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2.
Medicine (Baltimore) ; 99(20): e20205, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443344

RESUMO

BACKGROUND: Autoimmune liver disease (ALD) is a chronic liver disease caused by immune dysfunction in the body. However, no causative or curative medical treatment with proven efficacy exists to cure ALDs, and liver transplantation (LT) remains the only effective treatment available. However, the problem of recurrence of ALDs (rALDs) still remains after LT, which seriously affects the survival rate of the patients. Therefore, clinicians need to be aware of the risk factors affecting rALDs after LT. Therefore, this meta-analysis aims to define the risk factors for rALDs, which include the recurrence of primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. METHODS: A systematic search in Pubmed, Embase, Cochrane library and Web of Science databases was performed from 1980 to 2019. The inclusion criteria were risk factors for developing rALDs after LT. However, case series, case reports, reviews, meta-analysis and studies only including human immunodeficiency virus cases, children, and pregnant patients were excluded. RESULTS: The electronic database search yielded 1728 results. Sixty-three retrospective cohort studies met the inclusion criteria and 13 were included in the meta-analysis. The final cohort included 5077 patients, and among them, 21.96% developed rALDs. Colectomy before LT, HR 0.59 (95% confidence interval [CI]: 0.37-0.96), cholangiocarcinoma, HR 3.42 (95% CI: 1.88-6.21), multiple episodes of acute cellular rejection, HR 2.07 (95% CI: 1.27-3.37), model for end-stage liver disease score, HR 1.05 (95% CI: 1.02-1.08), use of mycophenolate mofetil, HR 1.46 (95% CI: 1.00-2.12) and the use of cyclosporin A, HR 0.69 (95% CI: 0.49-0.97) were associated with the risk of rprimary sclerosing cholangitis. In addition, the use of tacrolimus, HR 1.73 (95% CI: 1.00-2.99) and cyclosporin A, HR 0.59 (95% CI: 0.39-0.88) were associated with the risk of rALD. CONCLUSIONS: Multiple risk factors for rALDs were identified, such as colectomy before LT, cholangiocacinoma, multiple episodes of acute cellular rejection, model for end-stage liver disease score, and especially the use of mycophenolate mofetil, cyclosporin A and tacrolimus.


Assuntos
Colangite Esclerosante/etiologia , Hepatopatias/imunologia , Transplante de Fígado/efeitos adversos , Adulto , Inibidores de Calcineurina/efeitos adversos , Colangiocarcinoma/complicações , Colangite Esclerosante/induzido quimicamente , Colangite Esclerosante/epidemiologia , Colectomia/efeitos adversos , Colectomia/estatística & dados numéricos , Ciclosporina/efeitos adversos , Doença Hepática Terminal/complicações , Inibidores Enzimáticos/efeitos adversos , Feminino , Rejeição de Enxerto/complicações , Hepatite Autoimune/complicações , Hepatite Autoimune/epidemiologia , Humanos , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/epidemiologia , Hepatopatias/etiologia , Hepatopatias/mortalidade , Hepatopatias/patologia , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Recidiva , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Tacrolimo/efeitos adversos
4.
Cochrane Database Syst Rev ; 4: CD002290, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32297308

RESUMO

BACKGROUND: About 80% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. Of these children, half relapse frequently, and are at risk of adverse effects from corticosteroids. While non-corticosteroid immunosuppressive medications prolong periods of remission, they have significant potential adverse effects. Currently, there is no consensus about the most appropriate second-line agent in children who are steroid sensitive, but who continue to relapse. In addition, these medications could be used with corticosteroids in the initial episode of SSNS to prolong the period of remission. This is the fourth update of a review first published in 2001 and updated in 2005, 2008 and 2013. OBJECTIVES: To evaluate the benefits and harms of non-corticosteroid immunosuppressive medications in SSNS in children with a relapsing course of SSNS and in children with their first episode of nephrotic syndrome. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 10 March 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs were included if they involved children with SSNS and compared non-corticosteroid immunosuppressive medications with placebo, corticosteroids (prednisone or prednisolone) or no treatment; compared different non-corticosteroid immunosuppressive medications or different doses, durations or routes of administration of the same non-corticosteroid immunosuppressive medication. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility, risk of bias of the included studies and extracted data. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). The certainty of the evidence was assessed using GRADE. MAIN RESULTS: We identified 43 studies (91 reports) and included data from 2428 children. Risk of bias assessment indicated that 21 and 24 studies were at low risk of bias for sequence generation and allocation concealment respectively. Nine studies were at low risk of performance bias and 10 were at low risk of detection bias. Thirty-seven and 27 studies were at low risk of incomplete and selective reporting respectively. Rituximab (in combination with calcineurin inhibitors (CNI) and prednisolone) versus CNI and prednisolone probably reduces the number of children who relapse at six months (5 studies, 269 children: RR 0.23, 95% CI 0.12 to 0.43) and 12 months (3 studies, 198 children: RR 0.63, 95% CI 0.42 to 0.93) (moderate certainty evidence). At six months, rituximab resulted in 126 children/1000 relapsing compared with 548 children/1000 treated with conservative treatments. Rituximab may result in infusion reactions (4 studies, 252 children: RR 5.83, 95% CI 1.34 to 25.29). Mycophenolate mofetil (MMF) and levamisole may have similar effects on the number of children who relapse at 12 months (1 study, 149 children: RR 0.90, 95% CI 0.70 to 1.16). MMF may have a similar effect on the number of children relapsing compared to cyclosporin (2 studies, 82 children: RR 1.90, 95% CI 0.66 to 5.46) (low certainty evidence). MMF compared to cyclosporin is probably less likely to result in hypertrichosis (3 studies, 140 children: RR 0.23, 95% CI 0.10 to 0.50) and gum hypertrophy (3 studies, 144 children: RR 0.09, 95% CI 0.07 to 0.42) (low certainty evidence). Levamisole compared with steroids or placebo may reduce the number of children with relapse during treatment (8 studies, 474 children: RR 0.52, 95% CI 0.33 to 0.82) (low certainty evidence). Levamisole compared to cyclophosphamide may make little or no difference to the risk for relapse after 6 to 9 months (2 studies, 97 children: RR 1.17, 95% CI 0.76 to 1.81) (low certainty evidence). Cyclosporin compared with prednisolone may reduce the number of children who relapse (1 study, 104 children: RR 0.33, 95% CI 0.13 to 0.83) (low certainty evidence). Alkylating agents compared with cyclosporin may make little or no difference to the risk of relapse during cyclosporin treatment (2 studies, 95 children: RR 0.91, 95% CI 0.55 to 1.48) (low certainty evidence) but may reduce the risk of relapse at 12 to 24 months (2 studies, 95 children: RR 0.51, 95% CI 0.35 to 0.74), suggesting that the benefit of the alkylating agents may be sustained beyond the on-treatment period (low certainty evidence). Alkylating agents (cyclophosphamide and chlorambucil) compared with prednisone probably reduce the number of children, who experience relapse at six to 12 months (6 studies, 202 children: RR 0.44, 95% CI 0.32 to 0.60) and at 12 to 24 months (4 studies, 59 children: RR 0.20, 95% CI 0.09 to 0.46) (moderate certainty evidence). IV cyclophosphamide may reduce the number of children with relapse compared with oral cyclophosphamide at 6 months (2 studies, 83 children: RR 0.54, 95% CI 0.34 to 0.88), but not at 12 to 24 months (2 studies, 83 children: RR 0.99, 95% CI 0.76 to 1.29) and may result in fewer infections (2 studies, 83 children: RR 0.14, 95% CI 0.03 to 0.72) (low certainty evidence). Cyclophosphamide compared to chlorambucil may make little or no difference in the risk of relapse after 12 months (1 study, 50 children: RR 1.31, 95% CI 0.80 to 2.13) (low certainty evidence). AUTHORS' CONCLUSIONS: New studies incorporated in this review indicate that rituximab is a valuable additional agent for managing children with steroid-dependent nephrotic syndrome. However, the treatment effect is temporary, and many children will require additional courses of rituximab. The long-term adverse effects of this treatment are not known. Comparative studies of CNIs, MMF, levamisole and alkylating agents have demonstrated little or no differences in efficacy but, because of insufficient power; clinically important differences in treatment effects have not been completely excluded.


Assuntos
Imunossupressores/uso terapêutico , Síndrome Nefrótica/tratamento farmacológico , Adolescente , Alquilantes/efeitos adversos , Alquilantes/uso terapêutico , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Criança , Pré-Escolar , Clorambucila/efeitos adversos , Clorambucila/uso terapêutico , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Ciclosporina/efeitos adversos , Ciclosporina/uso terapêutico , Humanos , Imunossupressores/efeitos adversos , Lactente , Levamisol/efeitos adversos , Levamisol/uso terapêutico , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/uso terapêutico , Síndrome Nefrótica/prevenção & controle , Prednisolona/efeitos adversos , Prednisolona/uso terapêutico , Prednisona/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Ribonucleosídeos/uso terapêutico , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Prevenção Secundária
6.
BMC Immunol ; 21(1): 13, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32183695

RESUMO

BACKGROUND: Hypoxia is a potent molecular signal for cellular metabolism, mitochondrial function, and migration. Conditions of low oxygen tension trigger regulatory cascades mediated via the highly conserved HIF-1 α post-translational modification system. In the adaptive immune response, B cells (Bc) are activated and differentiate under hypoxic conditions within lymph node germinal centers, and subsequently migrate to other compartments. During migration, they traverse through changing oxygen levels, ranging from 1-5% in the lymph node to 5-13% in the peripheral blood. Interestingly, the calcineurin inhibitor cyclosporine A is known to stimulate prolyl hydroxylase activity, resulting in HIF-1 α destabilization and may alter Bc responses directly. Over 60% of patients taking calcineurin immunosuppressant medications have hypo-gammaglobulinemia and poor vaccine responses, putting them at high risk of infection with significantly increased morbidity and mortality. RESULTS: We demonstrate that O 2 tension is a previously unrecognized Bc regulatory switch, altering CXCR4 and CXCR5 chemokine receptor signaling in activated Bc through HIF-1 α expression, and controlling critical aspects of Bc migration. Our data demonstrate that calcineurin inhibition hinders this O 2 regulatory switch in primary human Bc. CONCLUSION: This previously unrecognized effect of calcineurin inhibition directly on human Bc has significant and direct clinical implications.


Assuntos
Agamaglobulinemia/imunologia , Linfócitos B/imunologia , Ciclosporina/efeitos adversos , Centro Germinativo/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/imunologia , Imunossupressores/efeitos adversos , Agamaglobulinemia/etiologia , Animais , Movimento Celular , Células Cultivadas , Feminino , Humanos , Hipóxia/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Oxigênio/metabolismo , Receptores CXCR4/metabolismo , Receptores CXCR5/metabolismo , Transdução de Sinais
7.
Clin Lab ; 66(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32162881

RESUMO

BACKGROUND: Cyclosporine injection is usually applied in allogeneic hematopoietic stem cell transplantation (Allo-HSCT) during induction phase. Anaphylaxis to cyclosporine injection is rare and how to deal with this issue in clinical practice is intractable. METHODS: We report a Chinese male patient with aplastic anemia who underwent allogeneic bone marrow transplantation (BMT) from his brother where HLA totally matched (10/10). Cyclosporine at a dose of 3 mg/kg was started by continuous infusion over 24 hours on day -1 of BMT and the patient showed sever anaphylaxis symptoms. He was then given oral capsules of cyclosporine (Sandimmun) at a conversion ratio 2:1. No further anaphylactic reaction was observed. The BM cells were successfully engrafted without causing severe GVHD. Moreover, frequent TDM monitoring as well as CYP3A4/CYP3A5/MDR1 genotyping were given so as to tailor the oral dosage of cyclosporine individually and prevent the adverse reaction between cyclosporine and posaconazole. RESULTS: The patient carried CYP3A5*3 GG genotype and the concentration of cyclosporine remained steady in the period of conversion and combination of cyclosporine and posaconazole. Consequently, the patient reported no allergy after conversion to oral cyclosporine. CONCLUSIONS: Polyoxyethylated castor oil that is contained in cyclosporine may be the main allergen. Changing to oral capsules that do not contain this medicinal excipient instead of cyclosporine injection would no longer cause an allergic reaction. Rational use of immunosuppressants and prophylaxis antibiotics may need close cooperation between physicians and pharmacists to avoid side effects and harmful interactions.


Assuntos
Anafilaxia/induzido quimicamente , Anemia Aplástica/cirurgia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante Homólogo/efeitos adversos , Administração Oral , Adulto , Ciclosporina/administração & dosagem , Ciclosporina/efeitos adversos , Ciclosporina/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Infusões Intravenosas , Masculino , Transplante Homólogo/métodos , Adulto Jovem
8.
J Biochem Mol Toxicol ; 34(5): e22467, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32040235

RESUMO

Oxidative stress induced by long-term cyclosporine A (CsA) administration is a major cause of chronic nephrotoxicity, which is characterized by tubular atrophy, tubular cell apoptosis, and interstitial fibrosis in the progression of organ transplantation. Although hydrogen-rich water (HRW) has been used to prevent various oxidative stress-related diseases, its underlying mechanisms remain unclear. This study investigated the effects of HRW on CsA-induced nephrotoxicity and its potential mechanisms. After administration of CsA (25 mg/kg/day), rats were treated with or without HRW (12 mL/kg) for 4 weeks. Renal function and vascular activity were investigated. Histological changes in kidney tissues were analyzed using Masson's trichrome and terminal deoxynucleotidyl transferase dUTP nick-end labeling stains. Oxidative stress markers and the activation of the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway were also measured. We found that CsA increased the levels of reactive oxygen species (ROS) and malonaldehyde (MDA), but it reduced glutathione (GSH) and superoxide dismutase (SOD) levels. Such alterations induced vascular dysfunction, tubular atrophy, interstitial fibrosis, and tubular apoptosis. This was evident secondary to an increase in urinary protein, serum creatinine, and blood urea nitrogen, ultimately leading to renal dysfunction. Conversely, HRW decreased levels of ROS and MDA while increasing the activity of GSH and SOD. This was accompanied by an improvement in vascular and renal function. Moreover, HRW significantly decreased the level of Keap1 and increased the expression of Nrf2, NADPH dehydrogenase quinone 1, and heme oxygenase 1. In conclusion, HRW restored the balance of redox status, suppressed oxidative stress damage, and improved kidney function induced by CsA via activation of the Keap1/Nrf2 signaling pathway.


Assuntos
Ciclosporina/efeitos adversos , Hidrogênio/farmacologia , Imunossupressores/efeitos adversos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Substâncias Protetoras/farmacologia , Insuficiência Renal/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Água/farmacologia , Animais , Apoptose/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Creatinina/urina , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal/urina , Superóxido Dismutase/metabolismo , Água/química
9.
Ann Hematol ; 99(4): 737-741, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32030447

RESUMO

For patients with pure red cell aplasia (PRCA), cyclosporine (CsA) is the first line therapy. Occasionally, some patients who suffer from renal insufficiency cannot tolerate CsA. To explore the efficacy and tolerance of sirolimus treatment for those patients, twelve PRCA patients with renal insufficiency from May 2014 to May 2018 in Peking Union Medical College Hospital were enrolled, treated with sirolimus, and followed up at the median time of 16 (10-50) months. Eleven patients (91.7%) responded to sirolimus, with 58.3% complete response (CR) and 41.7% partial response (PR). The median time to achieve the optimum effect was 4 (1-7) months. The serum creatinine level remained stable or even reduced during the treatment period for eleven patients. Seven patients (58.3%) reported adverse events during sirolimus therapy, including increased blood glucose, infection, skin rash, elevated triglyceride or total cholesterol, and elevated serum creatinine compared with baseline. No treatment-related death was noticed during the follow-up time. Three patients relapsed with an overall response rate of 75.0% at 1 year. These results suggested that sirolimus was effective and tolerable for patients with PRCA complicated with renal insufficiency.


Assuntos
Imunossupressores/uso terapêutico , Aplasia Pura de Série Vermelha/tratamento farmacológico , Insuficiência Renal/etiologia , Sirolimo/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Creatinina/sangue , Ciclosporina/efeitos adversos , Ciclosporina/uso terapêutico , Erupção por Droga/etiologia , Avaliação de Medicamentos , Substituição de Medicamentos , Feminino , Humanos , Hiperglicemia/induzido quimicamente , Hipertrigliceridemia/induzido quimicamente , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva , Aplasia Pura de Série Vermelha/complicações , Indução de Remissão , Insuficiência Renal/sangue , Estudos Retrospectivos , Sirolimo/efeitos adversos , Resultado do Tratamento
10.
Pediatr Hematol Oncol ; 37(3): 259-268, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32028812

RESUMO

Relapse of acute myeloblastic leukemia (AML) after first allogenic hematopoietic stem-cell transplantation (allo-HSCT) is a fatal complication. Sixty-five children transplanted for AML were included in a prospective national study from June 2005 to July 2008 to explore the feasibility of preemptive immune modulation based on the monitoring of blood chimerism. Relapse occurred in 23 patients (35%). The median time between the last complete chimerism and relapse was 13.5 days (2-138). Prompt discontinuation of cyclosporin and the administration of donor lymphocyte infusions (DLIs) based on chimerism monitoring failed as a preemptive tool, either for detecting relapse or certifying long-term remission.


Assuntos
Ciclosporina/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Imunomodulação , Leucemia Mieloide Aguda , Transfusão de Linfócitos , Doadores de Tecidos , Quimeras de Transplante/sangue , Aloenxertos , Criança , Ciclosporina/efeitos adversos , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/prevenção & controle , Masculino , Estudos Prospectivos , Recidiva
11.
J Surg Res ; 249: 50-57, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31918330

RESUMO

BACKGROUND: Immunosuppressive medications are widely used for the prevention of allograft rejection in transplantation and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Despite their clinical utility, these medications are accompanied by multiple off-target effects, some of which may be mediated by their effects on mitochondria. METHODS: We examined the effect of commonly used immunosuppressive reagents, mycophenolate mofetil (MMF), cyclosporine A (CsA), rapamycin, and tacrolimus on mitochondrial function in human T-cells. T-cells were cultured in the presence of immunosuppressive medications in a range of therapeutic doses. After incubation, mitochondrial membrane potential, reactive oxygen species (ROS) production, and apoptotic cell death were measured by flow cytometry after staining with DiOC6, MitoSOX Red, and Annexin V and 7-AAD, respectively. Increases in cytosolic cytochrome c were demonstrated by Western blot. T-cell basal oxygen consumption rates were measured using a Seahorse bioanalyzer. RESULTS: T-cells demonstrated significant levels of mitochondrial depolarization after treatment with therapeutic levels of MMF but not after treatment with CsA, tacrolimus, or rapamycin. Only MMF induced T-cell ROS production and induced significant levels of apoptotic cell death that were associated with increased levels of cytosolic cytochrome c. MMF decreased T-cell basal oxygen consumption within its therapeutic range, and CsA demonstrated a trend toward this result. CONCLUSIONS: The impairment of mitochondrial function by commonly used immunosuppressive reagents may impair T-cell differentiation and function by decreasing energy production, producing toxic ROS, and inducing apoptotic cell death.


Assuntos
Imunossupressores/efeitos adversos , Mitocôndrias/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Ciclosporina/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Células Jurkat , Potencial da Membrana Mitocondrial , Mitocôndrias/patologia , Ácido Micofenólico/efeitos adversos , Espécies Reativas de Oxigênio/metabolismo , Sirolimo/efeitos adversos , Linfócitos T/citologia , Linfócitos T/patologia , Tacrolimo/efeitos adversos
12.
Ocul Immunol Inflamm ; 28(3): 509-512, 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-31268769

RESUMO

Purpose: To report the efficacy of adalimumab in a case of chronic Vogt-Koyanagi-Harada (VKH) disease refractory to conventional corticosteroids and immunosuppressive therapy and complicated by central serous chorioretinopathy (CSC).Case report: A 66-year-old woman diagnosed with VKH was treated with intravenous corticosteroids followed by oral corticosteroids and cyclosporine. However, systemic corticosteroids could not be tapered because of recurrent ocular inflammation and systemic complications (diabetes mellitus, moon face, bone weakness), while CSC appeared in both eyes. A diagnosis of chronic VKH resistant to medications complicated by corticosteroid-induced CSC was made. Systemic corticosteroids and cyclosporine were tapered and adalimumab initiated. Bilateral ocular inflammation and CSC were gradually reduced and visual acuity improved without any adverse effect. Twelve months after starting adalimumab monotherapy, no signs of active VKH and CSC were present.Conclusions: Adalimumab is one of the effective therapeutic options for refractory VKH disease complicated with corticosteroid-induced adverse effects.


Assuntos
Adalimumab/administração & dosagem , Coriorretinopatia Serosa Central/etiologia , Ciclosporina/efeitos adversos , Tolerância a Medicamentos , Glucocorticoides/efeitos adversos , Síndrome Uveomeningoencefálica/tratamento farmacológico , Idoso , Anti-Inflamatórios/administração & dosagem , Coriorretinopatia Serosa Central/diagnóstico , Coriorretinopatia Serosa Central/tratamento farmacológico , Doença Crônica , Relação Dose-Resposta a Droga , Feminino , Angiofluoresceinografia , Fundo de Olho , Humanos , Imunossupressores/efeitos adversos , Tomografia de Coerência Óptica , Síndrome Uveomeningoencefálica/complicações , Síndrome Uveomeningoencefálica/diagnóstico , Acuidade Visual
13.
Am J Ophthalmol ; 212: 116-126, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31770513

RESUMO

PURPOSE: To assess the safety and efficacy of cyclosporine A cationic emulsion (CsA CE) 0.1% eye drops in pediatric patients with severe active vernal keratoconjunctivitis (VKC). DESIGN: Multicenter, double-masked, randomized controlled trial 8-month safety analysis. METHODS: Of 169 patients (age range, 4-17 years) initially randomized in the 4-month VErnal KeratoconjunctiviTIs Study (VEKTIS), 142 entered the 8-month follow-up period during which CsA CE patients remained on their original regimen (CsA CE 4 times daily [QID, high-dose] or CsA CE twice daily [BID, low-dose] + vehicle BID) and vehicle patients were allocated to one of these 2 active regimens. Main outcome measures were safety, including treatment-emergent adverse events, and efficacy, including corneal fluorescein staining (CFS) score. RESULTS: Improvements in CFS score, rescue medication use, key VKC symptoms (photophobia, tearing, itching, and mucous discharge), and quality of life (QoL) assessed by QUICK questionnaire observed with CsA CE compared with vehicle during the 4-month evaluation period remained stable during the 8-month follow-up period, with the high-dose regimen continuing to provide greater benefits in most efficacy measures. CsA CE was well tolerated. Treatment-related treatment-emergent adverse events during the 12-month study were reported in 15 (20.8%) and 11 (15.7%) of the CsA CE high-dose and low-dose patients, respectively, most commonly instillation site pain (13.9% and 7.1%, respectively). Laboratory data, vital signs, slit lamp examination, best-corrected distance visual acuity, and intraocular pressure raised no safety concerns. CONCLUSIONS: Improvements in keratitis, symptoms, and QoL achieved after CsA CE treatment for 4 months remained stable over the 8-month follow-up period. CsA continued to maintain a favorable safety profile.


Assuntos
Conjuntivite Alérgica/tratamento farmacológico , Ciclosporina/administração & dosagem , Imunossupressores/administração & dosagem , Adolescente , Anti-Inflamatórios/uso terapêutico , Criança , Pré-Escolar , Ciclosporina/efeitos adversos , Dexametasona/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Imunossupressores/efeitos adversos , Ceratite/tratamento farmacológico , Masculino , Segurança do Paciente , Resultado do Tratamento
14.
BMJ Case Rep ; 12(11)2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31772127

RESUMO

A 73-year-old woman presented with an acute exacerbation of her long-standing psoriasis. Ciclosporin was commenced due to the severity of her symptoms resulting in remission within 2 weeks. Full blood count, urea and electrolytes following initiation of treatment were unremarkable, although she complained of muscle aches, which was attributed to her known multiple sclerosis. Three weeks later she was admitted to the hospital with diarrhoea and vomiting. Repeat blood tests revealed raised creatinine (528 µmol/L (normal range (NR) n=45-84 µmol/L)), urea (32.6 mmol/L (NR 2.5-7.8 mmol/L)) and creatine kinase (6792 IU/L (NR 25-200 IU/L)) levels and reduced estimated glomerular filtration rate of 7. A diagnosis of acute kidney injury secondary to rhabdomyolysis was made due to an interaction between ciclosporin and simvastatin, precipitated by the dehydration from gastroenteritis. Haemofiltration was required to stabilise her renal function and she made a complete recovery.


Assuntos
Lesão Renal Aguda/etiologia , Anticolesterolemiantes/efeitos adversos , Ciclosporina/efeitos adversos , Imunossupressores/efeitos adversos , Rabdomiólise/induzido quimicamente , Sinvastatina/efeitos adversos , Lesão Renal Aguda/sangue , Idoso , Anticolesterolemiantes/uso terapêutico , Creatina Quinase/sangue , Creatinina/sangue , Ciclosporina/uso terapêutico , Diagnóstico Diferencial , Diarreia/diagnóstico , Diarreia/etiologia , Interações Medicamentosas , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Hemofiltração/métodos , Humanos , Imunossupressores/uso terapêutico , Rabdomiólise/complicações , Rabdomiólise/diagnóstico , Sinvastatina/uso terapêutico , Resultado do Tratamento , Vômito/diagnóstico , Vômito/etiologia
15.
Tunis Med ; 97(5): 639-643, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31729734

RESUMO

INTRODUCTION: The adenoviral keratoconjunctivitis infiltrates may be a source of significant visual impairment justifying the use of various therapeutic means. AIM: Evaluate the efficiency and safety of use of cyclosporine A 0,5% eye drop in the treatment of subepithelial infiltrates. METHODS: It was a prospective study of 37 eyes of 22 patients with adenoviral keratoconjunctivitis with subepithelial infiltrates treated with cyclosporine A 0,5% eye drop. Cyclosporine A 0,5% was prepared from the injectable form of cyclosporine (Sandimmun®) and artificial tears. The cyclosporine A 0,5% was first administered at 4 drops per day for 15 days, then at a rate of 2 drops per day for a variable period ranging from 15 days to 6 months. The use of this molecule has been motivated by the presence of a persistent dazzlement, by visual acuity under 6/10 or an astigmatism superior to 1 diopter. RESULTS: At the end of follow, dazzlement disappeared in all patients; the final average visual acuity was 8/10 and corneal astigmatism average was of 0.75 diopter. The slit lamp examination showed a marked decrease in the number and density of subepithelial infiltrates from the 15th day. A 29-year-old patient, however, presented some intercostal vesicles due to zonal recrudescence but with spontaneous and quick resolve in the same time of taking topical cyclosporine. No local complications were observed in our patients. The average follow-up was 13 months. CONCLUSION: Topical cyclosporine A is an effective and well-tolerated alternative to corticosteroids in the subepithelial infiltrates occurring as sequelae of adenoviral keratoconjunctivitis.


Assuntos
Infecções por Adenoviridae/tratamento farmacológico , Ciclosporina/administração & dosagem , Ceratoconjuntivite/tratamento farmacológico , Ceratoconjuntivite/virologia , Adulto , Ciclosporina/efeitos adversos , Feminino , Humanos , Masculino , Soluções Oftálmicas , Estudos Prospectivos , Resultado do Tratamento
16.
BMJ Case Rep ; 12(11)2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31748372

RESUMO

Use of medications including vitamin A derivatives and tetracyclines have been associated with papilledema and raised intracranial pressure. A 46-year-old woman was referred to neuro-ophthalmology for bilateral optic disc oedema and had a 7-year history of cyclosporine use after renal transplantation. She had preserved visual function and moderate bilateral optic disc oedema. Magnetic resonance imaging and magnetic resonance venography of the brain were normal apart from signs of raised intracranial pressure. Lumbar puncture revealed an elevated opening pressure of 40 cm of water with normal cerebrospinal fluid contents. Nephrology was consulted and cyclosporine was switched to tacrolimus and she was treated with acetazolamide. The papilledema resolved within 1 month of her initial visit. It is important to recognise the role that cyclosporine plays in raising intracranial pressure, especially in patients requiring immunosuppression, such as transplant patients. Tacrolimus is a suitable alternative in these cases.


Assuntos
Ciclosporina/efeitos adversos , Imunossupressores/efeitos adversos , Hipertensão Intracraniana/induzido quimicamente , Papiledema/induzido quimicamente , Papiledema/tratamento farmacológico , Acetazolamida/uso terapêutico , Ciclosporina/uso terapêutico , Diagnóstico Diferencial , Diuréticos/uso terapêutico , Feminino , Humanos , Imunossupressores/uso terapêutico , Hipertensão Intracraniana/diagnóstico , Pressão Intracraniana/efeitos dos fármacos , Transplante de Rim/efeitos adversos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Papiledema/diagnóstico por imagem , Punção Espinal/métodos , Tacrolimo/uso terapêutico , Resultado do Tratamento
17.
Can J Physiol Pharmacol ; 97(12): 1115-1123, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31613143

RESUMO

Cyclosporine, an immunosuppressive drug, exhibits a toxic effect on renal and vascular systems. The present study investigated whether resveratrol treatment alleviates renal and vascular injury induced by cyclosporine. Cyclosporine (25 mg/kg per day, s.c.) was given for 7 days to rats either alone or in combination with resveratrol (10 mg/kg per day, i.p.). Relaxation and contraction responses of aorta were examined. Serum levels of blood urea nitrogen, creatinine, angiotensin II, and angiotensin 1-7 were measured. Histopathological examinations as well as immunostaining for 4-hydroxynonenal and nitrotyrosine were performed in the kidney. RNA expressions of renin-angiotensin system components were also measured in renal and aortic tissues. Cyclosporine decreased the endothelium-dependent relaxation and increased vascular contraction in the aorta. It caused renal tubular degeneration and increased immunostaining for 4-hydroxynonenal, an oxidative stress marker. Cyclosporine also caused upregulations of the vasoconstrictive renin-angiotensin system components in renal (angiotensin-converting enzyme) and aortic (angiotensin II type 1 receptor) tissues. Resveratrol co-treatment prevented the cyclosporine-related deteriorations. Moreover, it induced the expressions of vasodilatory effective angiotensin-converting enzyme 2 and angiotensin II type 2 receptor in aorta and kidney, respectively. We conclude that resveratrol may be effective in preventing cyclosporine-induced renal tubular degeneration and vascular dysfunction at least in part by modulating the renin-angiotensin system.


Assuntos
Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Ciclosporina/efeitos adversos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Resveratrol/farmacologia , Angiotensina II/sangue , Animais , Citoproteção/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , NADPH Oxidase 4/genética , RNA Mensageiro/genética , Ratos , Ratos Wistar , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
18.
Pediatr Dermatol ; 36(6): 843-853, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31566785

RESUMO

BACKGROUND: Cyclosporine is a useful immunosuppressive agent for achieving disease control in moderate to severe atopic dermatitis in children and adults. However, it carries the potential for nephrotoxicity. Monitoring of drug levels is performed in other patient groups, such as transplant recipients, but is not commonplace in the management of atopic dermatitis. OBJECTIVES: To investigate levels of nephrotoxicity associated with cyclosporine use in atopic dermatitis and assess potential correlation with trough levels of cyclosporine. METHODS: An electronic search was conducted on MEDLINE, EMBASE, and Cochrane databases for randomized controlled trials and cohort studies assessing the safety profile of cyclosporine compared to placebo or other atopic dermatitis treatments, in adult and pediatric atopic dermatitis patients from 1966 to May 2019. Studies that did not assess renal toxicity were excluded from analysis. RESULTS: Thirty-eight trials were included for analysis, excluding 11 that did not assess renal toxicity. Descriptive statistical analysis only was performed, due to the high heterogeneity between study methodologies. Significant renal toxicity was seen in 0%-9% of pediatric participants. Monitoring of trough cyclosporine levels was performed in only 10 of the studies, and their correlation to toxicity or disease activity was not explored. CONCLUSION: There is limited evidence in atopic dermatitis regarding trough level monitoring of cyclosporine. Currently, the practice is not commonplace, particularly in pediatrics, and this is reflected in trial methodology. Monitoring may be useful in specific pediatric groups, such as those on multiple concurrent medications, patients with hepatic or renal dysfunction and non-responders to therapy.


Assuntos
Ciclosporina/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Imunossupressores/uso terapêutico , Nefropatias/induzido quimicamente , Criança , Ciclosporina/efeitos adversos , Ciclosporina/farmacocinética , Esquema de Medicação , Monitoramento de Medicamentos , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética
19.
Eur J Dermatol ; 29(4): 371-374, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31486404

RESUMO

BACKGROUND: Atopic dermatitis (AD) in adults over 45 years of age (AD≥45) has been poorly studied. OBJECTIVES: To determine whether the AD phenotype varies according to the pattern of AD onset in AD≥45 patients and whether response to cyclosporine A (CsA) is influenced by age. MATERIALS AND METHODS: This monocentric retrospective study was performed in a French university department of dermatology. We included 409 AD<45 patients (111 treated with CsA) and 124 AD≥45 patients (26 treated with CsA). Among AD≥45 patients, 20% were categorised into Subgroup 1 (persistence of AD since childhood), 52% into Subgroup 2 (recurrence of AD with a history of classic childhood AD), and 28% into Subgroup 3 (adult-onset AD). RESULTS: Gender, associated atopic comorbidities, a family history of atopy, and AD severity were similar regarding the different patterns of AD onset in AD≥45 patients. Skin lesions predominated on the face and neck in AD≥45 patients with AD since childhood (30% in Subgroups 1 and 2) compared to those with adult-onset AD (14% in Subgroup 3). The efficacy of CsA was similar between groups AD≥45 and AD<45, but 28% of AD≥45 patients versus 20% of AD<45 patients had increased serum creatinine levels under CsA. CONCLUSION: No significant association seems to exist between the onset of AD and demographic or clinical characteristics in AD≥45 patients (except that head and neck involvement is rarer in adult-onset AD). Patient age does not influence response to CsA, but this drug appears to be less well tolerated in older patients.


Assuntos
Ciclosporina/uso terapêutico , Dermatite Atópica/diagnóstico , Dermatite Atópica/tratamento farmacológico , Imunoglobulina E/sangue , Fatores Etários , Idoso , Estudos de Coortes , Ciclosporina/efeitos adversos , Dermatite Atópica/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Avaliação Geriátrica , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Resultado do Tratamento
20.
Adv Clin Exp Med ; 28(10): 1393-1401, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31518496

RESUMO

BACKGROUND: Cyclosporine-A (CsA) is widely used for immunosuppressive therapy in renal transplantation. Nephrotoxicity is the main dose-limiting undesirable consequence of CsA. Urotensin II (U-II), a novel peptide with a powerful influence on vascular biology, has been added to the list of potential renal vascular regulators. Upregulation of the urotensin receptors and elevation of plasma U-II levels are thought to possibly play a role in the etiology of renal failure. OBJECTIVES: The present study examines this hypothesis by evaluating renal function and histology with regard to the potential role of U-II and its antagonist, palosuran, in the pathogenesis of CsA-induced nephrotoxicity in rats. MATERIAL AND METHODS: Male Sprague-Dawley rats were treated with CsA (15 mg/kg, for 21 days, intraperitoneally) or CsA + palosuran (300 mg/kg, for 21 days). Renal function was measured and histopathology, U-II immunostaining and protein detection with western blotting of the kidneys were performed. RESULTS: Cyclosporine-A administration caused a marked decline in creatinine clearance (Ccr). Fractional sodium excretion (FENa) tended to increase in the CsA-treated rats. Plasma U-II levels decreased in the CsA-treated rats. Cyclosporine-A treatment resulted in a marked deterioration in renal histology and an increase in the expression of U-II protein in the kidneys. Palosuran's improvement of renal function manifested as a significant decrease in serum creatinine levels and a significant increase in urine creatinine levels, resulting in a marked increase in Ccr. Palosuran produced a significant normalization of kidney histology and prevented an increase in U-II expression. CONCLUSIONS: Cyclosporine-A-induced renal impairment was accompanied by an increase in U-II expression in kidneys and a contrary decrease in systemic U-II levels. Palosuran improved the condition of rats suffering from renal dysfunction by preventing the decrease in renal U-II expression without affecting the systemic levels of U-II. The protective effect of palosuran in CsA nephrotoxicity is possibly independent of its U-II receptor antagonism.


Assuntos
Ciclosporina/toxicidade , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Urotensinas/antagonistas & inibidores , Animais , Creatinina/sangue , Creatinina/urina , Ciclosporina/efeitos adversos , Imunossupressores , Rim/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Masculino , Modelos Animais , Quinolinas , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Ureia/análogos & derivados
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