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1.
Am J Transplant ; 24(7): 1132-1145, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38452932

RESUMEN

Mycophenolate mofetil (MMF) is one of the most used immunosuppressive drugs in organ transplantation, but frequent gastrointestinal (GI) side effects through unknown mechanisms limit its clinical use. Gut microbiota and its metabolites were recently reported to play a vital role in MMF-induced GI toxicity, but the specific mechanism of how they interact with the human body is still unclear. Here, we found that secondary bile acids (BAs), as bacterial metabolites, were significantly reduced by MMF administration in the gut of mice. Microbiome data and fecal microbiota transfer model supported a microbiota-dependent effect on the reduction of secondary BAs. Supplementation of the secondary BA lithocholic acid alleviated MMF-induced weight loss, colonic inflammation, and oxidative phosphorylation damage. Genetic deletion of the vitamin D3 receptor (VDR), which serves as a primary colonic BA receptor, in colonic epithelial cells (VDRΔIEC) abolished the therapeutic effect of lithocholic acid on MMF-induced GI toxicity. Impressively, we discovered that paricalcitol, a Food and Drug Administration-approved VDR agonist that has been used in clinics for years, could effectively alleviate MMF-induced GI toxicity. Our study reveals a previously unrecognized mechanism of gut microbiota, BAs, and VDR signaling in MMF-induced GI side effects, offering potential therapeutic strategies for clinics.


Asunto(s)
Ácidos y Sales Biliares , Microbioma Gastrointestinal , Ácido Micofenólico , Receptores de Calcitriol , Animales , Ácido Micofenólico/farmacología , Ratones , Microbioma Gastrointestinal/efectos de los fármacos , Receptores de Calcitriol/metabolismo , Ácidos y Sales Biliares/metabolismo , Inmunosupresores , Ratones Endogámicos C57BL , Masculino , Enfermedades Gastrointestinales/inducido químicamente , Ácido Litocólico , Humanos
2.
J Hepatol ; 80(4): 576-585, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38101756

RESUMEN

BACKGROUND & AIMS: Patients with autoimmune hepatitis (AIH) almost invariably require lifelong immunosuppressive treatment. There is genuine concern about the efficacy and tolerability of the current standard combination therapy of prednisolone and azathioprine. Mycophenolate mofetil (MMF) has emerged as an alternative option. The aim of this study was to compare MMF to azathioprine as induction therapy for AIH. METHODS: In this 24-week, prospective, randomised, open-label, multicentre superiority trial, 70 patients with treatment-naive AIH received either MMF or azathioprine, both in combination with prednisolone. The primary endpoint was biochemical remission defined as normalisation of serum levels of alanine aminotransferase and IgG after 24 weeks of treatment. Secondary endpoints included safety and tolerability. RESULTS: Seventy patients (mean 57.9 years [SD 14.0]; 72.9% female) were randomly assigned to the MMF plus prednisolone (n = 39) or azathioprine plus prednisolone (n = 31) group. The primary endpoint was met in 56.4% and 29.0% of patients assigned to the MMF group and the azathioprine group, respectively (difference, 27.4 percentage points; 95% CI 4.0 to 46.7; p = 0.022). The MMF group exhibited higher complete biochemical response rates at 6 months (72.2% vs. 32.3%; p = 0.004). No serious adverse events occurred in patients who received MMF (0%) but serious adverse events were reported in four patients who received azathioprine (12.9%) (p = 0.034). Two patients in the MMF group (5.1%) and eight patients in the azathioprine group (25.8%) discontinued treatment owing to adverse events or serious adverse events (p = 0.018). CONCLUSIONS: In patients with treatment-naive AIH, MMF with prednisolone led to a significantly higher rate of biochemical remission at 24 weeks compared to azathioprine combined with prednisolone. Azathioprine use was associated with more (serious) adverse events leading to cessation of treatment, suggesting superior tolerability of MMF. IMPACT AND IMPLICATIONS: This randomised-controlled trial directly compares azathioprine and mycophenolate mofetil, both in combination with prednisolone, for the induction of biochemical remission in treatment-naive patients with autoimmune hepatitis. Achieving complete remission is desirable to prevent disease progression. Patients assigned to the mycophenolate mofetil group reached biochemical remission more often and experienced fewer adverse events. The findings in this trial may contribute to the re-evaluation of international guidelines for the standard of care in treatment-naive patients with autoimmune hepatitis. TRIAL REGISTRATION NUMBER: #NCT02900443.


Asunto(s)
Azatioprina , Hepatitis Autoinmune , Humanos , Femenino , Masculino , Azatioprina/uso terapéutico , Ácido Micofenólico/efectos adversos , Hepatitis Autoinmune/tratamiento farmacológico , Estudios Prospectivos , Resultado del Tratamiento , Inmunosupresores/efectos adversos , Prednisolona/efectos adversos , Inducción de Remisión
3.
Small ; : e2403640, 2024 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-38963162

RESUMEN

Ensuring precise drug release at target sites is crucial for effective treatment. Here, pH-responsive nanoparticles for oral administration of mycophenolate mofetil, an alternative therapy for patients with inflammatory bowel disease unresponsive to conventional treatments is developed. However, its oral administration presents challenges due to its low solubility in the small intestine and high solubility and absorption in the stomach. Therefore, this aim is to design a drug delivery system capable of maintaining drug solubility compared to the free drug while delaying absorption from the stomach to the intestine. Successful synthesis and assembly of a block copolymer incorporating a pH-responsive functional group is achieved. Dynamic light scattering indicated a significant change in hydrodynamic size when the pH exceeded 6.5, confirming successful incorporation of the pH-responsive group. Encapsulation and controlled release of mycophenolate mofetil are efficiently demonstrated, with 90% release observed at intestinal pH. In vitro cell culture studies confirmed biocompatibility, showing no toxicity or adverse effects on Caco-2 cells. In vivo oral rat studies indicated reduced drug absorption in the stomach and enhanced absorption in the small intestine with the developed formulation. This research presents a promising drug delivery system with potential applications in the treatment of inflammatory bowel disease.

4.
J Autoimmun ; 147: 103246, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38788540

RESUMEN

OBJECTIVES: Systemic sclerosis (SSc) is a multiorgan disease with a 10-year mortality rate of up to 50 %. B cell-depleting therapy with rituximab (RTX) appears effective in SSc treatment, but data from randomized controlled trials (RCTs) are lacking, and the frequency and dosage of RTX in SSc have no consensus. We aimed to evaluate the long-term efficacy and safety of quarterly RTX administration in SSc. METHODS: This study retrospectively analyzed 40 patients with SSC treated with RTX twice within 14 days every 3 months from 2010 to 2020. The patients fulfilled the LeRoy and the American College of Rheumatology/European League Against Rheumatism Criteria for SSc. Modified Rodnan skin score (mRSS), lung function test results, and serum immunoglobulin (IgG, IgA, and IgM) concentrations were analyzed. RESULTS: A total of 40 patients with SSc received RTX over a median time of 3.9 years (range: 1-10 years). The median mRSS (baseline: 19, 24 months: 16, p < 0.001) demonstrated a significant improvement, and the predicted forced vital capacity was stable. No new or unexpected safety signals, especially regarding treatment-related infectious adverse events, were observed. Immunoglobulin concentrations were within normal range, and specific antibodies to pneumococcal polysaccharides were preserved despite long-term B cell-depleting therapy. None of the patients died during the observation period of up to 10 years. CONCLUSION: SSc was effectively and safely treated with low-dose RTX quarterly. RCTs are warranted to validate the advantage of continuous B cell depletion by quarterly low-dose RTX administration compared to other treatment intervals.


Asunto(s)
Linfocitos B , Depleción Linfocítica , Rituximab , Esclerodermia Sistémica , Humanos , Esclerodermia Sistémica/mortalidad , Esclerodermia Sistémica/inmunología , Esclerodermia Sistémica/terapia , Esclerodermia Sistémica/tratamiento farmacológico , Femenino , Masculino , Persona de Mediana Edad , Linfocitos B/inmunología , Rituximab/uso terapéutico , Estudios Retrospectivos , Adulto , Resultado del Tratamiento , Anciano
5.
Artículo en Inglés | MEDLINE | ID: mdl-39312626

RESUMEN

OBJECTIVES: Mycophenolate mofetil (MMF) is an immunosuppressant used to treat rheumatological diseases, including Systemic Sclerosis (SSc). While MMF is an established inhibitor of lymphocyte proliferation, recent evidence suggests MMF also mediates effects on other cell types. The goal of this study was to determine the effect of MMF on monocytes and macrophages, which have been implicated in SSc pathogenesis. METHODS: Human monocyte-derived macrophages were cultured with the active MMF metabolite, mycophenolic acid (MPA), and assessed for changes in viability and immuno-phenotype. Guanosine supplementation studies were performed to determine whether MPA-mediated effects were dependent on de novo purine synthesis. The ability of MPA-treated macrophages to induce fibroblast activation was evaluated, and dermal myeloid expression signatures were analyzed in MMF-treated SSc patients. RESULTS: MPA reduced viability and induced apoptosis in monocytes and macrophages at doses (average IC50 = 1.15 µg/ml) within the target serum concentration of MMF patients (1-3µg/ml). These effects were reversed by guanosine supplementation. Low-dose MPA (0.5 µg/ml) attenuated IL-4 or SSc plasma-mediated macrophage activation, and inhibited the ability of SSc plasma-activated macrophages to induce SSc fibroblast activation. Gene expression studies demonstrated significant reductions in dermal myeloid signatures in MMF-responsive SSc patients. CONCLUSIONS: For the first time, we demonstrate that MMF inhibits the viability and pro-fibrotic activation of human monocytes and macrophages, which is dependent on de novo purine synthesis. Coupled with myeloid gene expression attenuation following MMF treatment in patients, these results suggest that fibrotic inhibition observed with MMF may be attributable, at least in part, to direct effects on myeloid cells.

6.
Lupus ; 33(4): 319-327, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38232223

RESUMEN

OBJECTIVES: To evaluate the renal response to mycophenolate mofetil (MMF) as maintenance therapy for lupus nephritis (LN) in Japanese patients, we compared the efficacy of MMF and the sequential use of monthly intravenous cyclophosphamide (IVCY) followed by tacrolimus (TAC). METHODS: We examined 14 patients with LN who were treated with continuous MMF as induction and maintenance therapies (MMF group) and 10 patients with LN who received monthly IVCY as induction therapy followed by maintenance therapy with TAC (IVCY-TAC group). We assessed the therapeutic effects of each treatment regimen on renal manifestations and serological findings over a 36-month period after treatment initiation. RESULTS: Mean urine protein-to-creatinine ratios in the MMF and IVCY-TAC groups significantly decreased from 2.75 to 0.11 g/gCr and from 3.26 to 0.22 g/gCr, respectively. Significant improvements in serum immunological variables (serum complement C3 or C4 levels and the anti-double-stranded DNA antibody titer) and reductions in the SLE disease activity index and daily prednisolone dosages were observed in both groups during induction therapy and were maintained during maintenance therapy. Efficacy was similar between the MMF and IVCY-TAC groups. CONCLUSION: MMF has potential as an effective treatment for renal manifestations in Japanese patients throughout induction and maintenance therapies for LN, as an alternative to conventional IVCY-TAC therapy, and as a glucocorticoid-sparing agent.


Asunto(s)
Lupus Eritematoso Sistémico , Nefritis Lúpica , Humanos , Ácido Micofenólico , Tacrolimus , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/inducido químicamente , Inmunosupresores/efectos adversos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Ciclofosfamida/uso terapéutico , Resultado del Tratamiento
7.
J Pediatr Gastroenterol Nutr ; 79(3): 485-494, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39073133

RESUMEN

Hepatoxicity associated with recombinant adeno-associated virus gene therapy is being increasingly encountered by hepatologists in tertiary and quaternary referral units due to the recent increase of these therapies for neuromuscular and haematological disorders. The challenges in managing the condition stem from a lack of good-quality evidence on the appropriate protocols for immunosuppressants due to lack of representative animal models. There is a need for protocols for diagnosing and treating hepatotoxicity and this possible with further research to understand the problem and its management. The review also highlights the importance of a multidisciplinary team in managing hepatotoxicity and recommends further research to better identify at-risk individuals, define the extent of the problem and assess the long-term effects of liver injury and immunosuppressants.


Asunto(s)
Dependovirus , Terapia Genética , Vectores Genéticos , Humanos , Terapia Genética/métodos , Dependovirus/genética , Niño , Inmunosupresores/uso terapéutico , Pediatría/métodos , Gastroenterología/métodos , Enfermedad Hepática Inducida por Sustancias y Drogas/terapia , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología
8.
J Pediatr Gastroenterol Nutr ; 78(2): 328-338, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38374561

RESUMEN

OBJECTIVES: The Starzl Network for Excellence in Pediatric Transplantation identified optimizing immunosuppression (IS) as a priority practice improvement area for patients, families, and providers. We aimed to evaluate associations between clinical characteristics, early IS, and outcomes. METHODS: We analyzed pediatric liver transplant (LT) data from 2013 to 2018 in the United Network for Organ Sharing (UNOS) and the Society of Pediatric Liver Transplantation (SPLIT) registries. RESULTS: We included 2542 LT recipients in UNOS and 1590 in SPLIT. IS choice varied between centers with steroid induction and mycophenolate mofetil (MMF) use each ranging from 0% to 100% across centers. Clinical characteristics associated with early IS choice were inconsistent between the two data sets. T-cell depleting antibody use was associated with improved 1-year graft (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.34-0.76) and patient (HR 0.40, 95% CI 0.20-0.79) survival in UNOS but decreased 1-year patient survival (HR 4.12, 95% CI 1.31-12.93) and increased acute rejection (HR 1.58, 95% CI 1.07-2.34) in SPLIT. Non-T-cell depleting antibody use was not associated with differential risk of survival nor rejection. MMF use was associated with improved 1-year graft survival (HR 0.73, 95% CI 0.54-0.99) in UNOS only. CONCLUSIONS: Variation exists in center choice of early IS regimen. UNOS and SPLIT data provide conflicting associations between IS and outcomes in multivariable analysis. These results highlight the need for future multicenter collaborative work to identify evidence-based IS best practices.


Asunto(s)
Trasplante de Riñón , Trasplante de Hígado , Niño , Humanos , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Terapia de Inmunosupresión/métodos , Inmunosupresores/uso terapéutico , Ácido Micofenólico/uso terapéutico
9.
Pediatr Nephrol ; 39(3): 771-780, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37682369

RESUMEN

BACKGROUND: We aimed to investigate the efficacy and safety of repeated use of rituximab (RTX) in pediatric patients with nephrotic syndrome (NS). METHODS: Retrospective review of 50 patients with steroid-dependent NS (SDNS) who had received more than three cycles of RTX was conducted; each consisted of one to four infusions until B lymphocytes were depleted. RESULTS: The median age of starting the first RTX cycle was 12.4 years (interquartile ranges (IQR) 10.2-14.6). During a median follow-up period of 6.3 (IQR 3.6-8.6) years, patients received a median of 5.0 RTX cycles (IQR 4.0-7.3). The number of relapses decreased from a median of 2.0 relapses per year (IQR 1.0-3.0) to 0.2 relapses per year (IQR 0.0-0.5) after long-term RTX treatments (P < 0.001). Longer relapse-free periods were associated with more than four RTX cycles, longer B-cell depletion, older age at each RTX treatment, and lower cholesterol levels. B lymphocytes recovered to 1% at a median of 5.9 months (95% confidence interval 5.7-6.1) after RTX administration. Factors related to a longer period of B-cell depletion included more than five RTX cycles, a higher dose of RTX, older age at treatment, and concurrent use of antimetabolites. During repeated RTX treatments, 8.0%, 6.0%, and 2.0% of patients developed hypogammaglobulinemia, severe infection, and severe neutropenia, respectively. CONCLUSIONS: Long-term repeated use of RTX may be effective and safe in pediatric NS patients. Furthermore, the redosing of RTX could be chosen by considering predictive factors for relapse-free and B-cell depletion periods.


Asunto(s)
Síndrome Nefrótico , Niño , Humanos , Rituximab/efectos adversos , Síndrome Nefrótico/tratamiento farmacológico , Resultado del Tratamiento , Factores de Tiempo , Recurrencia , Estudios Retrospectivos , Inmunosupresores/uso terapéutico
10.
Pediatr Nephrol ; 39(11): 3193-3200, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38607424

RESUMEN

A 14-year-old patient presents with hematuria and proteinuria. Clinical evaluation reveals a positive anti-nuclear antibody titer, positive anti-double stranded DNA antibody and hypocomplementemia. Systemic lupus erythematosus (SLE) is diagnosed based on the 2019 EULAR/ACR (European League Against Rheumatism/American College of Rheumatology) classification criteria (Aringer et al. Arthritis Rheumatol 71:1400-1412, 2019). A kidney biopsy is performed that confirms the presence of immune complex glomerulonephritis, ISN-RPS (International Society of Nephrology/Renal Pathology Society) class IV (Bajema et al. Kidney Int 93:789-796, 2018). According to the latest clinical practice guidelines (Rovin et al. Kidney Int 100:753-779, 2021; Fanouriakis et al. Ann Rheum Dis 83:15-29, 2023), there are alternatives to treating this patient with cyclophosphamide. But what if this patient also presented with oliguria and volume overload requiring intensive care and dialysis? What if this patient also presented with altered mental status and seizures, and was diagnosed with neuropsychiatric lupus? What if this patient was also diagnosed with a pulmonary hemorrhage and respiratory failure? The clinical practice guidelines do not address these scenarios that are not uncommon in patients with SLE. Moreover, in some countries worldwide, patients do not have the privilege of access to biologics or more expensive alternatives. The purpose of this review is to evaluate the contemporary options for initial treatment of nephritis in patients with SLE.


Asunto(s)
Ciclofosfamida , Inmunosupresores , Nefritis Lúpica , Humanos , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/diagnóstico , Ciclofosfamida/uso terapéutico , Adolescente , Inmunosupresores/uso terapéutico , Femenino , Riñón/patología , Riñón/efectos de los fármacos , Riñón/inmunología
11.
Pediatr Nephrol ; 39(11): 3263-3269, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38632123

RESUMEN

BACKGROUND: Between 5 and 50% of atypical hemolytic uremic syndrome (aHUS) cases in children are caused by autoantibodies against complement factor H (CFH). Given the acquired autoimmune nature of the disease, plasma exchange (PE) and various immunosuppressive treatments have been used. More recently, eculizumab has been proposed. METHODS: In this multicenter, retrospective study, we report outcomes of 12 children with anti-FH antibody-associated HUS treated with eculizumab associated with various immunosuppressive regimens. RESULTS: Patients were treated with eculizumab for 15.5 [9.5;23.0] months and 3 received PE or IgG adsorption. Three patients received mycophenolate mofetil (MMF) alone, 1 patient received MMF and steroids, 1 patient received MMF and rituximab, 3 patients received MMF/steroids and rituximab, and 4 patients did not receive any immunosuppression. Anti-FH antibody levels significantly decreased but no difference was observed based on the immunosuppressive regimen. Eculizumab was discontinued in 7/10 patients after 11 [7.5;15.5] months and MMF in 6/8 patients after 36 [35;40] months. Anti-FH titers at MMF discontinuation ranged from 257 to 3425 UI/L. None of these patients relapsed and eGFR at last follow-up was above 70 mL/min/1.73 m2 in all patients. CONCLUSIONS: Eculizumab is effective and safe in inducing and maintaining remission in aHUS secondary to anti-FH antibodies and renders reduction of anti-FH titers less urgent. Anti-FH antibody titers decreased in most patients irrespective of the immunosuppressive treatment chosen, so that a strategy consisting of combining eculizumab with MMF monotherapy seems sufficient at least in non-Indian or less severe forms of anti-FH antibody-associated HUS.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Factor H de Complemento , Inmunosupresores , Intercambio Plasmático , Humanos , Estudios Retrospectivos , Masculino , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Preescolar , Inmunosupresores/uso terapéutico , Niño , Factor H de Complemento/inmunología , Resultado del Tratamiento , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Lactante , Síndrome Hemolítico Urémico Atípico/terapia , Síndrome Hemolítico Urémico Atípico/inmunología , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Síndrome Hemolítico Urémico Atípico/sangre , Síndrome Hemolítico Urémico Atípico/diagnóstico , Ácido Micofenólico/uso terapéutico , Síndrome Hemolítico-Urémico/inmunología , Síndrome Hemolítico-Urémico/terapia , Síndrome Hemolítico-Urémico/sangre , Síndrome Hemolítico-Urémico/tratamiento farmacológico , Síndrome Hemolítico-Urémico/diagnóstico , Adolescente , Rituximab/uso terapéutico
12.
Pediatr Nephrol ; 2024 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-39320552

RESUMEN

BACKGROUND: Anti-GBM disease is a rare vasculitis mediated by pathogenic antibodies against collagen IV. Anti-GBM disease presents with rapid progressive glomerulonephritis and leads to kidney failure if untreated. KDIGO recommends plasma exchanges (PEX) for antibody elimination and steroids plus cyclophosphamide (CTX) to suppress antibody production. CTX is associated with severe side effects including gonadal toxicity. Rituximab (RTX) and mycophenolate mofetil (MMF) might be a less toxic but equally efficient alternative to CTX. Studies in pediatric anti-GBM disease patients receiving RTX and MMF instead of CTX are lacking. METHODS: A retrospective survey in 8 tertiary German centers was performed. The clinical data of patients diagnosed between 2014 and 2022 were collected and analyzed. RESULTS: Five adolescent patients treated with PEX and RTX and/or MMF due to anti-GBM disease were analyzed. All patients had anti-GBM antibodies, hematuria, glomerular proteinuria, and pulmonary hemorrhage. eGFR was 124 ml/min/1.73 m2 (range 47-162), and all patients were non-dialysis-dependent but with relevant histological kidney affection (mean crescents on kidney biopsy 77%). Antibody clearance was achieved after 13 PEX cycles (range 6-31). Four out of 5 patients received methylprednisolone pulses. All patients received oral prednisolone and MMF, and four patients received a median of 4 RTX doses (range 2-4). After a mean follow-up of 27 months, 4/5 patients had conserved or improved kidney function, while one patient (20%) developed kidney failure. CONCLUSIONS: In this small series of pediatric non-dialysis-dependent anti-GBM disease patients, first-line treatment with RTX and MMF showed a favorable kidney outcome in 4/5 cases and had an acceptable side effect profile.

13.
Neurol Sci ; 45(1): 253-260, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37580515

RESUMEN

BACKGROUND: Mycophenolate mofetil (MMF) is frequently used in the treatment of neurological autoimmune disorders. However, its effect on the relapse risk in anti-leucine-rich glioma-inactivated protein 1 (anti-LGI1) encephalitis is not well studied. METHODS: In this prospective observational cohort study, anti-LGI1 encephalitis patients were grouped according to MMF treatment status (MMF and non-MMF groups). The primary outcome was relapse after disease onset. RESULTS: A total of 83 patients were included, with a median onset age of 60 years. Fifty-four patients were men (65.1%). The MMF group comprised 28 patients and the non-MMF group comprised 55. Median follow-up from symptom onset was 26 months. Relapse occurred in 43 patients (51.8%). Median modified Rankin scale (mRS) score at enrollment was significantly higher in the MMF group than the non-MMF group (3 vs. 2; p = 0.001). Median mRS score at last follow-up was comparable between groups (1 vs. zero; p = 0.184). Both MMF treatment (HR 0.463; 95% CI, 0.231-0.929; p = 0.030) and cognitive impairment at enrollment (HR 3.391; 95% CI, 1.041-11.044; p = 0.043) were independent predictors of relapse. Starting immunotherapy before development of cognitive impairment trended towards reducing relapse risk. Outcome at last follow-up was good (mRS score 0-2) in all patients except for one in the non-MMF group. Adverse events associated with MMF treatment were mild and transient. CONCLUSION: Although the outcome of anti-LGI1 encephalitis patients is generally favorable, relapse is common, especially in those with cognitive impairment. MMF treatment is well-tolerated and can significantly reduce the risk of relapse.


Asunto(s)
Encefalitis , Glioma , Masculino , Humanos , Persona de Mediana Edad , Femenino , Ácido Micofenólico/uso terapéutico , Leucina , Estudios Prospectivos , Estudios Retrospectivos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/inducido químicamente , Encefalitis/tratamiento farmacológico , Encefalitis/inducido químicamente , Proteínas , Glioma/tratamiento farmacológico
14.
Nephrology (Carlton) ; 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-39022897

RESUMEN

This mini-review explores glucocorticoids, mycophenolate mofetil (MMF), and hydroxychloroquine (HCQ) in IgA nephropathy (IgAN). It discusses conflicting findings from pivotal trials like TESTING and STOP-IgAN regarding glucocorticoid efficacy, emphasizing reduced-dose protocols as potentially safer options. MMF's effectiveness varies among populations, demonstrating promise in Chinese cohorts but yielding inconclusive results elsewhere. HCQ shows potential in reducing proteinuria, with ongoing trials investigating its long-term benefits.

15.
BMC Nephrol ; 25(1): 296, 2024 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-39251984

RESUMEN

INTRODUCTION: There is a scarcity of research comparing the efficacy of cyclophosphamide and mycophenolate mofetil in childhood nephrotic syndrome. The aim was to evaluate the efficacy and safety of oral cyclophosphamide (CYC) and mycophenolate mofetil (MMF) in children with steroid-sensitive nephrotic syndrome in terms of the proportion of children who have been off steroids for at least 6 months without proteinuria (responders). METHODS: This open-label retrospective-prospective comparative study was conducted in a pediatric nephrology clinic of a referral center for children between 1 and 18 years of age with FR/SD nephrotic syndrome. Group A consisted of patients who received oral cyclophosphamide (100, 25% female) at a dose of 2-2.5 mg/kg once daily for a period of 8-12 weeks. Group B consisted of patients who received oral mycophenolate mofetil (n = 61, 18% female) (dose: 800-1200 mg/m2) for at least 12 months. Responders were defined as children who were off steroids for at least 6 months along with absence of proteinuria. RESULTS: In the CYC group, 50% of the patients were responders, whereas 54% of the patients in the MMF group were responders (p = 0.614). The time to first relapse with CYC was 7 months (IQR 5.25-11) compared to 7 months (IQR 3.5-12) with MMF (p = 0.092). The relapse rate in the CYC group was 1.77 relapses per patient-year compared to 1.295 relapses per patient-year in the MMF group. The difference in relapse rate was significant (-0.474; 95% CI, 0.09 to 0.86 relapses/person-year) (p value = 0.009). Multivariate analysis revealed that an age of less than 5 years at the start of treatment was a significant factor for a better response to MMF (p value = 0.039, OR = 2.988, CI -1.055-8.468). CONCLUSIONS: The efficacy of MMF was similar to that of CYC in terms of response (6 months without steroids) in children with FR/SD nephrotic syndrome. MMF showed a favorable response in terms of the frequency of relapse and treatment failure. REGISTRATION OF THE STUDY WITH CLINICAL TRIALS REGISTRY OF INDIA: ( http://ctri.nic.in ;CTRI/2021/06/034421) (Dt: 28/06/2021).


Asunto(s)
Ciclofosfamida , Inmunosupresores , Ácido Micofenólico , Síndrome Nefrótico , Humanos , Ácido Micofenólico/uso terapéutico , Ácido Micofenólico/administración & dosificación , Síndrome Nefrótico/tratamiento farmacológico , Femenino , Niño , Masculino , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Preescolar , Adolescente , Inmunosupresores/uso terapéutico , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Administración Oral , Lactante , Resultado del Tratamiento , Estudios Retrospectivos , Estudios Prospectivos
16.
Adv Exp Med Biol ; 1447: 131-138, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38724790

RESUMEN

The treatment of atopic dermatitis (AD) with oral treatments has been limited in the past due to the increased risk of adverse effects associated with oral agents. However, in recent years, a shift toward the minimization of adverse effects has been explored. Although existing treatment options like oral corticosteroids and Immunosuppressive therapies have been utilized for acute flare-ups of AD, their long-term use is limited by adverse effects and the need for lab monitoring. New systemic treatment options such as Janus kinase (JAK) inhibitors are emerging as a promising therapy, due to their quick onset and antipruritic features. However, the black box warning associated with this medication class requires careful selection of appropriate candidates and patient education despite early favorable safety profiles seen in AD trials. Discussion of other oral agents, like antibiotics and antihistamines, and their role in AD management are also clarified.


Asunto(s)
Dermatitis Atópica , Humanos , Administración Oral , Dermatitis Atópica/tratamiento farmacológico , Antagonistas de los Receptores Histamínicos/uso terapéutico , Antagonistas de los Receptores Histamínicos/efectos adversos , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/efectos adversos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Corticoesteroides/uso terapéutico , Corticoesteroides/efectos adversos
17.
Biopharm Drug Dispos ; 2024 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-39324420

RESUMEN

Relationship between the areas under the curve (AUC) of mycophenolic acid (MPA) and the likelihood of rejection is well-established in solid organ transplantation recipients. In hematopoietic stem cell transplantation (HSCT), MPA AUC is also linked to graft versus host disease. This study aimed to develop a simplified method to estimate MPA AUC0-12 in Chinese patients undergoing allogeneic HSCT (allo-HSCT). Intensive sampling was conducted in 22 patients who were orally administered mycophenolate mofetil. Plasma concentrations of total MPA were measured, and a model predicting AUC0-12 using data from these 22 patients was constructed through regression analysis. The accuracy of the most suitable model was assessed in an additional 20 patients. None of the individual MPA concentrations showed a strong correlation with AUC0-12 (r2 < 0.7). Models utilizing 4 or more concentrations were found to effectively estimate MPA AUC0-12 (r2 > 0.87). The most operationally feasible model demonstrated good predictive performance with a mean absolute percentage error (APE%) < 20%. Single MPA concentrations showed poor correlation with MPA AUC0-12. A model utilizing 4 oral concentrations (0, 0.5, 1, and 4 h postdose) over a 12-h period could effectively estimate MPA AUC0-12 with precise results and minimal bias.

18.
J Vet Pharmacol Ther ; 47(4): 280-287, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38334367

RESUMEN

Additional immunomodulatory treatment is needed for the management of immune-mediated disease in horses. Mycophenolate mofetil (MMF) is an immunomodulatory agent used in human and veterinary medicine for the prevention of graft rejection and the management of autoimmune diseases. Few studies exist investigating the pharmacokinetics of MMF in horses. The aim of this study was to evaluate the pharmacokinetics of a single dose of MMF in healthy horses in the fed vs. fasted state. Six healthy Standardbred mares were administered MMF 10 mg/kg by a nasogastric (NG) tube in a fed and fasted state. A six-day washout period was performed between the two doses. No statistically significant differences in mycophenolic acid (MPA) concentrations were seen at any time point apart from 8 h, when plasma metabolite concentrations were significantly higher in the fasted state compared to the fed state (p = .038). Evidence of enterohepatic recirculation was seen only in the fasted state; this did not yield clinical differences in horses administered a single-dose administration but may be significant in horses receiving long-term MMF treatment.


Asunto(s)
Inmunosupresores , Ácido Micofenólico , Animales , Caballos/metabolismo , Caballos/sangre , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/sangre , Femenino , Inmunosupresores/farmacocinética , Inmunosupresores/administración & dosificación , Inmunosupresores/sangre , Interacciones Alimento-Droga , Área Bajo la Curva , Semivida , Estudios Cruzados
19.
Int J Mol Sci ; 25(4)2024 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-38397035

RESUMEN

Immunosuppression management in transplant recipients is a critical component of pharmacotherapy. This becomes particularly crucial when patients are exposed to multiple medications that may lead to pharmacological interactions, potentially compromising the effectiveness of immunosuppression. We present the case of a 46-year-old patient diagnosed with cystic fibrosis in childhood at our hospital, who underwent bilateral lung transplantation and is undergoing immunosuppressive therapy. The patient was hospitalized due to an acute pulmonary exacerbation. During the hospitalization, the patient was administered various classes of antibiotics while continuing the standard antirejection regimen of everolimus and mycophenolate. Plasma concentrations of immunosuppressants, measured after antibiotic therapy, revealed significantly lower levels than the therapeutic thresholds, providing the basis for formulating the hypothesis of a drug-drug interaction phenomenon. This hypothesis is supported by the rationale of antibiotic-induced disruption of the intestinal flora, which directly affects the kinetics of mycophenolate. These levels increased after discontinuation of the antimicrobials. Patients with CF undergoing lung transplantation, especially prone to pulmonary infections due to their medical condition, considering the enterohepatic circulation of mycophenolate mediated by intestinal bacteria, necessitate routine monitoring of mycophenolate concentrations during and immediately following the cessation of antibiotic therapies, that could potentially result in insufficient immunosuppression.


Asunto(s)
Fibrosis Quística , Trasplante de Pulmón , Humanos , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Ácido Micofenólico/farmacología , Fibrosis Quística/complicaciones , Fibrosis Quística/tratamiento farmacológico , Antibacterianos/uso terapéutico , Inmunosupresores/efectos adversos , Inhibidores Enzimáticos
20.
Z Rheumatol ; 83(Suppl 1): 140-147, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37278824

RESUMEN

OBJECTIVE: This study aimed to assess the relative efficacy and safety of calcineurin inhibitor (CNI), mycophenolate mofetil (MMF), and azathioprine (AZA) as maintenance therapies for lupus nephritis. METHODS: Randomized controlled trials (RCTs) examining the efficacy and safety of CNI, MMF, and AZA as maintenance therapies in patients with lupus nephritis were included. We performed a Bayesian random-effects network meta-analysis to combine the direct and indirect evidence from RCTs. RESULTS: Ten RCTs comprising 884 patients were included in the study. Although the difference was not statistically significant, MMF showed a trend toward a lower relapse rate compared with AZA (odds ratio [OR] 0.72, 95% credible interval [CrI] 0.45-1.22). Similarly, tacrolimus showed a trend toward a lower relapse rate compared with AZA (OR 0.85, 95% CrI 0.34-2.00). Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that MMF had the highest probability of being the best treatment based on the relapse rate, followed by CNI and AZA. The incidence of leukopenia in the MMF and CNI groups was significantly lower than that in the AZA group (OR 0.12, 95% CrI 0.04-0.34; OR 0.16, 95% CrI 0.04-0.50; respectively). Fewer patients with infections were observed in the MMF group than in the AZA group, although the difference was not statistically significant. The analysis of withdrawals due to adverse events showed a similar pattern. CONCLUSION: Lower relapse rates combined with a more favorable safety profile suggest that CNI and MMF are superior to AZA as maintenance treatments in lupus nephritis patients.


Asunto(s)
Azatioprina , Nefritis Lúpica , Humanos , Azatioprina/efectos adversos , Ácido Micofenólico/efectos adversos , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/tratamiento farmacológico , Inmunosupresores/efectos adversos , Inhibidores de la Calcineurina/efectos adversos , Metaanálisis en Red , Resultado del Tratamiento , Recurrencia
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