RESUMEN
To investigate the changes in meibomian gland dysfunction (MGD) and tear matrix metalloproteinase-9 (MMP-9) levels in patients with moderate-to-severe MGD after combined treatment with intense pulsed light (IPL) therapy and cyclosporine 0.05%. Thirty-six patients concurrently treated with IPL and cyclosporine 0.05% ophthalmic drops were retrospectively enrolled. Tear break up time (TBUT), corneal and conjunctival staining scores, Schirmer test, and ocular surface disease index (OSDI) questionnaire responses were recorded. Meibum quality, consistency, and eyelid margin telangiectasia were evaluated. MMP-9 levels were examined by the positivity and signal intensity of red lines (scored 0-4). IPL was performed four times with a vascular filter at 2-week intervals, followed by a 1-month follow-up after treatment cessation. Immediately after each IPL treatment, gentle meibomian gland expression was performed in both the upper and lower eyelids using meibomian gland expressor forceps. TBUT (1.88 ± 1.02 s to 3.12 ± 1.08 s, p < 0.001), corneal and conjunctival staining (6.19 ± 2.11 to 3.12 ± 1.89, p < 0.001), Oxford staining grade (2.66 ± 0.89 to 1.35 ± 0.76, p < 0.001), and OSDI (52.97 ± 21.86 to 36.36 ± 22.45, p < 0.001) scores significantly improved after the combined treatment. Meibum quality, consistency and lid margin telangiectasia showed significant post-treatment improvement in both the upper and lower eyelids. MMP-9 positivity showed a significant decrease (97-69%, p = 0.026) with a reduction in signal intensity (2.72 ± 0.87 to 2.09 ± 0.95, p = 0.011). The combination of IPL therapy and 0.05% cyclosporine eye drops effectively treats moderate-to-severe MGD by reducing symptoms and signs of MGD and by decreasing ocular surface MMP-9-associated inflammation.
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Ciclosporina , Metaloproteinasa 9 de la Matriz , Disfunción de la Glándula de Meibomio , Soluciones Oftálmicas , Lágrimas , Humanos , Metaloproteinasa 9 de la Matriz/metabolismo , Ciclosporina/administración & dosificación , Femenino , Masculino , Persona de Mediana Edad , Soluciones Oftálmicas/administración & dosificación , Adulto , Estudios Retrospectivos , Disfunción de la Glándula de Meibomio/terapia , Disfunción de la Glándula de Meibomio/metabolismo , Lágrimas/metabolismo , Lágrimas/efectos de los fármacos , Tratamiento de Luz Pulsada Intensa/métodos , Anciano , Terapia Combinada , Glándulas Tarsales/efectos de los fármacos , Glándulas Tarsales/metabolismo , Glándulas Tarsales/efectos de la radiación , Conjuntiva/efectos de la radiación , Conjuntiva/efectos de los fármacosRESUMEN
Cytokine storm syndromes (CSS) include different entities such as macrophage activation syndrome, primary and secondary hemophagocytic lymphohistiocytosis (HLH), and multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. An effective management strategy is critical in CSS. While biologics have become an essential part of CSS treatment, hematopoietic stem cell transplantation (HSCT) has changed the fate of primary HLH patients. This chapter will focus on the available alternative immunomodulatory therapies in CSS, which include corticosteroids, cyclosporine A, intravenous immunoglobulin, interleukin 18 binding protein, therapeutic plasmapheresis, HSCT, and mesenchymal stromal cell-based therapies.
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COVID-19 , Síndrome de Liberación de Citoquinas , Humanos , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/terapia , COVID-19/inmunología , COVID-19/terapia , COVID-19/complicaciones , Trasplante de Células Madre Hematopoyéticas , SARS-CoV-2/inmunología , Linfohistiocitosis Hemofagocítica/terapia , Linfohistiocitosis Hemofagocítica/inmunología , Plasmaféresis/métodos , Agentes Inmunomoduladores/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Trasplante de Células Madre Mesenquimatosas/métodos , Ciclosporina/uso terapéutico , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/terapiaRESUMEN
Dry eye disease (DED) is caused by inflammation and damage to the corneal surface due to tear film instability and hyperosmolarity. Various eye drops are used to treat this condition. Each eye drop has different properties and mechanisms of action, so the appropriate drug should be used according to clinical phenotypes. This study aims to compare the therapeutic mechanisms of cyclosporine A (CsA) and diquafosol tetrasodium (DQS). An experimental in vivo/in vitro model of DED using hyperosmolarity showed decreased cell viability, inhibited wound healing, and corneal damage compared to controls. Treatment with cyclosporine or diquafosol restored cell viability and wound healing and reduced corneal damage by hyperosmolarity. The expression of the inflammation-related genes il-1ß, il-1α, and il-6 was reduced by cyclosporine and diquafosol, and the expression of Tnf-α, c1q, and il-17a was reduced by cyclosporine. Increased apoptosis in the DED model was confirmed by increased Bax and decreased Bcl-2 and Bcl-xl expression, but treatment with cyclosporine or diquafosol resulted in decreased apoptosis. Diquafosol increased NGF expression and translocation into the extracellular space. DED has different damage patterns depending on the progression of the lesion. Thus, depending on the type of lesion, eye drops should be selected according to the therapeutic target, focusing on repairing cellular damage when cellular repair is needed or reducing inflammation when inflammation is high and cellular damage is severe.
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Córnea , Ciclosporina , Modelos Animales de Enfermedad , Síndromes de Ojo Seco , Factor de Crecimiento Nervioso , Nucleótidos de Uracilo , Cicatrización de Heridas , Nucleótidos de Uracilo/farmacología , Factor de Crecimiento Nervioso/metabolismo , Factor de Crecimiento Nervioso/genética , Cicatrización de Heridas/efectos de los fármacos , Animales , Síndromes de Ojo Seco/tratamiento farmacológico , Síndromes de Ojo Seco/metabolismo , Síndromes de Ojo Seco/patología , Córnea/efectos de los fármacos , Córnea/patología , Córnea/metabolismo , Ciclosporina/farmacología , Humanos , Supervivencia Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Polifosfatos/farmacología , RatonesRESUMEN
A 6-year-old spayed female domestic short-hair cat was presented for primary complaints of anorexia and lethargy. The cat was being treated with cyclosporine (25 mg/cat, PO q24h) and prednisolone (1 mg/kg, PO q12h) for feline hypersensitivity dermatitis and inflammatory bowel disease for 1 year, wherein prednisolone was withdrawn 2 weeks prior to presentation. At presentation, dehydration, hyperglycaemia, ketonaemia, increased fructosamine, glucosuria, ketonuria and metabolic acidosis were observed. The cat was diagnosed with diabetic ketoacidosis (DKA). Immediate treatments with insulin continuous-rate infusion and intravenous fluid therapy were initiated. A serum cyclosporine concentration was >2100 ng/mL, indicating cyclosporine toxicity. Cyclosporine was discontinued immediately. The cat's acidosis and ketonaemia were resolved within a week, allowing a switch from insulin continuous-rate infusion to subcutaneous glargine (1 IU/cat), which was eventually discontinued due to persistent normoglycaemia 12 days after initial presentation. Hyperglycaemia was not observed for 28 days thereafter without insulin, indicating remission of diabetes mellitus. This report suggests that using prednisolone, particularly immune suppressive doses, could be problematic in cats receiving long-term cyclosporine therapy. Additionally, diabetic cats receiving immune-suppressive agents can possibly achieve diabetic remission after surviving DKA through regular monitoring of blood glucose concentration, elimination of prednisolone and intensive blood glucose management.
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Enfermedades de los Gatos , Ciclosporina , Inmunosupresores , Prednisolona , Animales , Gatos , Femenino , Ciclosporina/uso terapéutico , Enfermedades de los Gatos/tratamiento farmacológico , Enfermedades de los Gatos/inducido químicamente , Prednisolona/uso terapéutico , Prednisolona/administración & dosificación , Inmunosupresores/uso terapéutico , Diabetes Mellitus/veterinaria , Diabetes Mellitus/tratamiento farmacológico , Quimioterapia CombinadaRESUMEN
Macrocyclic drugs can address an increasing range of molecular targets but enabling central nervous system (CNS) access to these drugs has been viewed as an intractable problem. We designed and synthesized a series of quinolinium-modified cyclosporine derivatives targeted to the mitochondrial cyclophilin D protein. Modification of the cation to enable greater delocalization was confirmed by x-ray crystallography of the cations. Critically, greater delocalization improved brain concentrations. Assessment of the compounds in preclinical assays and for pharmacokinetics identified a molecule JP1-138 with at least 20 times the brain levels of a non-delocalized compound or those reported for cyclosporine. Levels were maintained over 24 hours together with low hERG potential. The paradigm outlined here could have widespread utility in the treatment of CNS diseases.
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Compuestos de Quinolinio , Animales , Humanos , Compuestos de Quinolinio/química , Compuestos de Quinolinio/farmacocinética , Ciclosporina/química , Ciclosporina/farmacocinética , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/efectos de los fármacos , Cristalografía por Rayos X , Péptidos/química , Péptidos/farmacocinética , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , RatonesRESUMEN
BACKGROUND/OBJECTIVES: To evaluate the effect of topical cyclosporine A (CsA) 0.05% in patients with pterygium surgery using fibrin glue (FG). SUBJECTS/METHODS: Patients with primary nasal pterygium were retrospectically analyzed and categorized into two groups: Group 1 with 41 eyes from 38 patients as a control group and group 2 with 39 eyes from 36 patients who received topical CsA twice a day for 6 months. Patients were assessed for recurrence rate, tear film parameters, side effects, and complications at postoperative intervals of 1-7 days; 1st, 3rd, 6th and 12th months. The follow-up period was 1 year. RESULTS: The two groups were age (p = 0.934) and sex (p = 0.996) matched. CsA drop was discontinued in one patient due to burning sensation and conjunctival hyperemia after 1 week. There was no statistically significant difference between the mean preoperative and postoperative 1st year Schirmer I and tear break-up time (TBUT) values in group 1 (p = 0.136; p = 0.069). Although the difference between the mean preoperative and postoperative 1st year TBUT values in group 2 was not statistically different (p = 0.249), Schirmer I results were higher postoperatively (p = 0.003). There was no statistically significant difference between preoperative Schirmer (p = 0.496), postoperative Schirmer (p = 0.661), preoperative TBUT (p = 0.240) and postoperative TBUT (p = 0.238) results of the two groups. Recurrence was observed in only one patient from group 1. CONCLUSION: No recurrent pterygium cases were observed in group 2. Schirmer I values were higher postoperatively in group 2; thus,topical CsA treatment may improve lacrimal secretion and be effective after pterygium surgery with FG.
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Ciclosporina , Adhesivo de Tejido de Fibrina , Inmunosupresores , Pterigion , Humanos , Pterigion/cirugía , Pterigion/diagnóstico , Ciclosporina/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Adhesivo de Tejido de Fibrina/administración & dosificación , Inmunosupresores/administración & dosificación , Estudios Retrospectivos , Estudios de Seguimiento , Adulto , Adhesivos Tisulares/administración & dosificación , Adhesivos Tisulares/uso terapéutico , Resultado del Tratamiento , Anciano , Soluciones Oftálmicas/administración & dosificación , Procedimientos Quirúrgicos Oftalmológicos/métodos , Procedimientos Quirúrgicos Oftalmológicos/efectos adversos , Recurrencia , Conjuntiva , Lágrimas/metabolismo , Lágrimas/fisiologíaRESUMEN
The post-organ transplant immunosuppressive therapy includes the administration of tacrolimus (Tac) or cyclosporine (CsA), along with antimetabolites (Antim) or mTOR inhibitors, with or without prednisone. A survey was conducted to investigate clinical experience regarding the use, efficacy, safety profile, and determinants of choice of maintenance immunosuppressive therapies. The questionnaire was sent to healthcare workers of 45 transplant centers specializing in kidney (K), liver (L), heart (H), and lung (P) transplants. Seventy-one responses were received from 15 Italian regions. The indicated first-choice therapy was Tac + Antim, except in the hepatic field where Tac monotherapy was favored. According to 44.1% of respondents, the first-choice therapy has changed over the last 15 years due to the replacement of CsA with Tac and increased use of mTOR inhibitors. Regarding the determinants of the index therapy, the choice of schemes to be applied depends mainly on international guidelines, previous experience, and internal protocols within the facility (80.3%; 54.9%; 50.7%, respectively). Compared to standard therapy, the criteria guiding the prescription of different therapies mainly involve the presence of comorbidities (K: 81.3%; L: 88.2%; H: 73.3%; P: 85.7%) and the evaluation of specific clinical parameters of the recipient. Additionally, the majority of respondents are in favor of using generic versions where available. The survey reveals dimensions not detectable by current healthcare administrative flows; such integrations provide a broader picture of the factors influencing the choice of post-transplant immunosuppressive therapeutic schemes.
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Ciclosporina , Inmunosupresores , Trasplante de Órganos , Tacrolimus , Humanos , Italia , Inmunosupresores/administración & dosificación , Encuestas y Cuestionarios , Ciclosporina/administración & dosificación , Tacrolimus/administración & dosificación , Encuestas de Atención de la Salud , Quimioterapia CombinadaRESUMEN
Chronic urticaria is a common and debilitating mast cell-driven skin disease presenting with itchy wheals, angio-oedema, or both. Chronic urticaria is classified as spontaneous (without definite triggers) and inducible (with definite and subtype-specific triggers; eg, cold or pressure). Current management guidelines recommend step-up administration of second-generation H1-antihistamines to four-fold the approved dose, followed by omalizumab and ciclosporin. However, in many patients, chronic urticaria does not respond to this linear approach due to heterogeneous underlying mechanisms. A personalised endotype-based approach is emerging based on the identification of autoantibodies and other drivers of urticaria pathogenesis. Over the past decade, clinical trials have presented promising options for targeted treatment of chronic urticaria with the potential for disease modification, including Bruton's tyrosine kinase inhibitors, anti-cytokine therapies, and mast cell depletion. This Therapeutics article focuses on the evidence for these novel drugs and their role in addressing an unmet need for personalised management of patients with chronic urticaria.
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Urticaria Crónica , Medicina de Precisión , Humanos , Urticaria Crónica/tratamiento farmacológico , Omalizumab/uso terapéutico , Ciclosporina/uso terapéutico , Mastocitos/inmunología , Mastocitos/efectos de los fármacos , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidoresRESUMEN
INTRODUCTION: The calcineurin inhibitor cyclosporine A (CsA) has been shown to effectively reduce proteinuria. However, its precise mechanism is still not fully understood. Our previous study showed that CsA reduced proteinuria by directly stabilizing the foot process (FP) cytoskeletal structure via cofilin-1, suggesting that synaptopodin, a podocyte-specific actin protein, is not the sole target of CsA in podocytes. METHODS: In this study, we established an adriamycin (ADR)-induced nephropathy rat model and a cultured podocyte injury model. We employed Western blotting and immunofluorescence techniques to assess the expression and distribution of transgelin, Krüppel-like factor-4 (KLF-4), nephrin, and synaptopodin. RESULTS: We observed a significant increase in proteinuria levels accompanied by loss of normal FP structure in the ADR-induced nephropathy rat model. The levels of the actin cross-linking protein transgelin were increased significantly, while those of the podocyte-specific molecules nephrin and synaptopodin were decreased in vivo. Treatment with CsA effectively reduced proteinuria while restoring FP effacement stability in ADR-induced nephropathy models and restoring the expression of transgelin, nephrin, and synaptopodin both in vivo and in vitro. Furthermore, CsA treatment dose-dependently decreased transgelin levels while significantly increasing KLF-4 expression in injured podocytes. In addition, CsA failed to downregulate transgelin when KLF-4 was specifically knocked down. CONCLUSION: Our findings suggest that CsA protects against podocyte injury by downregulating abnormally high levels of transgelin via upregulation of KLF-4 expression.
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Ciclosporina , Doxorrubicina , Factor 4 Similar a Kruppel , Proteínas de Microfilamentos , Proteínas Musculares , Podocitos , Podocitos/efectos de los fármacos , Podocitos/patología , Podocitos/metabolismo , Animales , Proteínas de Microfilamentos/metabolismo , Ratas , Ciclosporina/farmacología , Factor 4 Similar a Kruppel/metabolismo , Proteínas Musculares/metabolismo , Proteínas Musculares/biosíntesis , Masculino , Proteínas de la Membrana/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Ratas Sprague-Dawley , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , ProteinuriaRESUMEN
INTRODUCTION: Posterior leukoencephalopathy syndrome (PRES) is a rare neurological disease possibly associated with the use of calcineurin inhibitors like cyclosporine A (CSA). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the outbreak of coronavirus disease 19 (COVID-19) can cause neurological manifestations. We described a case of CSA-related PRES whose diagnosis was difficult due to a concurrent infection with SARS-CoV-2. OBSERVATION: The 16-year-old patient was known to have corticosteroid-resistant nephrotic syndrome secondary to minimal change disease. CSA was introduced, and on the fifth day of treatment, the patient presented with seizures followed by fever. Biological and magnetic resonance imaging data were in favor of SARS-CoV-2 encephalitis. Relief of immunosuppression by discontinuation of CSA was decided and the patient was put on anticonvulsants. After being declared cured of COVID-19, which was without other clinical signs, the CSA was reintroduced but the patient presented with seizures the next day. This allowed the physicians to rectify the diagnosis and relate the seizures to a CSA-related PRES. CONCLUSION: Infection with SARS-CoV-2 could be a differential diagnosis of a PRES related to calcineurin inhibitors.
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COVID-19 , Ciclosporina , Síndrome de Leucoencefalopatía Posterior , Humanos , Síndrome de Leucoencefalopatía Posterior/inducido químicamente , Síndrome de Leucoencefalopatía Posterior/diagnóstico , COVID-19/complicaciones , COVID-19/diagnóstico , Ciclosporina/efectos adversos , Ciclosporina/uso terapéutico , Diagnóstico Diferencial , Adolescente , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Masculino , Convulsiones/etiología , Convulsiones/diagnóstico , Inhibidores de la Calcineurina/efectos adversos , Encefalitis Viral/diagnóstico , Encefalitis Viral/tratamiento farmacológico , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Long-term immunosuppressive maintenance therapy is necessary to prevent the rejection of xenografts. However, it is still unclear which oral immunosuppressant is most suitable for pig-to-human xenotransplantation . METHODS: A xenogeneic mixed lymphocyte reaction (MLR) system was established using peripheral blood mononuclear cells (PBMCs) isolated from wildtype (WT) or GTKO/CMAHKO/ß4GalNT2KO (TKO) pigs as stimulator cells and human PBMCs as responder cells. Various concentrations of tacrolimus (Tac), cyclosporine (CsA), or rapamycin (Rapa) were added to the MLR system as interventions. The inhibitory effects of the three immunosuppressants on the proliferation and cytokine production of human T cells were studied and compared. The inhibitory effect of anti-CD154 mAb alone or in combination with Tac/CsA/Rapa on xenoreactive MLR was also investigated. RESULTS: PBMCs from both WT and TKO pigs stimulated significant proliferation of human T cells. Tac had a strong inhibitory effect on human T-cell proliferation stimulated by pig PBMCs. CsA inhibited human T-cell proliferation in a typical dose-dependent manner. When Tac and CsA concentrations reached 5 and 200 ng/mL, respectively, the proliferation rates of CD3+/CD4+/CD8+ T cells were reduced almost to a negative level. Even at high concentrations, Rapa had only a moderate inhibitory effect on xenogeneic MLR. The inhibitory effects of these three immunosuppressants on xenogeneic T-cell responses were further confirmed by the detection of CD25 expression and supernatant cytokines (IL-2, IL-6, IFN-γ, TNF-α, IL-4, IL-10, and IL-17). Although anti-CD154 mAb monotherapy showed only moderate inhibitory effects on xenoreactive T-cell proliferation, low-dose anti-CD154 mAb combined with low-dose Tac, CSA, or Rapa could produce significant synergistic inhibitory effects. CONCLUSION: Tac is more efficient than CsA or Rapa in inhibiting xenogeneic T-cell responses in vitro. If used in combination with anti-CD154 mAb, all the three immunosuppressants can achieve satisfactory synergistic inhibitory effects.
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Proliferación Celular , Ciclosporina , Inmunosupresores , Prueba de Cultivo Mixto de Linfocitos , Sirolimus , Tacrolimus , Trasplante Heterólogo , Animales , Sirolimus/farmacología , Humanos , Tacrolimus/farmacología , Inmunosupresores/farmacología , Ciclosporina/farmacología , Trasplante Heterólogo/métodos , Porcinos , Proliferación Celular/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Citocinas/metabolismo , Citocinas/inmunología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/efectos de los fármacos , Animales Modificados GenéticamenteRESUMEN
INTRODUCTION: Cyclosporine-A (CsA) and post transplantation cyclophosphamide (PTCy) are common agents used for graft versus host disease (GVHD) prophylaxis in Haploidentical hematopoietic cell transplantation (haplo-HCT). However, the impact of CsA cessation timing in the posttransplant setting on clinical outcomes is uncertain. We aimed to investigate the impact of a novel approach that integrated early CsA cessation with PTCy utilization. PATIENTS AND METHODS: This study was a single arm retrospective study carried out at a tertiary referral hospital hematology and bone marrow transplantation center between 2009 and 2022. The patients who received haplo-HCT with ATG, PTCy and CsA as GVHD prophylaxis were included. CsA was planned for cessation starting at day 45 to day 60. Acute and chronic GVHD were evaluated and graded. CsA blood concentrations and its impact on acute and chronic GVHD was evaluated. RESULTS: Thirty-one patients composed of 19 (61.3%) male and 12 (38.7%) female patients with a median age of 31 years (20-58). Busulfan and TBI based conditioning regimens were the most utilized regimens. The majority of donors were first degree relatives. Stem cell origin was peripheral blood for all patients. GVHD prophylaxis consisted of ATG, CsA and PTCy. Acute GVHD was observed in 9 (29%) cases, whereas chronic GVHD was seen in 3 (9.7%) cases, with 2 of them having overlapping GVHD. Age, gender, number of chemotherapy lines, transplant characteristics, infused CD34 cell count, and engraftment durations were similar among patients with and without GVHD. Patients with GVHD had similar 1st, 2nd, 3rd and 4th week CsA concentrations compared to patients without GVHD (p > 0.05). The presence of GVHD was not associated with worse progression free survival and overall survival (p = 0.6, p = 0.5, respectively). CMV reactivation was more common in the GVHD group. CONCLUSION: In the current study, we did not find an impact of CsA concentration on GVHD and post-transplant outcomes in Haplo-HCT setting. Therefore, together with the use of PTCy, early CsA cessation can be an option; further studies are needed to understand all aspects of this approach.
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Ciclosporina , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores , Trasplante Haploidéntico , Humanos , Femenino , Masculino , Adulto , Estudios Retrospectivos , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/etiología , Persona de Mediana Edad , Ciclosporina/administración & dosificación , Ciclosporina/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adulto Joven , Estudios de Seguimiento , Inmunosupresores/uso terapéutico , Inmunosupresores/administración & dosificación , Pronóstico , Trasplante Haploidéntico/métodos , Acondicionamiento Pretrasplante/métodos , Factores de Riesgo , Supervivencia de Injerto/efectos de los fármacos , Neoplasias Hematológicas/terapia , Tasa de SupervivenciaRESUMEN
Colistin is a polymyxin antibiotic currently experiencing renewed clinical interest due to its efficacy in the treatment of multidrug resistant (MDR) bacterial infections. The frequent onset of acute dose-dependent kidney injury, with the potential of leading to long-term renal damage, has limited its use and hampered adequate dosing regimens, increasing the risk of suboptimal plasma concentrations during treatment. The mechanism of colistin-induced renal toxicity has been postulated to stem from mitochondrial damage, yet there is no direct evidence of colistin acting as a mitochondrial toxin. The aim of this study was to evaluate whether colistin can directly induce mitochondrial toxicity and, if so, uncover the underlying molecular mechanism. We found that colistin leads to a rapid permeability transition of mitochondria isolated from mouse kidney that was fully prevented by co-incubation of the mitochondria with desensitizers of the mitochondrial transition pore cyclosporin A or L-carnitine. The protective effect of L-carnitine was confirmed in experiments in primary cultured mouse tubular cells. Consistently, the relative risk of colistin-induced kidney damage, calculated based on histological analysis as well as by the early marker of tubular kidney injury, Kim-1, was halved under co-administration with L-carnitine in vivo. Notably, L-carnitine neither affected the pharmacokinetics of colistin nor its antimicrobial activity against relevant bacterial strains. In conclusion, colistin targets the mitochondria and induces permeability transition thereof. L-carnitine prevents colistin-induced permeability transition in vitro. Moreover, L-carnitine co-administration confers partial nephroprotection in mice treated with colistin, without interfering with its pharmacokinetics and antibacterial activity.
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Lesión Renal Aguda , Antibacterianos , Carnitina , Colistina , Mitocondrias , Animales , Colistina/efectos adversos , Colistina/administración & dosificación , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Carnitina/farmacología , Carnitina/administración & dosificación , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Antibacterianos/farmacología , Antibacterianos/administración & dosificación , Masculino , Poro de Transición de la Permeabilidad Mitocondrial/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Ratones Endogámicos C57BL , CiclosporinaAsunto(s)
Ciclosporina , Humanos , Ciclosporina/uso terapéutico , Ciclosporina/administración & dosificación , Femenino , Persona de Mediana Edad , Masculino , Presión Sanguínea/efectos de los fármacos , Enfermedades de la Piel/tratamiento farmacológico , Enfermedades de la Piel/diagnóstico , Adulto , Anciano , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Inmunosupresores/administración & dosificación , Hipertensión/tratamiento farmacológico , Hipertensión/diagnósticoRESUMEN
INTRODUCTION: The comorbidities of ischemic heart disease (IHD) and diabetes mellitus (DM) compromise the protection of the diabetic heart from ischemia/reperfusion (I/R) injury. We hypothesized that manipulation of reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways might protect the diabetic heart, and intervention of these pathways could be a new avenue for potentially protecting the diabetic heart. METHODS: All hearts were subjected to 30-min ischemia and 30-min reperfusion. During reperfusion, hearts were exposed to molecules proven to protect the heart from I/R injury. The hemodynamic data were collected using suitable software. The infarct size, troponin T levels, and protein levels in hearts were evaluated. RESULTS: Both cyclosporine-A and nitric oxide donor (SNAP) infusion at reperfusion protected 4-week diabetic hearts from I/R injury. However, 6-week diabetic hearts were protected only by SNAP, but not cyclosporin-A. These treatments significantly (p < 0.05) improved cardiac hemodynamics and decreased infarct size. CONCLUSIONS: The administration of SNAP to diabetic hearts protected both 4- and 6-week diabetic hearts; however, cyclosporine-A protected only the 4-week diabetic hearts. The eNOS/GLUT-4 pathway executed the SNAP-mediated cardioprotection.
Asunto(s)
Ciclosporina , Diabetes Mellitus Experimental , Daño por Reperfusión Miocárdica , Miocardio , Donantes de Óxido Nítrico , Óxido Nítrico , Transducción de Señal , Animales , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Óxido Nítrico/metabolismo , Diabetes Mellitus Experimental/complicaciones , Masculino , Ciclosporina/farmacología , Donantes de Óxido Nítrico/farmacología , Miocardio/metabolismo , Miocardio/patología , Infarto del Miocardio/patología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/prevención & control , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Factores de Tiempo , Ratas Sprague-Dawley , Troponina T/metabolismo , Hiperglucemia/metabolismo , Hiperglucemia/complicaciones , Transportador de Glucosa de Tipo 4RESUMEN
Cyclosporine is an immunosuppressant used to prevent organ rejection in kidney, liver, and heart allogeneic transplants. This study aimed to assess the safety of cyclosporine through the analysis of adverse events (AEs) related to cyclosporine in the US Food and Drug Administration Adverse Event Reporting System (FAERS). To detect AEs associated with cyclosporine, a pharmacovigilance analysis was conducted using four algorithms on the FAERS database: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM). A statistical analysis was performed on data extracted from the FAERS database, covering 19,582 case reports spanning from 2013 to 2022. Among these cases, 3,911 AEs were identified, with 476 linked to cyclosporine as the primary suspected drug. Cyclosporin-induced AEs targeted 27 System Organ Classes (SOCs). Notably, the highest case at the SOC level included eye disorders, injury, poisoning, and procedural complications, as well as immune system disorders, all of which are listed on the cyclosporine label. Furthermore, we discovered novel potential AEs associated with hepatobiliary disorders, among others. Moreover, unexpected adverse drug reactions (ADRs), such as biliary anastomosis complication and spermatozoa progressive motility decrease, were identified. Importantly, these newly identified ADRs were not mentioned on the cyclosporine label, which were involved in injury, poisoning, and procedural complications, and investigations at the SOC level. The study used pharmacovigilance analysis of FAERS database to identify new and unexpected potential ADRs relating to cyclosporine, which can provide safety tips for the safe use of cyclosporine.
Asunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos , Ciclosporina , Bases de Datos Factuales , Inmunosupresores , Farmacovigilancia , United States Food and Drug Administration , Ciclosporina/efectos adversos , Humanos , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Estados Unidos , Inmunosupresores/efectos adversos , Masculino , Teorema de Bayes , Femenino , Adulto , Persona de Mediana Edad , AlgoritmosRESUMEN
BACKGROUND Thrombosis poses a grave threat to patients undergoing kidney transplants, with a heightened risk of mortality. While previous studies have established a link between COVID-19 and thrombosis, the specific association between COVID-19 and thrombosis in this patient population remains unexplored. MATERIAL AND METHODS We conducted a retrospective analysis utilizing data from 394 individuals who underwent kidney transplantation within the period of September 1, 2015, to April 1, 2023. To evaluate overall survival, we employed Kaplan-Meier analysis and utilized a logistic regression model for risk analysis. Furthermore, we developed a prediction model and assessed its accuracy through calibration curves. RESULTS Out of the 394 patients included in our study, a total of 51 individuals experienced thrombosis, resulting in 2 deaths. Our analysis revealed that COVID-19 infection significantly increased the risk of thrombosis (odds ratio [OR] 8.60, 95% confidence interval 3.13-24.74, P<0.01). Additionally, the use of cyclosporine was found to elevate the risk of death (OR 20.86, 95% CI 7.93-59.24, P<0.01) according to multifactorial analysis. Logistic models were employed to screen variables, and predictive models were constructed based on the presence of COVID-19 infection and the usage of cyclosporine. A nomogram was developed, demonstrating promising accuracy in estimating the risk of thrombosis during internal validation, with a corrected C-index of 0.869. CONCLUSIONS Our study suggests that both COVID-19 infection and the use of cyclosporine can serve as reliable predictors of thrombosis risk in patients undergoing renal transplantation. Furthermore, we developed a mortality risk prediction model based on COVID-19 in assessing thrombosis.
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COVID-19 , Trasplante de Riñón , Trombosis , Humanos , Trasplante de Riñón/efectos adversos , COVID-19/complicaciones , COVID-19/epidemiología , Trombosis/etiología , Trombosis/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Incidencia , Adulto , Pronóstico , Factores de Riesgo , Receptores de Trasplantes , SARS-CoV-2 , Modelos Logísticos , Anciano , Ciclosporina/uso terapéutico , Estimación de Kaplan-MeierRESUMEN
PF11_0189 is a putative insulin degrading enzyme present in Plasmodium falciparum genome. The catalytic domain of PF11_0189 is about 27 kDa. Substrate specificity study shows PF11_0189 acts upon different types of proteins. The substrate specificity is found to be highest when insulin is used as a substrate. Metal dependency study shows highest dependency of PF11_0189 towards zinc metal for its proteolytic activity. Chelation of zinc metal with EDTA shows complete absence of PF11_0189 activity. Peptide inhibitors, P-70 and P-121 from combinatorial peptide library prepared against PF11_0189 show inhibition with an IC50 value of 4.8 µM and 7.5 µM respectively. A proven natural anti-malarial peptide cyclosporin A shows complete inhibition against PF11_0189 with an IC50 value of 0.75 µM suggesting PF11_0189 as a potential target for peptide inhibitors. The study implicates that PF11_0189 is a zinc metalloprotease involved in catalysis of insulin. The study gives a preliminary insight into the mechanism of complications arising from glucose abnormalities during severe malaria.
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Insulisina , Plasmodium falciparum , Proteínas Protozoarias , Plasmodium falciparum/enzimología , Plasmodium falciparum/genética , Insulisina/genética , Insulisina/química , Insulisina/metabolismo , Proteínas Protozoarias/genética , Proteínas Protozoarias/química , Proteínas Protozoarias/metabolismo , Especificidad por Sustrato , Insulina/química , Insulina/metabolismo , Insulina/genética , Zinc/química , Zinc/metabolismo , Genoma de Protozoos , Proteínas Recombinantes/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/aislamiento & purificación , Expresión Génica , Clonación Molecular , Antimaláricos/química , Antimaláricos/farmacología , Ciclosporina/química , Ciclosporina/farmacologíaRESUMEN
BACKGROUND AND AIMS: Ciclosporin (CSA) is an immunosuppressive agent that requires therapeutic drug monitoring (TDM). High partitioning in erythrocytes indicates that whole blood (WB) is a suitable matrix for CSA determination. Alternative sampling strategies, such as volumetric absorptive microsampling (VAMS), are novel possibilities for blood collection during TDM for various analytes, including immunosuppressants. This technique is attractive for vulnerable pediatric patients, including home-based self-sampling, remote therapy, and adherence control. MATERIALS AND METHODS: This study aimed to develop and validate a new method for CSA determination based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) of WB and VAMS samples. Additionally, these methods were applied for CSA determination in clinical samples from pediatric transplant recipients. A strong point of this study is the assessment of an external proficiency testing scheme. RESULTS: Both methods were successfully validated within the 1-2000 ng/mL calibration range, with LOD 0.5 and 1 ng/mL for WB and VAMS methods, respectively. All the validation parameters fulfilled the international acceptance criteria for bioanalytical methods. Cross-validation confirmed the interchangeability of the LC-MS/MS method developed in this study. CONCLUSION: This study developed and validated novel methods for CSA determination in whole blood and VAMS using LC-MS/MS. Clinical validation and proficiency testing confirmed their utility in routine clinical practice.
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Ciclosporina , Monitoreo de Drogas , Inmunosupresores , Trasplante de Riñón , Espectrometría de Masas en Tándem , Humanos , Ciclosporina/sangre , Ciclosporina/uso terapéutico , Monitoreo de Drogas/métodos , Niño , Inmunosupresores/sangre , Inmunosupresores/uso terapéutico , Cromatografía Liquida , Receptores de Trasplantes , Recolección de Muestras de Sangre , Adolescente , PreescolarRESUMEN
Introduction: Nanoparticles have the advantages of improving the solubility of poorly water-soluble drugs, facilitating the drug across biological barriers, and reducing macrophage phagocytosis in pulmonary drug delivery. However, nanoparticles have a small aerodynamic particle size, which makes it difficult to achieve optimal deposition when delivered directly to the lungs. Therefore, delivering nanoparticles to the lungs effectively has become a popular research topic. Methods: Nanoaggregate microparticles were used as a pulmonary drug delivery strategy for the improvement of the bioavailability of cyclosporine A (CsA). The nanoaggregate microparticles were prepared with polyvinyl pyrrolidone (PVP) as the excipient by combining the anti-solvent method and spray drying process. The physicochemical properties, aerodynamic properties, in vivo pharmacokinetics and inhalation toxicity of nanoaggregate microparticles were systematically evaluated. Results: The optimal nanoparticles exhibited mainly spherical shapes with the particle size and zeta potential of 180.52 nm and -19.8 mV. The nanoaggregate microparticles exhibited irregular shapes with the particle sizes of less than 1.6 µm and drug loading (DL) values higher than 70%. Formulation NM-2 as the optimal nanoaggregate microparticles was suitable for pulmonary drug delivery and probably deposited in the bronchiole and alveolar region, with FPF and MMAD values of 89.62% and 1.74 µm. In addition, inhaled NM-2 had C max and AUC0-∞ values approximately 1.7-fold and 1.8-fold higher than oral cyclosporine soft capsules (Neoral®). The inhalation toxicity study suggested that pulmonary delivery of NM-2 did not result in lung function damage, inflammatory responses, or tissue lesions. Conclusion: The novel nanoaggregate microparticles for pulmonary drug delivery could effectively enhance the relative bioavailability of CsA and had great potential for clinical application.