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1.
N Engl J Med ; 386(26): 2482-2494, 2022 06 30.
Article in English | MEDLINE | ID: covidwho-1984509

ABSTRACT

BACKGROUND: Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma. METHODS: We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed. RESULTS: Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group. CONCLUSIONS: Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.).


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Lymphoma, Mantle-Cell , Adenine/administration & dosage , Adenine/analogs & derivatives , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bendamustine Hydrochloride/administration & dosage , Bendamustine Hydrochloride/adverse effects , Disease Progression , Humans , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/mortality , Maintenance Chemotherapy , Piperidines/administration & dosage , Piperidines/adverse effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Remission Induction , Rituximab/administration & dosage , Rituximab/adverse effects , Survival Analysis
2.
Molecules ; 27(1)2021 Dec 28.
Article in English | MEDLINE | ID: covidwho-1580565

ABSTRACT

Baricitinib (BTB) is an orally administered Janus kinase inhibitor, therapeutically used for the treatment of rheumatoid arthritis. Recently it has also been approved for the treatment of COVID-19 infection. In this study, four different BTB-loaded lipids (stearin)-polymer (Poly(d,l-lactide-co-glycolide)) hybrid nanoparticles (B-PLN1 to B-PLN4) were prepared by the single-step nanoprecipitation method. Next, they were characterised in terms of physicochemical properties such as particle size, zeta potential (ζP), polydispersity index (PDI), entrapment efficiency (EE) and drug loading (DL). Based on preliminary evaluation, the B-PLN4 was regarded as the optimised formulation with particle size (272 ± 7.6 nm), PDI (0.225), ζP (-36.5 ± 3.1 mV), %EE (71.6 ± 1.5%) and %DL (2.87 ± 0.42%). This formulation (B-PLN4) was further assessed concerning morphology, in vitro release, and in vivo pharmacokinetic studies in rats. The in vitro release profile exhibited a sustained release pattern well-fitted by the Korsmeyer-Peppas kinetic model (R2 = 0.879). The in vivo pharmacokinetic data showed an enhancement (2.92 times more) in bioavailability in comparison to the normal suspension of pure BTB. These data concluded that the formulated lipid-polymer hybrid nanoparticles could be a promising drug delivery option to enhance the bioavailability of BTB. Overall, this study provides a scientific basis for future studies on the entrapment efficiency of lipid-polymer hybrid systems as promising carriers for overcoming pharmacokinetic limitations.


Subject(s)
Azetidines/pharmacokinetics , Drug Carriers/chemistry , Drug Liberation , Liposomes/chemistry , Nanoparticles/chemistry , Polymers/chemistry , Purines/pharmacokinetics , Pyrazoles/pharmacokinetics , Sulfonamides/pharmacokinetics , Administration, Oral , Animals , Azetidines/administration & dosage , Azetidines/chemistry , Biological Availability , Male , Purines/administration & dosage , Purines/chemistry , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Rats , Rats, Wistar , Sulfonamides/administration & dosage , Sulfonamides/chemistry
3.
Int Immunopharmacol ; 103: 108463, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1587490

ABSTRACT

Therapeutics that impair the innate immune responses of the liver during the inflammatory cytokine storm like that occurring in COVID-19 are greatly needed. Much interest is currently directed toward Janus kinase (JAK) inhibitors as potential candidates to mitigate this life-threatening complication. Accordingly, this study investigated the influence of the novel JAK inhibitor ruxolitinib (RXB) on concanavalin A (Con A)-induced hepatitis and systemic hyperinflammation in mice to simulate the context occurring in COVID-19 patients. Mice were orally treated with RXB (75 and 150 mg/kg) 2 h prior to the intravenous administration of Con A (20 mg/kg) for a period of 12 h. The results showed that RXB pretreatments were efficient in abrogating Con A-instigated hepatocellular injury (ALT, AST, LDH), necrosis (histopathology), apoptosis (cleaved caspase-3) and nuclear proliferation due to damage (PCNA). The protective mechanism of RXB were attributed to i) prevention of Con A-enhanced hepatic production and systemic release of the proinflammatory cytokines TNF-α, IFN-γ and IL-17A, which coincided with decreasing infiltration of immune cells (monocytes, neutrophils), ii) reducing Con A-induced hepatic overexpression of IL-1ß and CD98 alongside NF-κB activation, and iii) lessening Con A-induced consumption of GSH and GSH peroxidase and generation of oxidative stress products (MDA, 4-HNE, NOx) in the liver. In summary, JAK inhibition by RXB led to eminent protection of the liver against Con A-deleterious manifestations primarily via curbing the inflammatory cytokine storm driven by TNF-α, IFN-γ and IL-17A.


Subject(s)
Concanavalin A/toxicity , Cytokine Release Syndrome/chemically induced , Cytokine Release Syndrome/drug therapy , Nitriles/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Aldehydes/metabolism , Animals , Chemical and Drug Induced Liver Injury , Dose-Response Relationship, Drug , Inflammation/chemically induced , Liver/drug effects , Liver/metabolism , Male , Malondialdehyde/metabolism , Mice , Mice, Inbred BALB C , Nitrates/metabolism , Nitriles/administration & dosage , Nitrites/metabolism , Oxidative Stress , Peroxidase/metabolism , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage
4.
J Med Virol ; 94(4): 1523-1534, 2022 04.
Article in English | MEDLINE | ID: covidwho-1540137

ABSTRACT

The benefits of baricitinib in coronavirus disease-2019 are inadequately defined. We performed a systematic review and meta-analysis of studies of baricitinib to determine its clinical efficacy and adverse events in patients with COVID-19. Databases were searched from their inception to September 5, 2021. The primary outcome was the coefficient of mortality. We also compared secondary indicators and adverse events between baricitinib treatment and placebo or other treatments. Twelve studies of 3564 patients were included and assessed qualitatively (modified Jadad and Newcastle-Ottawa Scale scores). Baricitinib effectively improved the mortality rate (relative risk of mortality = 0.56; 95% confidence interval: 0.46-0.69; p < 0.001; I2 = 2%), and this result was unchanged by subgroup analysis. Baricitinib improved intensive care unit admission, the requirement for invasive mechanical ventilation, and improved the oxygenation index. Data from these studies also showed that baricitinib slightly reduced the risk of adverse events. Regarding the choice of the drug dosage of baricitinib, the high-dose group appeared to have additional benefits for clinical efficacy. Our study shows that baricitinib may be a promising, safe, and effective anti-severe acute respiratory syndrome-coronavirus-2 drug candidate, with the advantages of low cost, easy production, and convenient storage.


Subject(s)
Azetidines/therapeutic use , COVID-19/drug therapy , Purines/therapeutic use , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use , Azetidines/administration & dosage , COVID-19/mortality , Dose-Response Relationship, Drug , Humans , Purines/administration & dosage , Pyrazoles/administration & dosage , SARS-CoV-2 , Sulfonamides/administration & dosage , Treatment Outcome
5.
JAMA ; 326(17): 1703-1712, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1525396

ABSTRACT

Importance: Acutely ill inpatients with COVID-19 typically receive antithrombotic therapy, although the risks and benefits of this intervention among outpatients with COVID-19 have not been established. Objective: To assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19. Design, Setting, and Participants: The ACTIV-4B Outpatient Thrombosis Prevention Trial was designed as a minimal-contact, adaptive, randomized, double-blind, placebo-controlled trial to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19. The trial was conducted at 52 US sites between September 2020 and June 2021; final follow-up was August 5, 2021. Prior to initiating treatment, participants were required to have platelet count greater than 100 000/mm3 and estimated glomerular filtration rate greater than 30 mL/min/1.73 m2. Interventions: Random allocation in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days. Main Outcomes and Measures: The primary end point was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause. The primary analyses for efficacy and bleeding events were limited to participants who took at least 1 dose of trial medication. Results: On June 18, 2021, the trial data and safety monitoring board recommended early termination because of lower than anticipated event rates; at that time, 657 symptomatic outpatients with COVID-19 had been randomized (median age, 54 years [IQR, 46-59]; 59% women). The median times from diagnosis to randomization and from randomization to initiation of study treatment were 7 days and 3 days, respectively. Twenty-two randomized participants (3.3%) were hospitalized for COVID-19 prior to initiating treatment. Among the 558 patients who initiated treatment, the adjudicated primary composite end point occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5-mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group. The risk differences compared with placebo for the primary end point were 0.0% (95% CI not calculable) in the aspirin group, 0.7% (95% CI, -2.1% to 4.1%) in the 2.5-mg apixaban group, and 1.4% (95% CI, -1.5% to 5.0%) in the 5-mg apixaban group. Risk differences compared with placebo for bleeding events were 2.0% (95% CI, -2.7% to 6.8%), 4.5% (95% CI, -0.7% to 10.2%), and 6.9% (95% CI, 1.4% to 12.9%) among participants who initiated therapy in the aspirin, prophylactic apixaban, and therapeutic apixaban groups, respectively, although none were major. Findings inclusive of all randomized patients were similar. Conclusions and Relevance: Among symptomatic clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome. However, the study was terminated after enrollment of 9% of participants because of an event rate lower than anticipated. Trial Registration: ClinicalTrials.gov Identifier: NCT04498273.


Subject(s)
Aspirin/therapeutic use , COVID-19/drug therapy , Factor Xa Inhibitors/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Pyridones/therapeutic use , Thrombosis/prevention & control , Adult , Aspirin/adverse effects , COVID-19/complications , Dose-Response Relationship, Drug , Double-Blind Method , Early Termination of Clinical Trials , Factor Xa Inhibitors/administration & dosage , Factor Xa Inhibitors/adverse effects , Female , Hemorrhage/chemically induced , Hospitalization , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/adverse effects , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyridones/administration & dosage , Pyridones/adverse effects
6.
Naunyn Schmiedebergs Arch Pharmacol ; 395(1): 99-104, 2022 01.
Article in English | MEDLINE | ID: covidwho-1473988

ABSTRACT

A massive vaccination campaign against the global COVID-19 pandemic caused by SARS-CoV-2 virus began worldwide in January 2021. However, studies continue to investigate the most effective and safe drug therapies to manage the various stages of viral infection. It is critical in the therapeutic management of the patient, with ongoing COVID-19 infection, to reduce viral load and replication, and to regulate the generalized hyperinflammatory state caused by the cytokine storm that occurs in the most severe phases. Probably the right drug therapy is represented by the use of different drugs acting in different modalities and on different targets, to avoid also viral drug resistance. In this article, we describe an interesting scientific pharmacological hypothesis arising from the evidence in the literature; we believe that the association of baricitinib/remdesivir/rhACE2, administered at the right time and dose, represents an important pharmacological synergism that can be therapeutically more effective for the treatment of COVID-19 infection than the single administration of drugs and avoid the phenomenon of drug resistance caused by the virus.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Angiotensin-Converting Enzyme 2/administration & dosage , Antiviral Agents/administration & dosage , Azetidines/administration & dosage , COVID-19/drug therapy , Disease Management , Purines/administration & dosage , Pyrazoles/administration & dosage , Sulfonamides/administration & dosage , Adenosine Monophosphate/administration & dosage , Alanine/administration & dosage , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , COVID-19/diagnosis , Clinical Trials as Topic/methods , Drug Administration Schedule , Drug Synergism , Drug Therapy, Combination , Humans
7.
Molecules ; 26(16)2021 Aug 22.
Article in English | MEDLINE | ID: covidwho-1376916

ABSTRACT

Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a "two-bottle" as well as a "drinking in the dark" paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.


Subject(s)
Alcohol Drinking/pathology , Cannabinoid Receptor Antagonists/pharmacology , Endotoxemia/pathology , Ethanol/adverse effects , Nitric Oxide Synthase Type II/antagonists & inhibitors , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Alcohol Drinking/blood , Animals , Anxiety/blood , Anxiety/complications , Behavior, Animal/drug effects , Catalepsy/chemically induced , Catalepsy/complications , Cyclohexanols/administration & dosage , Elevated Plus Maze Test , Endotoxemia/blood , Endotoxemia/complications , Endotoxins/blood , Gastrointestinal Tract/drug effects , Gastrointestinal Tract/metabolism , Hypothermia, Induced , Mice, Inbred C57BL , Nitric Oxide Synthase Type II/metabolism , Pyrazoles/administration & dosage , Receptor, Cannabinoid, CB1/metabolism , Rimonabant/administration & dosage , Rimonabant/pharmacology , Stereoisomerism , Sulfonamides/administration & dosage
8.
J Am Geriatr Soc ; 69(10): 2752-2758, 2021 10.
Article in English | MEDLINE | ID: covidwho-1301522

ABSTRACT

BACKGROUND: Older adults are at the highest risk of severe disease and death due to COVID-19. Randomized data have shown that baricitinib improves outcomes in these patients, but focused stratified analyses of geriatric cohorts are lacking. Our objective was to analyze the efficacy of baricitinib in older adults with COVID-19 moderate-to-severe pneumonia. METHODS: This is a propensity score [PS]-matched retrospective cohort study. Patients from the COVID-AGE and Alba-Score cohorts, hospitalized for moderate-to-severe COVID-19 pneumonia, were categorized in two age brackets of age <70 years old (86 with baricitinib and 86 PS-matched controls) or ≥70 years old (78 on baricitinib and 78 PS-matched controls). Thirty-day mortality rates were analyzed with Kaplan-Meier and Cox proportional hazard models. RESULTS: Mean age was 79.1 for those ≥70 years and 58.9 for those <70. Exactly 29.6% were female. Treatment with baricitinib resulted in a significant reduction in death from any cause by 48% in patients aged 70 or older, an 18.5% reduction in 30-day absolute mortality risk (n/N: 16/78 [20.5%] baricitinib, 30/78 [38.5%] in PS-matched controls, p < 0.001) and a lower 30-day adjusted fatality rate (HR 0.21; 95% CI 0.09-0.47; p < 0.001). Beneficial effects on mortality were also observed in the age group <70 (8.1% reduction in 30-day absolute mortality risk; HR 0.14; 95% CI 0.03-0.64; p = 0.011). CONCLUSIONS: Baricitinib is associated with an absolute mortality risk reduction of 18.5% in adults older than 70 years hospitalized with COVID-19 pneumonia.


Subject(s)
Azetidines , COVID-19 , Pneumonia, Viral , Purines , Pyrazoles , Sulfonamides , Age Factors , Aged , Aged, 80 and over , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Azetidines/administration & dosage , Azetidines/adverse effects , COVID-19/drug therapy , COVID-19/mortality , COVID-19/physiopathology , Female , Hospital Mortality , Humans , Janus Kinase Inhibitors/administration & dosage , Janus Kinase Inhibitors/adverse effects , Male , Mortality , Outcome and Process Assessment, Health Care , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Purines/administration & dosage , Purines/adverse effects , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , SARS-CoV-2/isolation & purification , Severity of Illness Index , Spain/epidemiology , Sulfonamides/administration & dosage , Sulfonamides/adverse effects
9.
Sci Rep ; 11(1): 3847, 2021 02 15.
Article in English | MEDLINE | ID: covidwho-1242037

ABSTRACT

Ruxolitinib is the first janus kinase 1 (JAK1) and JAK2 inhibitor that was approved by the United States Food and Drug Administration (FDA) agency for the treatment of myeloproliferative neoplasms. The drug targets the JAK/STAT signalling pathway, which is critical in regulating the gliogenesis process during nervous system development. In the study, we assessed the effect of non-maternal toxic dosages of ruxolitinib (0-30 mg/kg/day between E7.5-E20.5) on the brain of the developing mouse embryos. While the pregnant mice did not show any apparent adverse effects, the Gfap protein marker for glial cells and S100ß mRNA marker for astrocytes were reduced in the postnatal day (P) 1.5 pups' brains. Gfap expression and Gfap+ cells were also suppressed in the differentiating neurospheres culture treated with ruxolitinib. Compared to the control group, adult mice treated with ruxolitinib prenatally showed no changes in motor coordination, locomotor function, and recognition memory. However, increased explorative behaviour within an open field and improved spatial learning and long-term memory retention were observed in the treated group. We demonstrated transplacental effects of ruxolitinib on astrogenesis, suggesting the potential use of ruxolitinib to revert pathological conditions caused by gliogenic-shift in early brain development such as Down and Noonan syndromes.


Subject(s)
Astrocytes/drug effects , Learning/drug effects , Maternal Exposure , Memory/drug effects , Neurogenesis/drug effects , Nitriles/administration & dosage , Protein Kinase Inhibitors/administration & dosage , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage , Age Factors , Animals , Astrocytes/metabolism , Behavior, Animal/drug effects , Biomarkers , Female , Janus Kinases/antagonists & inhibitors , Male , Maternal Exposure/adverse effects , Mice , Neurogenesis/genetics , Nitriles/adverse effects , Organ Specificity/drug effects , Pregnancy , Protein Kinase Inhibitors/adverse effects , Pyrazoles/adverse effects , Pyrimidines/adverse effects
10.
BMC Infect Dis ; 21(1): 427, 2021 May 07.
Article in English | MEDLINE | ID: covidwho-1219337

ABSTRACT

PURPOSE: Hyperinflammation in severe COVID-19 infection increases the risk of respiratory failure and one of the cogent reasons of mortality associated with COVID-19. Baricitinib, a janus kinases inhibitor, can potentially suppress inflammatory cascades in severe COVID-19 pneumonia. METHODS: The objective of this study was to compare the clinical outcomes of high dose of baricitinib with its usual dose in patients with severe COVID-19 pneumonia. This prospective cohort study was conducted on 238 adult patients with severe COVID-19 pneumonia. Eight milligram and 4 mg of baricitinib was given orally to 122 patients in the high dose (HD) group and 116 patients the usual dose (UD) group, respectively daily for 14 days, and clinical outcomes were compared among the groups. RESULTS: Blood oxygen saturation level was stabilized (≥94% on room air) earlier in the HD group compared to the UD group [5 (IQR: 4-5)/8 (IQR: 6-9), P < 0.05]. Patients in the HD group required intensive care unit (ICU) and intubation supports more in the UD group than that in patients of the HD group [17.2%/9%, P < 0.05; 11.2%/4.1%, P > 0.05; N = 116/122, respectively]. The 30-day mortality and 60-day rehospitalization rate were higher in the UD group than the HD group [6%/3.3%, P < 0.01; 11.9%/7.6%, P > 0.05; N = 116/122, respectively]. CONCLUSION: The daily high dose of baricitinib in severe COVID-19 results in early stabilization of the respiratory functions, declined requirements of critical care supports, reduced rehospitalization with mortality rate compared to its daily usual dose.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Azetidines/administration & dosage , COVID-19/drug therapy , Purines/administration & dosage , Pyrazoles/administration & dosage , Sulfonamides/administration & dosage , Administration, Oral , Aged , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Azetidines/therapeutic use , Bangladesh , COVID-19/mortality , Comorbidity , Critical Care , Female , Hospital Mortality , Humans , Male , Middle Aged , Patient Readmission , Prospective Studies , Purines/therapeutic use , Pyrazoles/therapeutic use , Respiratory Insufficiency/drug therapy , Respiratory Insufficiency/virology , Sulfonamides/therapeutic use , Treatment Outcome
11.
Lancet ; 397(10286): 1749, 2021 05 08.
Article in English | MEDLINE | ID: covidwho-1219082
12.
Neurologist ; 26(3): 108-111, 2021 May 05.
Article in English | MEDLINE | ID: covidwho-1214713

ABSTRACT

INTRODUCTION: The coronavirus disease 2019 (COVID-19) has been associated with a hypercoagulable state, increasing the risk for ischemic stroke. In select cases, patients are already on anticoagulation therapy. Such examples highlight the severity of COVID-19's hyperthrombotic state, and raise questions regarding optimal stroke prevention in these patients. CASE REPORT: An 84-year-ool male with past medical history of chronic obstructive pulmonary disease, hypertension, and paroxysmal atrial fibrillation was admitted for respiratory failure secondary to COVID-19 pneumonia. He was continued on his home apixaban 5 mg twice daily. On day 2 of admission, he developed a new aphasia, and right-sided facial droop. Computed tomography (CT) head was unrevealing. CT angiography did not show large vessel occlusion. CT perfusion demonstrated a left middle cerebral artery ischemic penumbra, without core. He was not eligible for thrombolysis or thrombectomy interventions. Later CT head confirmed L middle cerebral artery infarct. The patient's D-dimer was 1,184 ng/mL on day 1 of admission, and increased to 111,574 by day 4. His hypoxia worsened, requiring intubation and transfer to the ICU. He experienced further clinical decline and eventual demise. CONCLUSION: Ischemic stroke in anticoagulated patients with COVID-19 has been previously reported. Such cases emphasize the severity of the coronavirus virus associated hypercoagulable state. A majority of reported cases have occurred in patients continuing their ambulatory therapy. Overall, such cases are likely underreported. There are current trials comparing therapeutic versus prophylactic dose anticoagulation in patients with COVID-19. There are no studies specifically addressing anticoagulation agent failure in these patients. Further research is required this area to determine the optimal therapy for patients with COVID-19.


Subject(s)
COVID-19/complications , Factor Xa Inhibitors/administration & dosage , Ischemic Stroke/etiology , Aged, 80 and over , Atrial Fibrillation/drug therapy , Fatal Outcome , Humans , Hypertension/drug therapy , Male , Pulmonary Disease, Chronic Obstructive/drug therapy , Pyrazoles/administration & dosage , Pyridones/administration & dosage
13.
Leukemia ; 35(2): 485-493, 2021 02.
Article in English | MEDLINE | ID: covidwho-1065836

ABSTRACT

We report the clinical presentation and risk factors for survival in 175 patients with myeloproliferative neoplasms (MPN) and COVID-19, diagnosed between February and June 2020. After a median follow-up of 50 days, mortality was higher than in the general population and reached 48% in myelofibrosis (MF). Univariate analysis, showed a significant relationship between death and age, male gender, decreased lymphocyte counts, need for respiratory support, comorbidities and diagnosis of MF, while no association with essential thrombocythemia (ET), polycythemia vera (PV), and prefibrotic-PMF (pre-PMF) was found. Regarding MPN-directed therapy ongoing at the time of COVID-19 diagnosis, Ruxolitinib (Ruxo) was significantly more frequent in patients who died in comparison with survivors (p = 0.006). Conversely, multivariable analysis found no effect of Ruxo alone on mortality, but highlighted an increased risk of death in the 11 out of 45 patients who discontinued treatment. These findings were also confirmed in a propensity score matching analysis. In conclusion, we found a high risk of mortality during COVID-19 infection among MPN patients, especially in MF patients and/or discontinuing Ruxo at COVID-19 diagnosis. These findings call for deeper investigation on the role of Ruxo treatment and its interruption, in affecting mortality in MPN patients with COVID-19.


Subject(s)
COVID-19/mortality , Myeloproliferative Disorders/mortality , Pyrazoles/administration & dosage , SARS-CoV-2/isolation & purification , Withholding Treatment/statistics & numerical data , Aged , COVID-19/complications , COVID-19/transmission , COVID-19/virology , Europe/epidemiology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Myeloproliferative Disorders/drug therapy , Myeloproliferative Disorders/epidemiology , Myeloproliferative Disorders/virology , Nitriles , Prognosis , Pyrimidines , Retrospective Studies , Survival Rate
16.
J Clin Invest ; 130(12): 6409-6416, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-1011054

ABSTRACT

BACKGROUNDPatients with coronavirus disease 2019 (COVID-19) develop pneumonia generally associated with lymphopenia and a severe inflammatory response due to uncontrolled cytokine release. These mediators are transcriptionally regulated by the JAK/STAT signaling pathways, which can be disabled by small molecules.METHODSWe treated a group of patients (n = 20) with baricitinib according to an off-label use of the drug. The study was designed as an observational, longitudinal trial and approved by the local ethics committee. The patients were treated with 4 mg baricitinib twice daily for 2 days, followed by 4 mg per day for the remaining 7 days. Changes in the immune phenotype and expression of phosphorylated STAT3 (p-STAT3) in blood cells were evaluated and correlated with serum-derived cytokine levels and antibodies against severe acute respiratory syndrome-coronavirus 2 (anti-SARS-CoV-2). In a single treated patient, we also evaluated the alteration of myeloid cell functional activity.RESULTSWe provide evidence that patients treated with baricitinib had a marked reduction in serum levels of IL-6, IL-1ß, and TNF-α, a rapid recovery of circulating T and B cell frequencies, and increased antibody production against the SARS-CoV-2 spike protein, all of which were clinically associated with a reduction in the need for oxygen therapy and a progressive increase in the P/F (PaO2, oxygen partial pressure/FiO2, fraction of inspired oxygen) ratio.CONCLUSIONThese data suggest that baricitinib prevented the progression to a severe, extreme form of the viral disease by modulating the patients' immune landscape and that these changes were associated with a safer, more favorable clinical outcome for patients with COVID-19 pneumonia.TRIAL REGISTRATIONClinicalTrials.gov NCT04438629.FUNDINGThis work was supported by the Fondazione Cariverona (ENACT Project) and the Fondazione TIM.


Subject(s)
Azetidines/administration & dosage , COVID-19 , Off-Label Use , Purines/administration & dosage , Pyrazoles/administration & dosage , SARS-CoV-2 , Sulfonamides/administration & dosage , Aged , Aged, 80 and over , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , COVID-19/blood , COVID-19/immunology , COVID-19/pathology , Cytokines/blood , Cytokines/immunology , Female , Humans , Longitudinal Studies , Male , Middle Aged , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Severity of Illness Index , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/pathology
17.
JAMA Dermatol ; 156(12): 1333-1343, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-1008230

ABSTRACT

Importance: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced disease severity in moderate to severe atopic dermatitis (AD) in 2 phase 3 monotherapy studies. Objective: To assess the efficacy and safety of 4 mg and 2 mg of baricitinib in combination with background topical corticosteroid (TCS) therapy in adults with moderate to severe AD who previously had an inadequate response to TCS therapy. Design, Setting, and Participants: This double-blind, placebo-controlled, phase 3 randomized clinical trial, BREEZE-AD7 (Study of Baricitinib [LY3009104] in Combination With Topical Corticosteroids in Adults With Moderate to Severe Atopic Dermatitis) was conducted from November 16, 2018, to August 22, 2019, at 68 centers across 10 countries in Asia, Australia, Europe, and South America. Patients 18 years or older with moderate to severe AD and an inadequate response to TCSs were included. After completing the study, patients were followed up for up to 4 weeks or enrolled in a long-term extension study. Interventions: Patients were randomly assigned (1:1:1) to receive 2 mg of baricitinib once daily (n = 109), 4 mg of baricitinib once daily (n = 111), or placebo (n = 109) for 16 weeks. The use of low-to-moderate potency TCSs was allowed. Main Outcomes and Measures: The primary end point was the proportion of patients achieving a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 (clear) or 1 (almost clear), with a 2-point or greater improvement from baseline at week 16. Results: Among 329 patients (mean [SD] age, 33.8 [12.4] years; 216 [66%] male), at week 16, a vIGA-AD score of 0 (clear) or 1 (almost clear) was achieved by 34 patients (31%) receiving 4 mg of baricitinib and 26 (24%) receiving 2 mg of baricitinib compared with 16 (15%) receiving placebo (odds ratio vs placebo, 2.8 [95% CI, 1.4-5.6]; P = .004 for the 4-mg group; 1.9 [95% CI, 0.9-3.9]; P = .08 for the 2-mg group). Treatment-emergent adverse events were reported in 64 of 111 patients (58%) in the 4-mg group, 61 of 109 patients (56%) in the 2-mg group, and 41 of 108 patients (38%) in the placebo group. Serious adverse events were reported in 4 patients (4%) in the 4-mg group, 2 (2%) in the 2-mg group, and 4 (4%) in the placebo group. The most common adverse events were nasopharyngitis, upper respiratory tract infections, and folliculitis. Conclusions and Relevance: A dose of 4 mg of baricitinib in combination with background TCS therapy significantly improved the signs and symptoms of moderate to severe AD, with a safety profile consistent with previous studies of baricitinib in AD. Trial Registration: ClinicalTrials.gov Identifier: NCT03733301.


Subject(s)
Azetidines/administration & dosage , Dermatitis, Atopic/drug therapy , Glucocorticoids/administration & dosage , Purines/administration & dosage , Pyrazoles/administration & dosage , Sulfonamides/administration & dosage , Administration, Cutaneous , Administration, Oral , Adult , Azetidines/adverse effects , Dermatitis, Atopic/diagnosis , Dermatitis, Atopic/immunology , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Drug Therapy, Combination/adverse effects , Drug Therapy, Combination/methods , Female , Folliculitis/chemically induced , Folliculitis/epidemiology , Folliculitis/immunology , Glucocorticoids/adverse effects , Humans , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/metabolism , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/metabolism , Male , Middle Aged , Nasopharyngitis/chemically induced , Nasopharyngitis/epidemiology , Nasopharyngitis/immunology , Purines/adverse effects , Pyrazoles/adverse effects , Respiratory Tract Infections/chemically induced , Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/immunology , Severity of Illness Index , Signal Transduction/drug effects , Signal Transduction/immunology , Sulfonamides/adverse effects , Young Adult
18.
BMJ Case Rep ; 13(12)2020 Dec 22.
Article in English | MEDLINE | ID: covidwho-999235

ABSTRACT

Intra-abdominal thromboses are a poorly characterised thrombotic complication of COVID-19 and are illustrated in this case. A 42-year-old man with chronic hepatitis B (undetectable viral load, FibroScan 7.4 kPa) developed fever and cough in March 2020. 14 days later, he developed right upper quadrant pain. After being discharged with reassurance, he re-presented with worsening pain on symptom day 25. Subsequent abdominal ultrasound suggested portal vein thrombosis. CT of the abdomen confirmed portal and mid-superior mesenteric vein thromboses. Concurrent CT of the chest suggested COVID-19 infection. While reverse transcription PCR was negative, subsequent antibody serology was positive. Thrombophilia screen excluded inherited and acquired thrombophilia. Having been commenced on apixaban 5 mg two times per day, he is currently asymptomatic. This is the first case of COVID-19-related portomesenteric thrombosis described in the UK. A recent meta-analysis suggests 9.2% of COVID-19 cases develop abdominal pain. Threshold for performing abdominal imaging must be lower to avoid this reversible complication.


Subject(s)
COVID-19 , Hepatitis B, Chronic/complications , Mesenteric Ischemia , Mesenteric Veins/diagnostic imaging , Portal Vein/diagnostic imaging , Pyrazoles/administration & dosage , Pyridones/administration & dosage , SARS-CoV-2/isolation & purification , Abdominal Pain/diagnosis , Adult , COVID-19/blood , COVID-19/complications , COVID-19/therapy , COVID-19 Serological Testing/methods , Diagnosis, Differential , Factor Xa Inhibitors/administration & dosage , Humans , Male , Mesenteric Ischemia/etiology , Mesenteric Ischemia/physiopathology , Mesenteric Ischemia/therapy , Portography/methods , Tomography, X-Ray Computed/methods , Treatment Outcome , Ultrasonography/methods
19.
BMJ Case Rep ; 13(11)2020 Nov 04.
Article in English | MEDLINE | ID: covidwho-957913

ABSTRACT

A 60-year-old man recently admitted for bipedal oedema, endocarditis and a persistently positive COVID-19 swab with a history of anticoagulation on rivaroxaban for atrial fibrillation, transitional cell carcinoma, cerebral amyloid angiopathy, diabetes and hypertension presented with sudden onset diplopia and vertical gaze palsy. Vestibulo-ocular reflex was preserved. Simultaneously, he developed a scotoma and sudden visual loss, and was found to have a right branch retinal artery occlusion. MRI head demonstrated a unilateral midbrain infarct. This case demonstrates a rare unilateral cause of bilateral supranuclear palsy which spares the posterior commisure. The case also raises a question about the contribution of COVID-19 to the procoagulant status of the patient which already includes atrial fibrillation and endocarditis, and presents a complex treatment dilemma regarding anticoagulation.


Subject(s)
Aspirin/administration & dosage , Atrial Fibrillation , Blindness , Brain Stem Infarctions , Coronavirus Infections , Diplopia , Endocarditis, Bacterial , Ophthalmoplegia , Pandemics , Pneumonia, Viral , Pyrazoles/administration & dosage , Pyridones/administration & dosage , Retinal Artery Occlusion , Atrial Fibrillation/complications , Atrial Fibrillation/drug therapy , Betacoronavirus/isolation & purification , Blindness/diagnosis , Blindness/etiology , Brain Stem Infarctions/diagnostic imaging , Brain Stem Infarctions/drug therapy , Brain Stem Infarctions/physiopathology , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/diagnosis , Coronavirus Infections/physiopathology , Diplopia/diagnosis , Diplopia/etiology , Endocarditis, Bacterial/complications , Endocarditis, Bacterial/diagnosis , Endocarditis, Bacterial/physiopathology , Factor Xa Inhibitors/administration & dosage , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Ophthalmoplegia/diagnosis , Ophthalmoplegia/etiology , Platelet Aggregation Inhibitors/administration & dosage , Pneumonia, Viral/complications , Pneumonia, Viral/diagnosis , Pneumonia, Viral/physiopathology , Retinal Artery Occlusion/diagnostic imaging , Retinal Artery Occlusion/drug therapy , Retinal Artery Occlusion/etiology , Retinal Artery Occlusion/physiopathology , SARS-CoV-2 , Tomography, Optical Coherence/methods , Treatment Outcome
20.
BMJ Case Rep ; 13(11)2020 Nov 30.
Article in English | MEDLINE | ID: covidwho-949258

ABSTRACT

We report an unusual complication of COVID-19 infection in a 53-year-old Caucasian man. He presented with shortness of breath, fever and pleuritic chest pain. A CT pulmonary angiogram (CTPA) demonstrated acute bilateral pulmonary embolism and bilateral multifocal parenchymal ground glass change consistent with COVID-19 (SARS-CoV-2) infection. Right adrenal haemorrhage was suspected on the CTPA which was confirmed on triple-phase abdominal CT imaging. A short Synacthen test revealed normal adrenal function. He was treated initially with an intravenous heparin infusion, which was changed to apixaban with a planned outpatient review in 3 months' time. He made an uncomplicated recovery and was discharged. Follow-up imaging nearly 5 months later showed near complete resolution of the right adrenal haemorrhage with no CT evidence of an underlying adrenal lesion.


Subject(s)
Adrenal Gland Diseases , Adrenal Glands/diagnostic imaging , COVID-19 , Computed Tomography Angiography/methods , Hemorrhage , Heparin/administration & dosage , Pulmonary Embolism , Pyrazoles/administration & dosage , Pyridones/administration & dosage , Adrenal Cortex Function Tests/methods , Adrenal Gland Diseases/diagnosis , Adrenal Gland Diseases/etiology , Adrenal Gland Neoplasms/diagnosis , Antithrombins/administration & dosage , COVID-19/complications , COVID-19/diagnosis , COVID-19/physiopathology , COVID-19/therapy , Clinical Deterioration , Diagnosis, Differential , Hemorrhage/diagnosis , Hemorrhage/etiology , Humans , Male , Middle Aged , Pulmonary Embolism/diagnosis , Pulmonary Embolism/etiology , Pulmonary Embolism/physiopathology , Pulmonary Embolism/therapy , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity , Treatment Outcome
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