/administração & dosagem , SARS-CoV-2 , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/efeitos adversos , Alanina/administração & dosagem , Alanina/efeitos adversos , Criança , Quimioterapia Combinada , Humanos , Masculino
6.
ACS Appl Mater Interfaces ; 13(27): 31379-31392, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34197081

RESUMO

Osteoarthritis (OA) is treated with the intra-articular injection of steroids such as dexamethasone (DEX) to provide short-term pain management. However, DEX treatment suffers from rapid joint clearance. Here, 20 × 10 µm, shape-defined poly(d,l-lactide-co-glycolide)acid microPlates (µPLs) are created and intra-articularly deposited for the sustained release of DEX. Under confined conditions, DEX release is projected to persist for several months, with only ∼20% released in the first month. In a highly rigorous murine knee overload injury model (post-traumatic osteoarthritis), a single intra-articular injection of Cy5-µPLs is detected in the cartilage surface, infrapatellar fat pad/synovium, joint capsule, and posterior joint space up to 30 days. One intra-articular injection of DEX-µPL (1 mg kg-1) decreased the expression of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, and matrix metalloproteinase (MMP)-13 by approximately half compared to free DEX at 4 weeks post-treatment. DEX-µPL also reduced load-induced histological changes in the articular cartilage and synovial tissues relative to saline or free DEX. In sum, the µPLs provide sustained drug release along with the capability to precisely control particle geometry and mechanical properties, yielding long-lasting benefits in overload-induced OA. This work motivates further study and development of particles that provide combined pharmacological and mechanical benefits.


Assuntos
Cartilagem Articular/metabolismo , Dexametasona/química , Dexametasona/metabolismo , Portadores de Fármacos/química , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Animais , Biomarcadores/metabolismo , Preparações de Ação Retardada , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Injeções Intra-Articulares , Camundongos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Estresse Mecânico
7.
Nutrients ; 13(6)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205537

RESUMO

In clinical practice, differences in glucocorticoid sensitivity among healthy subjects may influence the outcome and any adverse effects of glucocorticoid therapy. Thus, a fast and accurate methodology that could enable the classification of individuals based on their tissue glucocorticoid sensitivity would be of value. We investigated the usefulness of untargeted plasma metabolomics in identifying a panel of metabolites to distinguish glucocorticoid-resistant from glucocorticoid-sensitive healthy subjects who do not carry mutations in the human glucocorticoid receptor (NR3C1) gene. Applying a published methodology designed for the study of glucocorticoid sensitivity in healthy adults, 101 healthy subjects were ranked according to their tissue glucocorticoid sensitivity based on 8:00 a.m. serum cortisol concentrations following a very low-dose dexamethasone suppression test. Ten percent of the cohort, i.e., 11 participants, on each side of the ranking, with no NR3C1 mutations or polymorphisms, were selected, respectively, as the most glucocorticoid-sensitive and most glucocorticoid-resistant of the cohort to be analyzed and compared with untargeted blood plasma metabolomics using gas chromatography-mass spectrometry (GC-MS). The acquired metabolic profiles were evaluated using multivariate statistical analysis methods. Nineteen metabolites were identified with significantly lower abundance in the most sensitive compared to the most resistant group of the cohort, including fatty acids, sugar alcohols, and serine/threonine metabolism intermediates. These results, combined with a higher glucose, sorbitol, and lactate abundance, suggest a higher Cori cycle, polyol pathway, and inter-tissue one-carbon metabolism rate and a lower fat mobilization rate at the fasting state in the most sensitive compared to the most resistant group. In fact, this was the first study correlating tissue glucocorticoid sensitivity with serine/threonine metabolism. Overall, the observed metabolic signature in this cohort implies a worse cardiometabolic profile in the most glucocorticoid-sensitive compared to the most glucocorticoid-resistant healthy subjects. These findings offer a metabolic signature that distinguishes most glucocorticoid-sensitive from most glucocorticoid-resistant healthy subjects to be further validated in larger cohorts. Moreover, they support the correlation of tissue glucocorticoid sensitivity with insulin resistance and metabolic syndrome-associated pathways, further emphasizing the need for nutritionists and doctors to consider the tissue glucocorticoid sensitivity in dietary and exercise planning, particularly when these subjects are to be treated with glucocorticoids.


Assuntos
Dexametasona/farmacologia , Dieta , Glucocorticoides/farmacologia , Estilo de Vida Saudável , Metaboloma , Hormônio Adrenocorticotrópico/sangue , Adulto , Dexametasona/administração & dosagem , Feminino , Glucocorticoides/administração & dosagem , Humanos , Hidrocortisona/sangue , Masculino , Receptores de Glucocorticoides/genética , Adulto Jovem
9.
FASEB J ; 35(8): e21828, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34325494

RESUMO

Since prenatal glucocorticoids (GC) excess increases the risk of metabolic dysfunctions in the offspring and its effect on ß-cell recovery capacity remains unknown we investigated these aspects in offspring from mice treated with dexamethasone (DEX) in the late pregnancy. Half of the pups were treated with streptozotocin (STZ) on the sixth postnatal day (PN). Functional and molecular analyses were performed in male offspring on PN25 and PN225. Prenatal DEX treatment resulted in low birth weight. At PN25, both the STZ-treated offspring developed hyperglycemia and had lower ß-cell mass, in parallel with higher α-cell mass and glucose intolerance, with no impact of prenatal DEX on such parameters. At PN225, the ß-cell mass was partially recovered in the STZ-treated mice, but they remained glucose-intolerant, irrespective of being insulin sensitive. Prenatal exposition to DEX predisposed adult offspring to sustained hyperglycemia and perturbed islet function (lower insulin and higher glucagon response to glucose) in parallel with exacerbated glucose intolerance. ß-cell-specific knockdown of the Hnf4α in mice from the DS group resulted in exacerbated glucose intolerance. We conclude that high GC exposure during the prenatal period exacerbates the metabolic dysfunctions in adult life of mice exposed to STZ early in life, resulting in a lesser ability to recover the islets' function over time. This study alerts to the importance of proper management of exogenous GCs during pregnancy and a healthy postnatal lifestyle since the combination of adverse factors during the prenatal and postnatal period accentuates the predisposition to metabolic disorders in adult life.


Assuntos
Dexametasona/toxicidade , Glucocorticoides/toxicidade , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/fisiologia , Animais , Animais Geneticamente Modificados , Animais Recém-Nascidos , Dexametasona/administração & dosagem , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Teste de Tolerância a Glucose , Insulina/farmacologia , Camundongos , Neoplasias Experimentais , Gravidez , Efeitos Tardios da Exposição Pré-Natal , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
10.
EBioMedicine ; 69: 103434, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34218053

RESUMO

BACKGROUND: The symptom of heavy menstrual bleeding (HMB) diminishes quality-of-life for many mid-age women and imposes substantial societal burden. We investigated our hypothesis that HMB reflects impaired endometrial vasoconstriction due to endometrial glucocorticoid deficiency. Does reversing this deficiency, by short-term luteal-phase treatment with exogenous glucocorticoid (dexamethasone), ameliorate HMB? METHODS: In our Bayesian response-adaptive parallel-group placebo-controlled randomised trial, five pre-planned interim analyses used primary outcome data to adjust randomisation probabilities to favour doses providing most dose-response information. Participants with HMB, recruited from Lothian (Scotland) NHS clinics and via community invitations/advertisements, were aged over 18 years; reported regular 21-42 day menstrual cycles; and had measured menstrual blood loss (MBL) averaging ≥ 50 mL over two screening periods. Identically encapsulated placebo, or one of six Dexamethasone doses (0·2 mg, 0·4 mg, 0·5 mg, 0·6 mg, 0·75 mg, 0·9 mg), were taken orally twice-daily over five days in the mid-luteal phase of three menstrual cycles. Participants, investigators, and those measuring outcomes were masked to group assignment. Primary outcome, change in average MBL from screening to 'treatment', was analysed by allocated treatment, for all with data. TRIAL REGISTRATION: ClinicalTrials.gov NCT01769820; EudractCT 2012-003,405-98 FINDINGS: Recruitment lasted 29/01/2014 to 25/09/2017; 176 were screened, 107 randomised and 97 provided primary outcome data (n = 24,5,9,21,8,14,16 in the seven arms, placebo to 1·8 mg total daily active dose). In Bayesian normal dynamic linear modelling, 1·8 mg dexamethasone daily showed a 25 mL greater reduction in MBL from screening, than placebo (95% credible interval 1 to 49 mL), and probability 0·98 of benefit over placebo. Adverse events were reported by 75% (58/77) receiving dexamethasone, 58% (15/26) taking placebo. Three serious adverse events occurred, two during screening, one in a placebo participant. No woman withdrew due to adverse effects. INTERPRETATION: Our adaptive trial in HMB showed that dexamethasone 1·8 mg daily reduced menstrual blood loss. The role of dexamethasone in HMB management deserves further investigation. FUNDING: UK MRC DCS/DPFS grant MR/J003611/1.


Assuntos
Dexametasona/administração & dosagem , Glucocorticoides/administração & dosagem , Menorragia/tratamento farmacológico , Adulto , Dexametasona/uso terapêutico , Endométrio/irrigação sanguínea , Feminino , Glucocorticoides/uso terapêutico , Humanos , Menorragia/fisiopatologia , Pessoa de Meia-Idade , Vasoconstrição
11.
J Proteome Res ; 20(8): 4001-4009, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34291951

RESUMO

Glucocorticoids are the first-line treatment for sensorineural hearing loss, but little is known about the mechanism of their protective effect or the impact of route of administration. The recent development of hollow microneedles enables safe and reliable sampling of perilymph for proteomic analysis. Using these microneedles, we investigate the effect of intratympanic (IT) versus intraperitoneal (IP) dexamethasone administration on guinea pig perilymph proteome. Guinea pigs were treated with IT dexamethasone (n = 6), IP dexamethasone (n = 8), or untreated for control (n = 8) 6 h prior to aspiration. The round window membrane (RWM) was accessed via a postauricular approach, and hollow microneedles were used to perforate the RWM and aspirate 1 µL of perilymph. Perilymph samples were analyzed by liquid chromatography-mass spectrometry-based label-free quantitative proteomics. Mass spectrometry raw data files have been deposited in an international public repository (MassIVE proteomics repository at https://massive.ucsd.edu/) under data set # MSV000086887. In the 22 samples of perilymph analyzed, 632 proteins were detected, including the inner ear protein cochlin, a perilymph marker. Of these, 14 proteins were modulated by IP, and three proteins were modulated by IT dexamethasone. In both IP and IT dexamethasone groups, VGF nerve growth factor inducible was significantly upregulated compared to control. The remaining adjusted proteins modulate neurons, inflammation, or protein synthesis. Proteome analysis facilitated by the use of hollow microneedles shows that route of dexamethasone administration impacts changes seen in perilymph proteome. Compared to IT administration, the IP route was associated with greater changes in protein expression, including proteins involved in neuroprotection, inflammatory pathway, and protein synthesis. Our findings show that microneedles can mediate safe and effective intracochlear sampling and hold promise for inner ear diagnostics.


Assuntos
Dexametasona/administração & dosagem , Glucocorticoides/administração & dosagem , Perilinfa , Proteoma , Animais , Cobaias , Injeção Intratimpânica , Proteômica
12.
N Engl J Med ; 385(1): 46-58, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34192431

RESUMO

BACKGROUND: Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. METHODS: We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. RESULTS: A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy. CONCLUSIONS: Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
13.
Medicine (Baltimore) ; 100(25): e26508, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160471

RESUMO

ABSTRACT: This study was conducted to examine whether Korean veterans from the US-Vietnam War who had a diagnosis of type II diabetes mellitus (T2DM) as well as past history of exposure to agent orange (AO) are vulnerable to hyperglycemia when receiving intra-articular corticosteroid injection (IACI) for pain relief.The current study included a total of 49 patients (n = 49) who received an injection of triamcinolone 20 or 40 mg to the shoulder under sonographic guidance or did that of dexamethasone 10 mg or triamcinolone 40 mg combined with dexamethasone 20 mg to the spine under fluoroscopic guidance. Their 7-day fasting blood glucose (FBG) levels were measured and then averaged, serving as baseline levels. This is followed by measurement of FBG levels for 14 days of IACI. Respective measurements were compared with baseline levels. The patients were also evaluated for whether there are increases in FBG levels depending on insulin therapy as well as HbA1c ≥ 7% or HbA1c < 7%.Overall, there were significant increases in FBG levels by 64.7 ±â€Š42.5 mg/dL at 1 day of IACI from baseline (P < .05). HbA1c ≥ 7% and HbA1c < 7% showed increases in FBG levels by 106.1 ±â€Š49.0 mg/dL and 46.5 ±â€Š3.8 mg/dL, respectively, at 1 day of IACI from baseline (P < .05). In the presence and absence of insulin therapy, there were significant increases in them by 122.6 ±â€Š48.7 mg/dL and 48.0 ±â€Š20.4 mg/dL, respectively, at 1 day of IACI from baseline (P < .05). But there were decreases in them to baseline levels at 2 days of IACI.Clinicians should consider the possibility of hyperglycemia when using corticosteroids for relief of musculoskeletal pain in Korean veterans from the US-Vietnam War who had a history of exposure to AO.


Assuntos
Agente Laranja/efeitos adversos , Artralgia/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Glucocorticoides/efeitos adversos , Hiperglicemia/epidemiologia , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Idoso , Glicemia/análise , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Seguimentos , Glucocorticoides/administração & dosagem , Humanos , Hiperglicemia/sangue , Hiperglicemia/diagnóstico , Hiperglicemia/etiologia , Injeções Intra-Articulares , Insulina/administração & dosagem , Masculino , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Transtornos de Estresse Pós-Traumáticos/psicologia , Triancinolona/administração & dosagem , Triancinolona/efeitos adversos , Veteranos/psicologia , Veteranos/estatística & dados numéricos , Guerra do Vietnã , Exposição à Guerra/efeitos adversos
15.
Medicine (Baltimore) ; 100(22): e26242, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087911

RESUMO

RATIONALE: A special case of transient oculomotor nerve palsy after cerebral angiography. PATIENT CONCERNS: A 55-year-old man developed oculomotor nerve dysfunction after right radial artery puncture angiography. DIAGNOSES: Cerebral angiography-induced oculomotor nerve palsy. INTERVENTIONS: According to the patient's disease state, intravenous drip of dexamethasone 10 mg/d. OUTCOMES: Magnetic resonance imaging (MRI) showed no abnormalities, and the patient recovered completely after 48 hours of hormone therapy. LESSONS: Transient eye palsy caused by contrast agent encephalopathy is a clinically rare neurological dysfunction caused by adverse effects of contrast agents. Early prevention and correct treatment are critical.


Assuntos
Angiografia Cerebral/efeitos adversos , Doenças do Nervo Oculomotor/etiologia , Oftalmoplegia/etiologia , Administração Intravenosa , Assistência ao Convalescente , Meios de Contraste/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Encefalite/induzido quimicamente , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Doenças do Nervo Oculomotor/fisiopatologia , Oftalmoplegia/diagnóstico , Oftalmoplegia/tratamento farmacológico , Artéria Radial/cirurgia , Resultado do Tratamento
16.
BMJ ; 373: n1162, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078591

RESUMO

OBJECTIVE: To assess the effect of dexamethasone on complications or all cause mortality after major non-cardiac surgery. DESIGN: Phase III, randomised, double blind, placebo controlled trial. SETTING: 34 centres in France, December 2017 to March 2019. PARTICIPANTS: 1222 adults (>50 years) requiring major non-cardiac surgery with an expected duration of more than 90 minutes. The anticipated time frame for recruitment was 24 months. INTERVENTIONS: Participants were randomised to receive either dexamethasone (0.2 mg/kg immediately after the surgical procedure, and on day 1) or placebo. Randomisation was stratified on the two prespecified criteria of cancer and thoracic procedure. MAIN OUTCOMES MEASURES: The primary outcome was a composite of postoperative complications or all cause mortality within 14 days after surgery, assessed in the modified intention-to-treat population (at least one treatment administered). RESULTS: Of the 1222 participants who underwent randomisation, 1184 (96.9%) were included in the modified intention-to-treat population. 14 days after surgery, 101 of 595 participants (17.0%) in the dexamethasone group and 117 of 589 (19.9%) in the placebo group had complications or died (adjusted odds ratio 0.81, 95% confidence interval 0.60 to 1.08; P=0.15). In the stratum of participants who underwent non-thoracic surgery (n=1038), the primary outcome occurred in 69 of 520 participants (13.3%) in the dexamethasone group and 93 of 518 (18%) in the placebo group (adjusted odds ratio 0.70, 0.50 to 0.99). Adverse events were reported in 288 of 613 participants (47.0%) in the dexamethasone group and 296 of 609 (48.6%) in the placebo group (P=0.46). CONCLUSIONS: Dexamethasone was not found to significantly reduce the incidence of complications and death in patients 14 days after major non-cardiac surgery. The 95% confidence interval for the main result was, however, wide and suggests the possibility of important clinical effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov NCT03218553.


Assuntos
Anti-Inflamatórios/administração & dosagem , Dexametasona/administração & dosagem , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/prevenção & controle , Idoso , Método Duplo-Cego , Esquema de Medicação , Feminino , França , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Cuidados Pós-Operatórios
17.
Lancet Oncol ; 22(6): 801-812, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34087126

RESUMO

BACKGROUND: In a phase 1b study, intravenous daratumumab plus pomalidomide and dexamethasone induced a very good partial response or better rate of 42% and was well tolerated in patients with heavily pretreated multiple myeloma. We aimed to evaluate whether daratumumab plus pomalidomide and dexamethasone would improve progression-free survival versus pomalidomide and dexamethasone alone in patients with previously treated multiple myeloma. METHODS: In this ongoing, open-label, randomised, phase 3 trial (APOLLO) done at 48 academic centres and hospitals across 12 European countries, eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma with measurable disease, had an Eastern Cooperative Oncology Group performance status of 0-2, had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if only one previous line of therapy was received. Patients were randomly assigned (1:1) by an interactive web-response system in a random block size of two or four to receive pomalidomide and dexamethasone alone or daratumumab plus pomalidomide and dexamethasone. Randomisation was stratified by number of previous lines of therapy and International Staging System disease stage. All patients received oral pomalidomide (4 mg, once daily on days 1-21) and oral dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those aged 75 years or older) at each 28-day cycle. The daratumumab plus pomalidomide and dexamethasone group received daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3-6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT03180736. FINDINGS: Between June 22, 2017, and June 13, 2019, 304 patients (median age 67 years [IQR 60-72]; 161 [53%] men and 143 [47%] women) were randomly assigned to the daratumumab plus pomalidomide and dexamethasone group (n=151) or the pomalidomide and dexamethasone group (n=153). At a median follow-up of 16·9 months (IQR 14·4-20·6), the daratumumab plus pomalidomide and dexamethasone group showed improved progression-free survival compared with the pomalidomide and dexamethasone group (median 12·4 months [95% CI 8·3-19·3] vs 6·9 months [5·5-9·3]; hazard ratio 0·63 [95% CI 0·47-0·85], two-sided p=0·0018). The most common grade 3 or 4 adverse events were neutropenia (101 [68%] of 149 patients in the daratumumab plus pomalidomide and dexamethasone group vs 76 [51%] of 150 patients in the pomalidomide and dexamethasone group), anaemia (25 [17%] vs 32 [21%]), and thrombocytopenia (26 [17%] vs 27 [18%]). Serious adverse events occurred in 75 (50%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group versus 59 (39%) of 150 patients in the pomalidomide and dexamethasone group; pneumonia (23 [15%] vs 12 [8%] patients) and lower respiratory tract infection (18 [12%] vs 14 [9%]) were most common. Treatment-emergent deaths were reported in 11 (7%) patients in the daratumumab plus pomalidomide and dexamethasone group versus 11 (7%) patients in the pomalidomide and dexamethasone group. INTERPRETATION: Among patients with relapsed or refractory multiple myeloma, daratumumab plus pomalidomide and dexamethasone reduced the risk of disease progression or death versus pomalidomide and dexamethasone alone and could be considered a new treatment option in this setting. FUNDING: European Myeloma Network and Janssen Research and Development.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neutropenia/induzido quimicamente , Neutropenia/patologia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Talidomida/administração & dosagem , Talidomida/efeitos adversos
18.
Int J Mol Sci ; 22(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072013

RESUMO

The treatment of acute hearing loss is clinically challenging due to the low efficacy of drug delivery into the inner ear. Local intratympanic administration of dexamethasone (D) and insulin-like growth factor 1 (IGF1) has been proposed for treatment, but they do not persist in the middle ear because they are typically delivered in fluid form. We developed a dual-vehicle drug delivery system consisting of cross-linked hyaluronic acid and polylactide-co-glycolide microcapsules. The effect and biocompatibility of the dual vehicle in delivering D and IGF1 were evaluated using an animal model of acute acoustic trauma. The dual vehicle persisted 10.9 times longer (8.7 days) in the middle ear compared with the control (standard-of-care vehicle, 0.8 days). The dual vehicle was able to sustain drug release over up to 1 to 2 months when indocyanine green was loaded as the drug. One-third of the animals experienced an inflammatory adverse reaction. However, it was transient with no sequelae, which was validated by micro CT findings, endoscopic examination, and histological assessment. Hearing restoration after acoustic trauma was satisfactory in both groups, which was further supported by comparable numbers of viable hair cells. Overall, the use of a dual vehicle for intratympanic D and IGF1 delivery may maximize the effect of drug delivery to the target organ because the residence time of the vehicle is prolonged.


Assuntos
Materiais Biocompatíveis , Cápsulas , Perda Auditiva Provocada por Ruído/tratamento farmacológico , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/química , Poliglactina 910/química , Animais , Biópsia , Contagem de Células , Dexametasona/administração & dosagem , Modelos Animais de Doenças , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Endoscopia , Potenciais Evocados Auditivos do Tronco Encefálico , Células Ciliadas Auditivas Internas , Perda Auditiva Provocada por Ruído/diagnóstico , Perda Auditiva Provocada por Ruído/etiologia , Perda Auditiva Provocada por Ruído/metabolismo , Injeção Intratimpânica , Camundongos , Microtomografia por Raio-X
19.
Nat Commun ; 12(1): 3554, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117221

RESUMO

Although the COVID-19 pandemic has left no country untouched there has been limited research to understand clinical and immunological responses in African populations. Here we characterise patients hospitalised with suspected (PCR-negative/IgG-positive) or confirmed (PCR-positive) COVID-19, and healthy community controls (PCR-negative/IgG-negative). PCR-positive COVID-19 participants were more likely to receive dexamethasone and a beta-lactam antibiotic, and survive to hospital discharge than PCR-negative/IgG-positive and PCR-negative/IgG-negative participants. PCR-negative/IgG-positive participants exhibited a nasal and systemic cytokine signature analogous to PCR-positive COVID-19 participants, predominated by chemokines and neutrophils and distinct from PCR-negative/IgG-negative participants. PCR-negative/IgG-positive participants had increased propensity for Staphylococcus aureus and Streptococcus pneumoniae colonisation. PCR-negative/IgG-positive individuals with high COVID-19 clinical suspicion had inflammatory profiles analogous to PCR-confirmed disease and potentially represent a target population for COVID-19 treatment strategies.


Assuntos
COVID-19/imunologia , Adulto , África ao Sul do Saara/epidemiologia , Antibacterianos/administração & dosagem , Anticorpos/sangue , COVID-19/sangue , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Coinfecção/imunologia , Citocinas/sangue , Dexametasona/administração & dosagem , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , SARS-CoV-2/isolamento & purificação
20.
Ann Hematol ; 100(8): 2061-2070, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33987683

RESUMO

Venetoclax is a BCL-2 inhibitor currently indicated for use in treating hematologic malignancies with recommended doses ranging from 400 to 600 mg/day. Although currently not FDA-approved to treat multiple myeloma (MM) patients, there is a growing number of reports indicating its efficacy as a salvage therapy for these patients, especially for those with the t(11;14) chromosomal marker. These studies, however, have also indicated that venetoclax given at doses ≥ 400 mg/day can cause serious adverse events (SAEs) especially when administered with bortezomib, commonly related to infections. The purpose of this single-center retrospective study was to determine the efficacy of low dose venetoclax (defined as ≤ 250 mg/day) in combination with low dose bortezomib (defined as 1.0 mg/m2 per dose), daratumumab, and dexamethasone (Dvvd) as a salvage therapy for relapsed/refractory myeloma (RRMM) patients. Twenty-two RRMM patients were given venetoclax orally at doses ranging from 100 to 250 mg daily using this four-drug regimen. While the low doses resulted in reduced venetoclax efficacy among those lacking t(11;14) (overall response rate [ORR] = 31%), those harboring the t(11;14) marker exhibited an ORR of 80%. Notably, this response was without frequent infection-related SAEs as reported in previous studies. Together, the results of this study demonstrate that treatment of t(11;14) positive RRMM patients with Dvvd is both effective and well-tolerated.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Dexametasona/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Sulfonamidas/uso terapêutico , Idoso , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bortezomib/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Dexametasona/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Retrospectivos , Sulfonamidas/administração & dosagem , Resultado do Tratamento
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