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1.
Ann Transplant ; 26: e929279, 2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33707409

RESUMEN

Coronavirus disease 19 (COVID-19) has been an ongoing pandemic since December 2019. Unfortunately, kidney transplant recipients are a high-risk group during the disease course, and scientific data are still limited in this patient group. Beyond the dosage of immunosuppressive drugs, pharmacological immunosuppression may also alter the infection response in the COVID-19 course. The effects of immunosuppressive agents on the development and process of infection should not be decided only by determining how potent they are and how much they suppress the immune system; it is also thought that the direct effect of the virus, increased oxidative stress, and cytokine storm play a role in the pathogenesis of COVID-19 disease. There are data about immunosuppressive drugs like calcineurin inhibitors (CNI) or mammalian target of rapamycin inhibitors (mTORi) therapy related to their beneficial effects during any infection course. Limited data suggest that the use of CNI or mTORi may have beneficial effects on the process. In this hypothetical review, the probable impacts of CNI and mTORi on the pathogenesis of the COVID-19 were investigated.


Asunto(s)
/inmunología , Inhibidores de la Calcineurina/uso terapéutico , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Complicaciones Posoperatorias/inmunología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inmunidad Adaptativa/efectos de los fármacos , Inhibidores de la Calcineurina/farmacología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/prevención & control , Síndrome de Liberación de Citoquinas/virología , Rechazo de Injerto/inmunología , Humanos , Inmunidad Innata/efectos de los fármacos , Huésped Inmunocomprometido , Inmunosupresores/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/inmunología , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/virología , Inhibidores de Proteínas Quinasas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores
2.
Rev Neurol ; 72(7): 250-260, 2021 04 01.
Artículo en Español | MEDLINE | ID: mdl-33764494

RESUMEN

INTRODUCTION: The recent availability of SARS-CoV-2 vaccines has raised concerns in certain patient groups, such as those with multiple sclerosis. However, there are currently few publications that provide information on this issue. We pooled the information available on the safety and efficacy of vaccination against SARS-CoV-2 in patients with multiple sclerosis, with and without disease-modifying therapy. DEVELOPMENT: The study consisted in a literature search focused on the types of SARS-CoV-2 vaccines, the current status of their approval, and the data available on the safety and efficacy of vaccines in patients with multiple sclerosis, including the new COVID-19 vaccines. Based on this search, the document has been designed taking into account current evidence and expert recommendations. There are no data on the safety and efficacy of SARS-CoV-2 vaccines in patients with multiple sclerosis. However, evidence does exist to suggest that messenger RNA (mRNA) vaccines against SARS-CoV-2 are as safe in these patients as in other individuals. Some therapies with immunosuppressants might reduce the effectiveness of these vaccines and require the scheduling of their administration, preferably before the start of treatment if possible. CONCLUSION: The data available make it possible to recommend mRNA vaccines against SARS-CoV-2 in patients with multiple sclerosis. In patients on fingolimod, cladribine, alemtuzumab, ocrelizumab and rituximab, vaccination prior to the initiation of medication administration would be recommendable whenever possible.


Asunto(s)
/prevención & control , Inmunosupresores/efectos adversos , Esclerosis Múltiple/inmunología , Vacunación , Anticuerpos Antivirales/biosíntesis , Formación de Anticuerpos/efectos de los fármacos , /administración & dosificación , /inmunología , Control de Enfermedades Transmisibles/métodos , Humanos , Esquemas de Inmunización , Huésped Inmunocomprometido , Inmunogenicidad Vacunal , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Vacunas contra la Influenza/administración & dosificación , Máscaras , Esclerosis Múltiple/tratamiento farmacológico , Vacunación/efectos adversos
3.
Yonsei Med J ; 62(2): 177-181, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33527798

RESUMEN

We sought to analyze the efficacy of adalimumab in active noninfectious uveitis, and evaluate its efficacy and safety for the management of refractory noninfectious uveitis in Korean patients. A retrospective observational study was conducted. A total of 23 eyes of 14 Korean patients with noninfectious uveitis refractory to conventional treatment, including corticosteroid and immunosuppressive agents, were treated with adalimumab between December 2017 and February 2020. The primary outcomes were vitreous haziness grades, anterior chamber cell grades, and central macular thickness measured prior to injection and at 1, 3, 6, and 12 months after the first adalimumab injection. Among the 23 eyes, 14 eyes (60.9%) were diagnosed with panuveitis and 9 eyes (39.1%) with posterior uveitis [mean follow-up period: 22.3 months (7-27)]. The most common etiologic diagnoses requiring adalimumab injection were Behçet's disease (9 eyes, 39.1%), followed by undifferentiated inflammation (6 eyes, 26.1%), Vogt-Koyanagi-Harada disease (3 eyes, 13.0%), psoriasis (2 eyes, 8.7%), serpiginous chorioretinopathy (2 eyes, 8.7%), and systemic lupus erythematosus (1 eye, 4.3%). At the 1-year follow-up after the first injection, anterior chamber cell grade decreased from 0.5±0.4 to 0.3±0.4, and vitreous haziness grade decreased from 1.1±1.1 to 0.3±0.5 (p<0.05). Central macular thickness improved from 347.2±98.1 µm to 264.3±61.1 µm (p<0.05). Adalimumab injection in patients with refractory noninfectious uveitis decreased the anterior chamber cell grade, vitreous haziness grade, and central macular thickness with no severe side effect. Overall, adalimumab injection may, therefore, be an effective and relatively safe treatment modality for noninfectious uveitis in Korean patients.


Asunto(s)
Adalimumab/uso terapéutico , Uveítis/tratamiento farmacológico , Adalimumab/administración & dosificación , Adalimumab/efectos adversos , Adolescente , Adulto , Femenino , Humanos , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , República de Corea , Estudios Retrospectivos , Resultado del Tratamiento , Uveítis/diagnóstico , Uveítis/fisiopatología , Agudeza Visual/efectos de los fármacos , Adulto Joven
4.
Med Clin North Am ; 105(2): 213-225, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33589098

RESUMEN

Patients with rheumatic diseases are susceptible to infections due to their underlying disease states as well as from immunosuppressive medications, highlighting the importance of vaccination, these same factors also pose challenges to vaccine efficacy, safety, and uptake. This article reviews the impact of immunosuppressive therapies and rheumatic disease on vaccine efficacy in this vulnerable patient population as well as discusses best practices.


Asunto(s)
Antirreumáticos/farmacología , Productos Biológicos/farmacología , Inmunogenicidad Vacunal , Inmunosupresores/farmacología , Enfermedades Reumáticas , Vacunación/métodos , Vacunas , Susceptibilidad a Enfermedades , Humanos , Inmunogenicidad Vacunal/efectos de los fármacos , Inmunogenicidad Vacunal/inmunología , Control de Infecciones/métodos , Enfermedades Reumáticas/tratamiento farmacológico , Enfermedades Reumáticas/inmunología , Vacunas/clasificación , Vacunas/farmacología
5.
ACS Chem Neurosci ; 12(5): 930-944, 2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-33606519

RESUMEN

The COVID-19 pandemic caused by SARS-CoV-2 represents a global public health emergency. The entry of SARS-CoV-2 into host cells requires the activation of its spike protein by host cell proteases. The serine protease, TMPRSS2, and cysteine proteases, Cathepsins B/L, activate spike protein and enable SARS-CoV-2 entry to the host cell through two completely different and independent pathways. Therefore, inhibiting either TMPRSS2 or cathepsin B/L may not sufficiently block the virus entry. We here hypothesized that simultaneous targeting of both the entry pathways would be more efficient to block the virus entry rather than targeting the entry pathways individually. To this end, we utilized the network-based drug repurposing analyses to identify the possible common drugs that can target both the entry pathways. This study, for the first time, reports the molecules like cyclosporine, calcitriol, and estradiol as candidate drugs with the binding ability to the host proteases, TMPRSS2, and cathepsin B/L. Next, we analyzed drug-gene and gene-gene interaction networks using 332 human targets of SARS-CoV-2 proteins. The network results indicate that, out of 332 human proteins, cyclosporine interacts with 216 (65%) proteins. Furthermore, we performed molecular docking and all-atom molecular dynamics (MD) simulations to explore the binding of drug with TMPRSS2 and cathepsin L. The molecular docking and MD simulation results showed strong and stable binding of cyclosporine A (CsA) with TMPRSS2 and CTSL genes. The above results indicate cyclosporine as a potential drug molecule, as apart from interacting with SARS-CoV-2 entry receptors, it also interacts with most of SARS-CoV-2 target host genes; thus it could potentially interfere with functions of SARS-CoV-2 proteins in human cells. We here also suggest that these antiviral drugs alone or in combination can simultaneously target both the entry pathways and thus can be considered as a potential treatment option for COVID-19.


Asunto(s)
/virología , Ciclosporina/farmacología , Inmunosupresores/farmacología , Internalización del Virus/efectos de los fármacos , Antivirales/farmacología , Catepsina B/metabolismo , Catepsina L/metabolismo , Reposicionamiento de Medicamentos , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Pandemias , Serina Endopeptidasas/metabolismo
6.
Int J Mol Sci ; 22(2)2021 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-33445786

RESUMEN

Bone marrow failure (BMF) syndromes are a heterogenous group of non-malignant hematologic diseases characterized by single- or multi-lineage cytopenia(s) with either inherited or acquired pathogenesis. Aberrant T or B cells or innate immune responses are variously involved in the pathophysiology of BMF, and hematological improvement after standard immunosuppressive or anti-complement therapies is the main indirect evidence of the central role of the immune system in BMF development. As part of this immune derangement, pro-inflammatory cytokines play an important role in shaping the immune responses and in sustaining inflammation during marrow failure. In this review, we summarize current knowledge of cytokine signatures in BMF syndromes.


Asunto(s)
Trastornos de Fallo de la Médula Ósea/metabolismo , Trastornos de Fallo de la Médula Ósea/patología , Citocinas/metabolismo , Animales , Trastornos de Fallo de la Médula Ósea/tratamiento farmacológico , Humanos , Inmunidad/efectos de los fármacos , Inmunidad/fisiología , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología
7.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-33451076

RESUMEN

Porcine heart xenotransplantation is a potential treatment for patients with end-stage heart failure. To understand molecular mechanisms of graft rejection after heart transplantation, we transplanted a 31-day-old alpha-1,3-galactosyltransferase knockout (GTKO) porcine heart to a five-year-old cynomolgus monkey. Histological and transcriptome analyses were conducted on xenografted cardiac tissue at rejection (nine days after transplantation). The recipient monkey's blood parameters were analyzed on days -7, -3, 1, 4, and 7. Validation was conducted by quantitative real-time PCR (qPCR) with selected genes. A non-transplanted GTKO porcine heart from an age-matched litter was used as a control. The recipient monkey showed systemic inflammatory responses, and the rejected cardiac graft indicated myocardial infarction and cardiac fibrosis. The transplanted heart exhibited a total of 3748 differentially expressed genes compared to the non-transplanted heart transcriptome, with 2443 upregulated and 1305 downregulated genes. Key biological pathways involved at the terminal stage of graft rejection were cardiomyopathies, extracellular interactions, and ion channel activities. The results of qPCR evaluation were in agreement with the transcriptome data. Transcriptome analysis of porcine cardiac tissue at graft rejection reveals dysregulation of the key molecules and signaling pathways, which play relevant roles on structural and functional integrities of the heart.


Asunto(s)
Rechazo de Injerto , Trasplante de Corazón , Trasplante Heterólogo , Animales , Biomarcadores , Biología Computacional/métodos , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Ontología de Genes , Rechazo de Injerto/genética , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Haplorrinos , Trasplante de Corazón/efectos adversos , Inmunosupresores/farmacología , Masculino , Anotación de Secuencia Molecular , Porcinos , Transcriptoma , Trasplante Heterólogo/efectos adversos
8.
Arq Bras Cir Dig ; 33(4): e1551, 2021.
Artículo en Inglés, Portugués | MEDLINE | ID: mdl-33503111

RESUMEN

BACKGROUND: Tacrolimus and mycophenolate mofetil are immunosuppressive agents widely used on the postoperative period of the transplants. AIM: To evaluate the influence of the association of them on the abdominal wall healing in rats. METHODS: Thirty-six Wistar rats were randomly assigned in three groups of 12. On the early postoperative period, four of the control group and three of the experimental groups died. The three groups were nominated as follow: control group (GC, n=8); group I (GI, n=11, standard operation, mycophenolate mofetil and tacrolimus); group II (GII, n=10, standard operation, mycophenolate mofetil and tacrolimus). The standard operation consisted of right total nephrectomy and 20 min ischemia of the left kidney followed by reperfusion. Both NaCl 0.9% and the immunosuppressive agents were administered starting on the first postoperative day and continuing daily until the day of death on the 14th day. On the day of their deaths, two strips of the anterior abdominal wall were collected and submitted to breaking strength measurement and histological examination. RESULTS: There were no significant differences in wound infection rates (p=0,175), in the breaking strength measurement and in the histological examination among the three groups. CONCLUSION: The combination of the immunosuppressive agents used in the study associated with renal ischemia and reperfusion does not interfere in the abdominal wall healing of rats.


Asunto(s)
Pared Abdominal/cirugía , Inmunosupresores/farmacología , Riñón/irrigación sanguínea , Ácido Micofenólico/farmacología , Daño por Reperfusión/complicaciones , Tacrolimus/farmacología , Animales , Isquemia , Ácido Micofenólico/administración & dosificación , Ratas , Ratas Wistar , Reperfusión , Tacrolimus/administración & dosificación
9.
Biomed Pharmacother ; 135: 111233, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33433350

RESUMEN

Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, has led to the ongoing global pandemic. Although most patients experience no or only mild symptoms, some patients can develop severe illness, such as progressive pneumonia, acute respiratory distress syndrome, secondary hemophagocytic lymphohistiocytosis and multiple organ failure caused by cytokine release syndrome. A majority of COVID-19 patients also develop gastrointestinal symptoms. These can present special challenges to the management of patients with inflammatory bowel disease (IBD) due to potential interactions between the immune response related to SARS-CoV-2 infection and dysregulated immunity associated with IBD. In this context, the pathogenesis of COVID-19 is reviewed in order to address these questions regarding immune interactions between COVID-19 and IBD.


Asunto(s)
/epidemiología , Inmunidad/fisiología , Enfermedades Inflamatorias del Intestino/epidemiología , Enfermedades Inflamatorias del Intestino/fisiopatología , /efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , /inmunología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/epidemiología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/fisiopatología , Humanos , Inmunidad/efectos de los fármacos , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/inmunología , /inmunología
10.
Arterioscler Thromb Vasc Biol ; 41(3): e160-e174, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33472405

RESUMEN

OBJECTIVE: Arteriovenous fistulae (AVF) are the preferred vascular access for hemodialysis, but the primary success rate of AVF remains poor. Successful AVF maturation requires vascular wall thickening and outward remodeling. A key factor determining successful AVF maturation is inflammation that is characterized by accumulation of both T-cells and macrophages. We have previously shown that anti-inflammatory (M2) macrophages are critically important for vascular wall thickening during venous remodeling; therefore, regulation of macrophage accumulation may be an important mechanism promoting AVF maturation. Since CD4+ T-cells such as T-helper type 1 cells, T-helper type 2 cells, and regulatory T-cells can induce macrophage migration, proliferation, and polarization, we hypothesized that CD4+ T-cells regulate macrophage accumulation to promote AVF maturation. Approach and Results: In a mouse aortocaval fistula model, T-cells temporally precede macrophages in the remodeling AVF wall. CsA (cyclosporine A; 5 mg/kg, sq, daily) or vehicle (5% dimethyl sulfoxide) was administered to inhibit T-cell function during venous remodeling. CsA reduced the numbers of T-helper type 1 cells, T-helper type 2, and regulatory T-cells, as well as M1- and M2-macrophage accumulation in the wall of the remodeling fistula; these effects were associated with reduced vascular wall thickening and increased outward remodeling in wild-type mice. However, these effects were eliminated in nude mice, showing that the effects of CsA on macrophage accumulation and adaptive venous remodeling are T-cell-dependent. CONCLUSIONS: T-cells regulate macrophage accumulation in the maturing venous wall to control adaptive remodeling. Regulation of T-cells during AVF maturation may be a strategy that can improve AVF maturation. Graphic Abstract: A graphic abstract is available for this article.


Asunto(s)
Derivación Arteriovenosa Quirúrgica/métodos , Ciclosporina/farmacología , Macrófagos/fisiología , Linfocitos T/efectos de los fármacos , Remodelación Vascular/efectos de los fármacos , Remodelación Vascular/fisiología , Animales , Femenino , Inmunosupresores/farmacología , Macrófagos/citología , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Modelos Animales , Linfocitos T/inmunología , Linfocitos T/fisiología
11.
Theranostics ; 11(1): 316-329, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33391477

RESUMEN

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.


Asunto(s)
Antiinflamatorios/uso terapéutico , Síndrome de Liberación de Citoquinas/inmunología , Citocinas/metabolismo , Inmunosupresores/uso terapéutico , Antiinflamatorios/farmacología , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Azetidinas/farmacología , Azetidinas/uso terapéutico , /inmunología , Ensayos Clínicos como Asunto , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Citocinas/antagonistas & inhibidores , Citocinas/inmunología , Humanos , Inmunosupresores/farmacología , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Purinas/farmacología , Purinas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Resultado del Tratamiento
12.
Clin Neurol Neurosurg ; 201: 106451, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33388661

RESUMEN

At the end of 2019, the COVID-19 pandemic began, which at the time of writing continues to be a serious problem for many areas of medicine, including neurology. Since patients with multiple sclerosis (MS) often exhibit motor disability and receive disease-modifying therapy (DMT), which has an immunosuppressive effect, it is plausible that this will affect the susceptibility of MS patients to COVID-19, as well as the course of this disease. However, current data indicate that the use of DMT does not cause negative prognosis in COVID-19 sufferers, but the motor disability progression associated with MS does. In this study, we present the case reports of 4 patients with relapsing-remitting MS, who developed COVID-19, and despite the use of DMT the course of the disease was mild. Two patients were treated with dimethyl fumarate, one with Interferon ß1b and one with glatiramer acetate. One of the patients using dimethyl fumarate had lymphopenia. All patients had symptoms of COVID-19 from the nervous system, the most frequent being headache, which occurred in all patients. The aim of this article is to present a case series of four patients with MS and COVID-19, and to discuss the available literature on COVID-19 in patients with MS, with particular consideration of the impact of DMT.


Asunto(s)
/complicaciones , Inmunosupresores/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Femenino , Humanos , Inmunosupresores/farmacología , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen
13.
Nat Commun ; 12(1): 174, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33420030

RESUMEN

The immunosuppressive microenvironment that is shaped by hepatic metastatic pancreatic ductal adenocarcinoma (PDAC) is essential for tumor cell evasion of immune destruction. Neutrophils are important components of the metastatic tumor microenvironment and exhibit heterogeneity. However, the specific phenotypes, functions and regulatory mechanisms of neutrophils in PDAC liver metastases remain unknown. Here, we show that a subset of P2RX1-negative neutrophils accumulate in clinical and murine PDAC liver metastases. RNA sequencing of murine PDAC liver metastasis-infiltrated neutrophils show that P2RX1-deficient neutrophils express increased levels of immunosuppressive molecules, including PD-L1, and have enhanced mitochondrial metabolism. Mechanistically, the transcription factor Nrf2 is upregulated in P2RX1-deficient neutrophils and associated with PD-L1 expression and metabolic reprogramming. An anti-PD-1 neutralizing antibody is sufficient to compromise the immunosuppressive effects of P2RX1-deficient neutrophils on OVA-activated OT1 CD8+ T cells. Therefore, our study uncovers a mechanism by which metastatic PDAC tumors evade antitumor immunity by accumulating a subset of immunosuppressive P2RX1-negative neutrophils.


Asunto(s)
Inmunosupresores/farmacología , Neoplasias Hepáticas/inmunología , Neutrófilos/metabolismo , Neoplasias Pancreáticas/inmunología , Microambiente Tumoral/inmunología , Animales , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/inmunología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Modelos Animales de Enfermedad , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Noqueados , Mitocondrias/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Páncreas/inmunología , Páncreas/patología , Neoplasias Pancreáticas/patología , Receptores Purinérgicos P2X/genética , Receptores Purinérgicos P2X/inmunología , Receptores Purinérgicos P2X/metabolismo
14.
Psychopharmacology (Berl) ; 238(4): 1047-1057, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33349900

RESUMEN

RATIONALE: Calcineurin is a protein regulating cytokine expression in T lymphocytes and calcineurin inhibitors such as cyclosporine A (CsA) are widely used for immunosuppressive therapy. It also plays a functional role in distinct neuronal processes in the central nervous system. Disturbed information processing as seen in neuropsychiatric disorders is reflected by deficient sensorimotor gating, assessed as prepulse inhibition (PPI) of the acoustic startle response (ASR). OBJECTIVE: Patients who require treatment with immunosuppressive drugs frequently display neuropsychiatric alterations during treatment with calcineurin inhibitors. Importantly, knockout of calcineurin in the forebrain of mice is associated with cognitive impairments and symptoms of schizophrenia-like psychosis as seen after treatment with stimulants. METHODS: The present study investigated in rats effects of systemic acute and subchronic administration of CsA on sensorimotor gating. Following a single injection with effective doses of CsA, adult healthy male Dark Agouti rats were tested for PPI. For subchronic treatment, rats were injected daily with the same doses of CsA for 1 week before PPI was assessed. Since calcineurin works as a modulator of the dopamine pathway, activity of the enzyme tyrosine hydroxylase was measured in the prefrontal cortex and striatum after accomplishment of the study. RESULTS: Acute and subchronic treatment with the calcineurin inhibitor CsA disrupted PPI at a dose of 20 mg/kg. Concomitantly, following acute CsA treatment, tyrosine hydroxylase activity was reduced in the prefrontal cortex, which suggests that dopamine synthesis was downregulated, potentially reflecting a stimulatory impact of CsA on this neurotransmitter system. CONCLUSIONS: The results support experimental and clinical evidence linking impaired calcineurin signaling in the central nervous system to the pathophysiology of neuropsychiatric symptoms. Moreover, these findings suggest that therapy with calcineurin inhibitors may be a risk factor for developing neurobehavioral alterations as observed after the abuse of psychomotor stimulant drugs.


Asunto(s)
Inhibidores de la Calcineurina/farmacología , Ciclosporina/farmacología , Inmunosupresores/farmacología , Filtrado Sensorial/efectos de los fármacos , Animales , Dopamina/biosíntesis , Masculino , Neostriado/enzimología , Corteza Prefrontal/enzimología , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismo
15.
BMJ Case Rep ; 13(12)2020 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-33370944

RESUMEN

A 59-year-old man with refractory Cronkhite-Canada syndrome (CCS) had poor clinical response to high-dose intravenous steroids, azathioprine, total parenteral nutrition and best supportive care. He remained highly symptomatic with abdominal pain, diarrhoea, recurrent sepsis and profound weight loss. Infliximab induction was given as rescue therapy, with marked clinical improvement observed within 3 weeks. This allowed steroid taper. Within 12 months of infliximab therapy, he achieved complete clinical remission and returned to his baseline weight and a full oral diet. Sequential endoscopies observed significant regression of previous marked gastrointestinal polyposis, including histological remission on colonic biopsies at 3.5 and 5 years of treatment. He currently remains in remission following 6 years of combination therapy with 5 mg/kg 8 weekly infliximab and azathioprine, and there is ongoing discussion with regard to the benefits and risks of therapy de-escalation. This case demonstrates the effectiveness of infliximab in inducing and maintaining remission in refractory CCS.


Asunto(s)
Fármacos Gastrointestinales/uso terapéutico , Inmunosupresores/farmacología , Infliximab/uso terapéutico , Poliposis Intestinal/tratamiento farmacológico , Azatioprina/farmacología , Azatioprina/uso terapéutico , Colon/diagnóstico por imagen , Colon/patología , Colonoscopía , Resistencia a Medicamentos , Fármacos Gastrointestinales/farmacología , Gastroscopía , Glucocorticoides/farmacología , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Quimioterapia de Inducción/métodos , Infliximab/farmacología , Mucosa Intestinal/diagnóstico por imagen , Mucosa Intestinal/patología , Poliposis Intestinal/diagnóstico , Masculino , Persona de Mediana Edad , Antro Pilórico/diagnóstico por imagen , Antro Pilórico/patología , Resultado del Tratamiento
16.
Medicine (Baltimore) ; 99(52): e23810, 2020 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-33350767

RESUMEN

BACKGROUND: Percutaneous coronary intervention with the new generation drug eluting stents (DES) is 1 among the revascularization procedures required to treat patients with coronary artery disease (CAD). Since late stent thrombosis and silent myocardial infarction are highly associated with type 2 diabetes mellitus (T2DM), an analysis comparing the newer generation DES in this specific subgroup of patients would be scientifically relevant.In this analysis, we aimed to systematically compare the cardiovascular outcomes observed with the ultrathin bioresorbable polymer sirolimus eluting stents (SES) versus thin, durable polymer everolimus eluting stents (EES) following percutaneous coronary intervention in patients with T2DM. METHODS: Through online databases, relevant studies comparing ultrathin bioresorbable polymer SES versus the durable polymer EES were carefully searched. The cardiovascular outcomes were assessed during a follow-up time period of 1 year and more than 1 year (1-5 years) respectively. This meta-analysis was carried out by the latest version of the RevMan software. Following analysis, the results were represented by odds ratios (OR) with 95% confidence intervals (CI). RESULTS: A total number of 1967 patients with T2DM were included in this analysis. During a 1 year follow-up time period, target lesion failure (TLF) (OR: 0.59, 95% CI: 0.34-1.02; P = .06, target vessel revascularization (TVR) (OR: 0.97, 95% CI: 0.55-1.70; P = .91) and target lesion revascularization (TLR) (OR: 0.91, 95% CI: 0.44-1.87; P = .79) were similarly observed with ultrathin bioresorbable polymer SES versus the thin, durable polymer EES in these patients with T2DM. Other cardiovascular outcomes including myocardial infarction (MI), major adverse cardiac events, all-cause mortality (OR: 0.72, 95% CI: 0.37-1.40; P = .34), cardiac death and stent thrombosis (OR: 0.85, 95% CI: 0.45-1.62; P = .63) were also similarly observed with these 2 types of new stents. During a follow-up time period above 1 year (1-5 years), still no significant difference was observed in TLF, TVR, TLR, major adverse cardiac events, MI, all-cause mortality, cardiac death and stent thrombosis (OR: 0.62, 95% CI: 0.33-1.16; P = .14). CONCLUSIONS: The ultrathin bioresorbable polymer SES were similar to the durable polymer EES in these patients with T2DM. These 2 types of new generation stents were comparable in terms of cardiovascular outcomes. Hence, they might be recommended in patients with T2DM. Upcoming trials should be able to confirm this hypothesis.


Asunto(s)
Implantes Absorbibles/efectos adversos , Enfermedades Cardiovasculares/epidemiología , Enfermedad de la Arteria Coronaria/cirugía , Diabetes Mellitus Tipo 2/complicaciones , Stents Liberadores de Fármacos/efectos adversos , Everolimus/farmacología , Intervención Coronaria Percutánea/instrumentación , Sirolimus/farmacología , Enfermedad de la Arteria Coronaria/complicaciones , Humanos , Inmunosupresores/farmacología , Evaluación de Resultado en la Atención de Salud
17.
Biochemistry (Mosc) ; 85(7): 833-837, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33040727

RESUMEN

Nrf2 is a key transcription factor responsible for antioxidant defense in many tissues and cells, including alveolar epithelium, endothelium, and macrophages. Furthermore, Nrf2 functions as a transcriptional repressor that inhibits expression of the inflammatory cytokines in macrophages. Critically ill patients with COVID-19 infection often present signs of high oxidative stress and systemic inflammation - the leading causes of mortality. This article suggests rationale for the use of Nrf2 inducers to prevent development of an excessive inflammatory response in COVID-19 patients.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/metabolismo , Citocinas/antagonistas & inhibidores , Citocinas/metabolismo , Terapia Molecular Dirigida/métodos , Factor 2 Relacionado con NF-E2/metabolismo , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/metabolismo , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Catequina/análogos & derivados , Catequina/farmacología , Catequina/uso terapéutico , Infecciones por Coronavirus/virología , Dimetilfumarato/farmacología , Dimetilfumarato/uso terapéutico , Femenino , Humanos , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Inflamación/metabolismo , Isotiocianatos/farmacología , Isotiocianatos/uso terapéutico , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacos , Pandemias , Neumonía Viral/virología , /metabolismo , Resveratrol/farmacología , Resveratrol/uso terapéutico , Transducción de Señal/efectos de los fármacos , Tiosulfatos/farmacología , Tiosulfatos/uso terapéutico
18.
Medicine (Baltimore) ; 99(44): e22894, 2020 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-33126341

RESUMEN

BACKGROUND: Positioning infliximab (IFX), cyclosporine and tacrolimus (TAC) for treating ulcerative colitis (UC) is in great debate. METHODS: A literature search identified studies that investigated IFX vs. cyclosporine or IFX vs TAC in UC patients. Short-term remission, short-term, 1-year and 3-year colectomy rate were employed as primary end-points to assess efficacy. Odds ratios (ORs) with 95% confidence intervals (CIs) were analyzed. RESULTS: Overall, 15 studies comprised 596 patients in IFX group and 866 in calcineurin inhibitors group (644 received cyclosporine and 222 received TAC). No significant difference was seen between IFX and calcineurin inhibitors with regard to short-term remission. IFX led to a lower short-term (OR: 0.59, 95% CI: 0.43-0.82, P:.001), 1-year (OR: 0.53, 95% CI: 0.38-0.73, P < .001), 3-year colectomy (OR: 0.41, 95% CI: 0.20-0.84, P:.02) than calcineurin inhibitors. IFX led to a lower short-term (OR: 0.51, 95% CI: 0.36-0.71, P < .001), 1-year (OR: 0.53, 95% CI: 0.37-0.74, P:.003) colectomy and a trend of lower 3-year colectomy (OR: 0.49, 95% CI: 0.22-1.06, P:.07) than cyclosporine while no significant difference was seen between IFX and TAC. Results of network meta-analysis showed that the order was cyclosporine, TAC and IFX from high rate to low with regard to short-term and 1-year colectomy. CONCLUSION: IFX treatment leads to a lower short-term, 1-year colectomy rate and a trend of lower 3-year colectomy rate in UC patients than cyclosporine while no significant difference is seen between IFX and TAC. TAC may be superior than cyclosporine with regard to efficacy based on indirect comparisons. Randomized trials with fixed protocol are warranted to identify the optimal medical strategy in patients with UC.


Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Ciclosporina/farmacología , Infliximab/farmacología , Tacrolimus/farmacología , Colectomía/estadística & datos numéricos , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/cirugía , Humanos , Inmunosupresores/farmacología , Inducción de Remisión/métodos , Resultado del Tratamiento
19.
Int J Nanomedicine ; 15: 7937-7949, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33116510

RESUMEN

Background: Cyclosporine A (CsA) is an exceptional immunosuppressant used for the treatment of immune disorders. Niosomal vesicles are promising drug carriers that are formed by self-association of nonionic surfactants and cholesterol in an aqueous phase. The objective of the study was to formulate combined nonionic surfactant based vesicles and to evaluate their in vitro characterization, release studies and in vivo studies. Materials and Methods: Five niosomal formulations (F7 to F11) were prepared using the thin film hydration method. The molar ratio of cholesterol and non-ionic surfactant taken was 1:1. In formulation F10, the combination of surfactants Span 20 and Brij 35 was used. The niosomes were characterized by zeta sizer and SEM for particle size analysis, in vitro drug release and stability studies. The pharmacokinetic studies were conducted on healthy albino rabbits. Results: The size of niosome was found in the range of 427.1 nm to 972.3 nm. SEM image of optimized formulations F10 exhibit the spherical nature of niosomal vesicles. DSC thermograms of niosomal formulations exhibited a broadened endothermic peak. The stability study exhibited that all formulations are stable and negligible change of vesicle size and entrapment was observed with time. The percentage drug release was significantly higher as compared to CsA plain dispersion for all niosomal formulations at pH 1.2 and 7.4. The release kinetic behavior showed that all preparations were best described by zero order and can release active ingredient in a sustained manner. The pharmacokinetic data showed the test formulation (F10) possessed greater bioavailability as compared to the reference formulation (CsA aqueous dispersion). Conclusion: The formulation F10 demonstrated a comparatively more delayed rate of release with enhanced dissolution as compared to a single surfactant scheme. The F10 formulation can be a remarkable nanotechnology for prolonged delivery of CsA orally with improved dissolution profile and bioavailability.


Asunto(s)
Portadores de Fármacos/química , Inmunosupresores/química , Inmunosupresores/farmacología , Tensoactivos/química , Animales , Disponibilidad Biológica , Colesterol/química , Ciclosporina/administración & dosificación , Ciclosporina/química , Ciclosporina/farmacocinética , Ciclosporina/farmacología , Liberación de Fármacos , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacocinética , Liposomas , Tamaño de la Partícula , Conejos
20.
Am Heart J ; 228: 109-115, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32882569

RESUMEN

BACKGROUND: Patients aged ≥80 years are often treated with new-generation drug-eluting stents (DES), but data from randomized studies are scarce owing to underrepresentation in most trials. We assessed 1-year clinical outcome of octogenarians treated with new-generation DES versus younger patients. METHODS: We pooled patient-level data of 9,204 participants in the TWENTE, DUTCH PEERS, BIO-RESORT, and BIONYX (TWENTE I-IV) randomized trials. The main clinical end point was target vessel failure (TVF), a composite of cardiac death, target vessel-related myocardial infarction (MI), or clinically indicated target vessel revascularization. RESULTS: The 671 octogenarian trial participants had significantly more comorbidities. TVF was higher in octogenarians than in 8,533 patients <80 years (7.3% vs 5.3%, hazard ratio [HR]: 1.36, 95% CI: 1.0-1.83, P = .04). The cardiac death rate was higher in octogenarians (3.9% vs 0.8%, P < .001). There was no significant between-group difference in target vessel MI (2.3% vs 2.3%, P = .88) and repeat target vessel revascularization (1.9% vs 2.8%, P = .16). In multivariate analyses, age ≥ 80 years showed no independent association with TVF (adjusted HR: 1.04, 95% CI: 0.76-1.42), whereas the risk of cardiac death remained higher in octogenarians (adjusted HR: 3.38, 95% CI: 2.07-5.52, P < .001). In 6,002 trial participants, in whom data on major bleeding were recorded, octogenarians (n = 459) showed a higher major bleeding risk (5.9% vs 1.9%; HR: 3.08, 95% CI: 2.01-4.74, P < .001). CONCLUSIONS: Octogenarian participants in 4 large-scale randomized DES trials had more comorbidities and a higher incidence of the main end point TVF. Cardiac mortality was higher in octogenarians, whereas there was no increase in MI or target vessel revascularization rates. Treatment of octogenarian patients with new-generation DES appears to be safe and effective.


Asunto(s)
Stents Liberadores de Fármacos/clasificación , Everolimus/farmacología , Infarto del Miocardio , Complicaciones Posoperatorias , Sirolimus/análogos & derivados , Sirolimus/farmacología , Anciano de 80 o más Años , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/cirugía , Femenino , Humanos , Inmunosupresores/farmacología , Masculino , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/etiología , Infarto del Miocardio/mortalidad , Intervención Coronaria Percutánea , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/mortalidad , Reoperación/métodos , Reoperación/estadística & datos numéricos , Ajuste de Riesgo/métodos , Factores de Riesgo , Resultado del Tratamiento
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