Targeted therapies for lupus nephritis: Current perspectives and future directions / 中华医学杂志(英文版)

Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus, poses a substantial risk of progression to end-stage renal disease, with increased mortality. Conventional therapy for LN relies on broad-spectrum immunosuppressants such as glucocorticoids, mycophenolate mofetil, and calcineurin inhibitors. Although therapeutic regimens have evolved over the years, they have inherent limitations, including non-specific targeting, substantial adverse effects, high relapse rates, and prolonged maintenance and remission courses. These drawbacks underscore the need for targeted therapeutic strategies for LN. Recent advancements in our understanding of LN pathogenesis have led to the identification of novel therapeutic targets and the emergence of biological agents and small-molecule inhibitors with improved specificity and reduced toxicity. This review provides an overview of the current evidence on targeted therapies for LN, elucidates the biological mechanisms of responses and failure, highlights the challenges ahead, and outlines strategies for subsequent clinical trials and integrated immunomodulatory approaches.

Audiological follow-up in transplant patients treated with calcineurin immunosuppressants "Calcineurin inhibitors and Ototoxicity" / Seguimiento audiológico en pacientes trasplantados en tratamiento con inmunosupresores inhibidores de calcineurina

BACKGROUND: Ototoxicity is a side effect of drugs and medications that usually leads to bilateral and symmetric sensorineural hearing loss that commonly affects the high-frequency range initially, with or preceded by tinnitus. Possible ototoxic side effects of calcineurin inhibitor immunosuppressants have been suggested, but this remains unclear. Therefore, this study aims to evaluate audiological changes in patients undergoing transplantation receiving immunosuppressive treatment with calcineurin inhibitors. METHODS: Prospective cohort study. Adult patients undergoing liver or kidney transplantation treated with calcineurin inhibitors were included. Pure-tone audiometry, distortion product otoacoustic emissions, and the Tinnitus Handicap Inventory questionnaire were completed at baseline, one, three, and six months after transplantation. Hearing thresholds were compared and correlated with plasma concentrations of calcineurin inhibitors. RESULTS: Seventeen patients were included, 59% males, with a median age of 54.7 years (29-68 years). Twelve patients underwent liver transplantation, four underwent kidney transplantation, and one patient underwent both. The medianfollow-up was 5.8 months (4-8 months). Significant pure-tone average shifts were observed in two patients. Both cases presented fluctuations in their hearing levels, which were not bilateral or symmetrical and affected the higher frequencies. All patients received tacrolimus within the therapeutic range during the follow-up period. Three different patients exceeded the expected range once; however, they were rapidly corrected and did not correlate with any changes in hearing. CONCLUSIONS: It appears that tacrolimus does not cause hearing loss when levels are within the therapeutic range for a follow-up period of six months post-transplantation.

INTRODUCCIÓN: La ototoxicidad corresponde a un efecto secundario a agentes terapéuticos que se manifiesta como hipoacusia sensorioneural bilateral simétrica de frecuencias agudas. Se postulan posibles efectos ototóxicos de los inmunosupresores inhibidores de la calcineurina, pero hasta la fecha es aún incierto. El objetivo de este estudio fue evaluar los cambios audiológicos en pacientes trasplantados en tratamiento inmunosupresor con inhibidores de calcineurina. MATERIAL Y MÉTODO: Cohorte prospectiva. Se incluyeron pacientes adultos sometidos a trasplante hepático o renal tratados con inhibidores de calcineurina. Se realizó una evaluación otorrinolaringo-lógica pre-trasplante con audiometría tonal, emisiones otoacústicas por producto de distorsión y cuestionario Tinnitus Handicap Inventory. Se realizó una evaluación audiológica de seguimiento uno, tres y seis meses después del trasplante. Se compararon los umbrales auditivos antes y después del inicio del tratamiento inmunosupresor y se correlacionaron con las concentraciones plasmáticas de IC. RESULTADOS: Se incluyeron 17 pacientes, 59% hombres, con una mediana de edad de 54,7 años. La mediana de seguimiento fue 5,8 meses. Se observaron cambios en el promedio tonal puro en dos pacientes, los cuales no seguían un patrón audiométrico sugerente de ototoxicidad. Todos los pacientes recibieron Tacrolimus dentro del rango terapéutico durante el seguimiento. Tres pacientes diferentes excedieron el rango esperado una vez sin embargo, se corrigieron rápidamente y no se correlacionaron con cambios auditivos, puntaje de tinnitus o emisiones otoacústicas. DISCUSIÓN: Impresiona que Tacrolimus no se asocia a hipoacusia cuando los niveles están en rango terapéutico durante un período de seguimiento de seis meses post trasplante.

Evidence-based recommendations for the treatment of rheumatic and immunologic diseases with calcineurin inhibitors: a consensus statement / 中华内科杂志

Calcineurin inhibitors (CNI), including oral cyclosporin A and tacrolimus, are intensive immunosuppressants that are extensively used in the treatment of rheumatic and immunologic diseases in China. CNI selectively inhibit the activation and proliferation of T lymphocytes and the transcription of cytokines [such as tumor necrosis factor-α, interleukin (IL)-6, and IL-17] through inhibiting the activation of calcineurin in cells and reducing the release of IL-2. To standardize the use of CNI in the field of rheumatic and immunologic diseases, this consensus statement was developed by the National Clinical Research Center for Dermatologic and Immunologic Diseases (Peking Union Medical College Hospital), in conjunction with the Chinese Association of Rheumatology and Immunology Physicians, the Chinese Research Hospital Association, the Rheumatology and Immunology Professional Committee, and the Chinese Association of Rehabilitation Medicine. The 2011 Oxford Centre for Evidence-Based Medicine Levels of Evidence was used to rate the quality of the evidence and the strength of the recommendations, and the RIGHT (Reporting Items for practice Guidelines in HealThcare) checklist was followed to report the consensus. The consensus offers recommendations addressing nine clinical challenges to Chinese clinicians. The primary objective of this consensus is to deliver scientific and detailed guidance on CNI for Chinese clinicians, and to improve the quality of patient-centered medical services.

Dermatite atópica grave: guia prático de tratamento da Associação Brasileira de Alergia e Imunologia e Sociedade Brasileira de Pediatria / Severe atopic dermatitis: a practical treatment guide from the Brazilian Association of Allergy and Immunology and the Brazilian Society of Pediatrics

A dermatite atópica (DA) é uma doença cutânea inflamatória, crônica, comum, complexa e de etiologia multifatorial, que se manifesta clinicamente com prurido muitas vezes incapacitante, lesões recorrentes do tipo eczema, xerose e que pode evoluir para liquenificação. Embora o conhecimento sobre a sua fisiopatologia venham crescendo nos últimos anos, ainda as formas graves são frequentes e representam um desafio para o clínico. Para o presente guia realizou-se revisão não sistemática da literatura relacionada à DA grave refratária aos tratamentos habituais com o objetivo de elaborar um documento prático e que auxilie na compreensão dos mecanismos envolvidos na DA, assim como dos possíveis fatores de risco associados à sua apresentação. A integridade da barreira cutânea é um dos pontos fundamentais para a manutenção da homeostase da pele. Além dos cuidados gerais: evitação dos agentes desencadeantes e/ou irritantes, o uso de hidratantes, suporte emocional, entre outros, o uso de agentes anti-inflamatórios/imunossupressores de uso tópico e/ou sistêmico também foi revisado. A aquisição de novos agentes, os imunobiológicos e as pequenas moléculas, melhorou a terapêutica para os pacientes com formas graves de DA, sobretudo as refratárias aos tratamentos convencionais.

Atopic dermatitis is a chronic, common, and complex inflammatory skin disease with a multifactorial etiology. It manifests clinically with often disabling pruritus, recurrent eczema-like lesions, and xerosis, and can progress to lichenification. Although understanding of the disease's pathophysiology has been growing in recent years, severe forms are still frequent and represent a challenge for clinicians. A non-systematic review of the literature on severe atopic dermatitis refractory to conventional treatment was conducted to develop the present guide, whose purpose is to help clarify the mechanisms involved in the disease and possible risk factors. The integrity of the skin barrier is fundamental for maintaining skin homeostasis. In addition to general care, patients should avoid triggering and/or irritating agents and moisturizers and seek emotional support, etc.; the use of topical and/or systemic anti-inflammatory/immunosuppressive agents was also reviewed. New agents, immunobiologicals, and small molecules have led to a broader range of therapies for patients with severe forms of the disease, especially cases refractory to conventional treatment.

Protocolo de inmunosupresión en trasplante hepático: revisión de la literatura / Immunosuppression protocol in liver transplantation: review article

El trasplante de hígado es el último recurso para el tratamiento de hepatopatías. Para evitar el rechazo del injerto se requieren esquemas de inmunosupresión que han ido evolucionando a lo largo de los años. Se realizó una revisión bibliográfica en la base de datos PubMed sobre las terapias inmunosupresoras disponibles para evitar el rechazo del injerto en el trasplante hepático, los esquemas utilizados, efectos adversos, interacciones y sus modificaciones desde la fase de inducción hasta el seguimiento posterior. Se encontró que la inducción habitual es con esteroides o terapia inmunológica clonal. En el mantenimiento, los inhibidores de la calcineurina son los más utilizados, las dosis se deben ajustar según sus niveles séricos y la presencia de efectos adversos como nefrotoxicidad o diabetes. Por otra parte, los inhibidores del mTOR han sido considerados como agentes reductores del riesgo de recidiva de cáncer hepatocelular. Las características del paciente y sus comorbilidades (embarazo, insuficiencia renal, diabetes, sepsis, carcinoma hepatocelular) requieren modificar el tratamiento e individualizarlo

Liver transplantation is the last option for the treatment of liver disease. Immunosuppression schemes are required to avoid graft rejection, which have evolved over the years. A literature review was carried out in PubMed on the immunosuppressive therapies available to avoid graft rejection in liver transplantation, as well as on the schemes used, adverse effects, interactions and their modifications from the induction phase to subsequent follow-up. The usual induction was found to be with steroids or clonal immune therapy. In maintenance, calcineurin inhibitors are the most widely used, and their doses should be adjusted according to their serum levels and the presence of adverse effects such as nephrotoxicity or diabetes. On the other hand, mTOR inhibitors have been considered to reduce the risk of hepatocellular cancer recurrence. The characteristics of the patient and their comorbidities (pregnancy, kidney failure, diabetes, sepsis, hepatocellular carcinoma) require modification and individualization of the treatment.

Incidência de reações adversas associadas ao uso de inibidores de calcineurina em pacientes submetidos ao transplante pulmonar / Incidence of adverse reactions associated with the use of calcineurin inhibitors in patients undergoing lung transplantation

Introdução: O uso de terapia imunossupressora é de extrema importância no transplante pulmonar, entretanto existem diversas reações adversas (RAMs) associadas ao seu uso. Neste trabalho buscamos descrever a incidência de perda de função renal (FR), diabetes mellitus (DM), hipertensão arterial sistêmica (HAS) e hipercolesterolemia associadas ao uso de ICN na população de transplantados pulmonares do Hospital de Clínicas de Porto Alegre após 1 ano de transplante.Metodologia: Estudo de coorte retrospectivo, conduzido no Hospital de Clínicas de Porto Alegre. Foram incluídos os pacientes transplantados de pulmão no período de 2016 a 2018.Resultados: Após um ano do transplante 56,5% (13/23) tiveram uma perda de FR em comparação ao basal, mas com valores ainda dentro da normalidade e 30,4% (7/23) perderam FR. A diferença de FR antes e após o transplante foi estatisticamente significativa com p < 0,001, no entanto não foi observado diferença entre os ICN (p = 0,499). Entre as variáveis: DM, HAS e Hipercolesterolemia, apenas o desenvolvimento de HAS foi estaticamente significativo quando comparado ao período pré-transplante (p < 0,001).Conclusão: Nossos dados demonstraram importante perda de FR após uso de imunossupressores ICN, corroborando com dados já publicados, no entanto, não foi possível identificar associação com ICN específico, sugerindo que benefícios na intercambialidade de terapias entre os ICN na tentativa de preservação da FR devem ser melhor estudados. Diante da possibilidade de desenvolvimento de RAMs associadas ao uso de imunossupressores, destacamos a importância da inserção do farmacêutico clínico nas equipes de transplante.

Introduction: Immunosuppressive therapy is extremely important in lung transplantation, but there are several adverse drug reactions (ADRs) associated with its use.Objective: To report the incidence of loss of renal function (RF), diabetes mellitus (DM), systemic arterial hypertension (SAH), and hypercholesterolemia associated with the use of calcineurin inhibitors (CNIs) in the population of lung transplant recipients at Hospital de Clínicas de Porto Alegre at 1 year after transplant. Methods: We conducted a retrospective cohort study of patients undergoing a lung transplant at Hospital de Clínicas de Porto Alegre from 2016 to 2018.Results: At 1 year after transplant, 56.5% (13/23) had loss of RF compared with baseline, but the values remained within the normal range, whereas 30.4% (7/23) had complete loss of RF. There was a statistically significant difference in RF before and after transplant (p < 0.001), but not in CNIs (p = 0.499). Among the variables DM, SAH, and hypercholesterolemia, only the development of SAH was statistically significant compared with the pre-transplant period (p < 0.001).Conclusion: Our data demonstrated an important loss of RF after the use of CNI immunosuppressants, which is consistent with published data. However, no association was identified with the type of CNI, suggesting that the benefits of the interchangeability of CNI therapies aimed at preserving RF should be further studied. Given the potential occurrence of ADRs associated with the use of immunosuppressants, we highlight the importance of the presence of a clinical pharmacist in the transplant team.

Influencia del polimorfismo de CYP3A4 y CYP3A5 en la farmacocinética de tacrolimus en receptores de trasplante renal. Revisión narrativa / Influence of CYP3A4 and CYP3A5 polymorphism of the pharmacokinetics of tacrolimus in renal transplant recipients. Narrative review

El uso de inhibidores de calcineurina, en particular de tacrolimus como terapia inmunosupresora se ha generalizado a nivel mundial, permitiendo mejorar la tasa de sobrevida del injerto y la calidad de vida del paciente trasplantado. Con el acceso a los estudios de farmacogenética, los grupos de trasplante a nivel mundial se han visto motivados a realizar estudios genéticos que permitan interpretar la influencia de polimorfismos de genes como mTOR, PPP3CA, FK BP1A, FKBP2, y FOXP3, sin embargo, los más estudiados en la población trasplantada para optimizar la dosis de tacrolimus y ciclosporina son los polimorfismos del citocromo p450, CYP3A4 y CYP3A5.El objetivo de la presente revisión narrativa es examinar publicaciones recientes que estudien la relación entre el polimorfismo de CYP3A4/5 y el metabolismo de tacrolimus en pacientes trasplantados renales.Se revisó literatura reciente extraída de los sitios NCBI PubMed y PharmGKB.org en la que se hubiera investigado la influencia de los polimorfismos de CYP3A4/5 en el metabolismo de tacrolimus en trasplantados renales. Se identificó variaciones genéticas de CYP3A4/5 en pacientes trasplantados tratados con tacrolimus que permitirán a los médicos trasplantólogos dosificar de manera precisa el inmunosupresor. El uso de análisis farmacogenéticos permite determinar las variables genéticas del CYP3A4/5, y por lo tanto la toma de decisiones personalizadas en la dosis de inicio y de mantenimiento del inmunosupresor tacrolimus para alcanzar los niveles óptimos y con ello disminuir el riesgo de rechazo, de infecciones asociadas a inmunosupresión, y de toxicidad por el medicamento.

The use of the calcineurin inhibitor tacrolimus as immunosuppressive therapy, has become widespread world-wide, improving the graft's survival rate and the quality of life of the transplanted patient. With access to pharmacogenetic studies, transplant groups worldwide have been motivated to conduct genetic studies to inter-pret the influence of polymorphisms of genes such asmTOR, PPP3CA, FK BP1A, FKBP2, and FOXP3, however the most studied in the transplanted population to optimize the dose of tacrolimus and cyclosporine are those of cytochrome p450,CYP3A4 and CYP3A5. The objective of this narrative review is to examine recent publications studying the relationship betweenCYP3A4/5polymorphism, and tacrolimus metabolism in renal transplant patients. Literature extracted from the NCBI PubMed site and PharmGKB.org, from the past five years, which investigated the influence ofCYP3A4/5polymorphism on tacrolimus metabolism in renal transplants had been reviewed. Genetic variations ofCYP3A4/5 were identified in transplant patients treated with tacrolimus that will allow transplant physicians to dose the immunosuppressant accurately. The use of pharmacogenetic analyses makes it possible to determine the genetic polymorphisms ofCYP3A4/5, and therefore the decision-making cus-tomized at the starting and maintenance dose of the tacrolimus immunosuppressant to achieve optimal levels and thereby reduce the risk of rejection, immunosuppression-associated infections, and drug toxicity.

Calcineurin inhibitors revisited: A new paradigm for COVID-19?

Abstract The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can cause mild, moderate or severe disease (COVID-19). In severe disease, there is hyperinflammation causing severe symptoms. Severe COVID-19 is an immunological phenomenon, rather than a direct viral damage disease. Therapies for COVID-19 are all investigational therapies. In case of severe disease, treatment with a calcineurin inhibitor could be promising. In this article we explain the mechanisms of calcineurin inhibitor treatment for COVID-19, based on experiences seen in solid organ transplant recipients who suffered from COVID-19.

Cyclosporine A impairs bone repair in critical defects filled with different osteoconductive bone substitutes

Abstract The aim of this study was to assess the influence of cyclosporine administration on the repair of critical-sized calvaria defects (CSDs) in rat calvaria filled with diverse biomaterials. Sixty animals were divided into two groups: the control (CTR) group (saline solution) and the cyclosporine (CCP) group (cyclosporine, 10 mg/kg/day). These medications were administered daily by gavage, beginning 15 days before the surgical procedure and lasting until the day the animals were euthanized. A CSD (5 mm Ø) was made in the calvaria of each animal, which was allocated to one of 3 subgroups, according to the biomaterial used to fill the defect: coagulum (COA), deproteinized bovine bone (DBB), or biphasic calcium phosphate ceramics of hydroxyapatite and β-phosphate tricalcium (HA/TCP). Euthanasia of the animals was performed 15 and 60 days after the surgical procedure (n = 5 animals/period/subgroup). Bone repair (formation) assessment was performed through microtomography and histometry, while the analyses of the expression of the BMP2, Osteocalcin, and TGFβ1 proteins were performed using immunohistochemistry. The CSDs not filled with biomaterials demonstrated lower bone formation in the CCP group. At 15 days, less bone formation was observed in the CSDs filled with DBB, a smaller volume of mineralized tissue was observed in the CSDs filled with HA/TCP, and the expression levels of BMP2 and osteocalcin were lower in the CCP group compared to the CTR group. The use of cyclosporine impaired bone repair in CSD, and this effect can be partially explained by the suppression of BMP2 and osteocalcin expression.

Cyclosporine A impairs bone repair in critical defects filled with different osteoconductive bone substitutes

Abstract The aim of this study was to assess the influence of cyclosporine administration on the repair of critical-sized calvaria defects (CSDs) in rat calvaria filled with diverse biomaterials. Sixty animals were divided into two groups: the control (CTR) group (saline solution) and the cyclosporine (CCP) group (cyclosporine, 10 mg/kg/day). These medications were administered daily by gavage, beginning 15 days before the surgical procedure and lasting until the day the animals were euthanized. A CSD (5 mm Ø) was made in the calvaria of each animal, which was allocated to one of 3 subgroups, according to the biomaterial used to fill the defect: coagulum (COA), deproteinized bovine bone (DBB), or biphasic calcium phosphate ceramics of hydroxyapatite and β-phosphate tricalcium (HA/TCP). Euthanasia of the animals was performed 15 and 60 days after the surgical procedure (n = 5 animals/period/subgroup). Bone repair (formation) assessment was performed through microtomography and histometry, while the analyses of the expression of the BMP2, Osteocalcin, and TGFβ1 proteins were performed using immunohistochemistry. The CSDs not filled with biomaterials demonstrated lower bone formation in the CCP group. At 15 days, less bone formation was observed in the CSDs filled with DBB, a smaller volume of mineralized tissue was observed in the CSDs filled with HA/TCP, and the expression levels of BMP2 and osteocalcin were lower in the CCP group compared to the CTR group. The use of cyclosporine impaired bone repair in CSD, and this effect can be partially explained by the suppression of BMP2 and osteocalcin expression.

Diagnostic and therapeutic guidelines for plaque psoriasis - Brazilian Society of Dermatology

Abstract: Psoriasis is a chronic inflammatory disease that affects 1.3% of the Brazilian population. The most common clinical manifestations are erythematous, scaling lesions that affect both genders and can occur on any anatomical site, preferentially involving the knees, elbows, scalp and genitals. Besides the impact on the quality of life, the systemic nature of the disease makes psoriasis an independent risk factor for cardiovascular disease, especially in young patients with severe disease. By an initiative of the Brazilian Society of Dermatology, dermatologists with renowned clinical experience in the management of psoriasis were invited to form a work group that, in a partnership with the Brazilian Medical Association, dedicated themselves to create the Plaque Psoriasis Diagnostic and Treatment Guidelines. The relevant issues for the diagnosis (evaluation of severity and comorbidities) and treatment of plaque psoriasis were defined. The issues generated a search strategy in the Medline-PubMed database up to July 2018. Subsequently, the answers to the questions of the recommendations were devised, and each reference selected presented the respective level of recommendation and strength of scientific evidence. The final recommendations for making up the final text were worded by the coordinators.

Consensus on the therapeutic management of atopic dermatitis - Brazilian Society of Dermatology

Abstract: BACKGROUND: Atopic dermatitis is a highly prevalent inflammatory and pruritic dermatosis with a multifactorial etiology, which includes skin barrier defects, immune dysfunction, and microbiome alterations. Atopic dermatitis is mediated by genetic, environmental, and psychological factors and requires therapeutic management that covers all the aspects of its complex pathogenesis. OBJECTIVES: The aim of this article is to present the experience, opinions, and recommendations of Brazilian dermatology experts regarding the therapeutic management of atopic dermatitis. METHODS: Eighteen experts from 10 university hospitals with experience in atopic dermatitis were appointed by the Brazilian Society of Dermatology to organize a consensus on the therapeutic management of atopic dermatitis. The 18 experts answered an online questionnaire with 14 questions related to the treatment of atopic dermatitis. Afterwards, they analyzed the recent international guidelines on atopic dermatitis of the American Academy of Dermatology, published in 2014, and of the European Academy of Dermatology and Venereology, published in 2018. Consensus was defined as approval by at least 70% of the panel. RESULTS/CONCLUSION: The experts stated that the therapeutic management of atopic dermatitis is based on skin hydration, topical anti-inflammatory agents, avoidance of triggering factors, and educational programs. Systemic therapy, based on immunosuppressive agents, is only indicated for severe refractory disease and after failure of topical therapy. Early detection and treatment of secondary bacterial and viral infections is mandatory, and hospitalization may be needed to control atopic dermatitis flares. Novel target-oriented drugs such as immunobiologicals are invaluable therapeutic agents for atopic dermatitis.

Evaluation of the use of tacrolimus ointment for the prevention of hypertrophic scars in experimental model

Abstract BACKGROUND: Tacrolimus, for its activity on modulation of collagen production and fibroblast activity, may have a role in the prevention of hypertrophic scars. OBJECTIVES: Evaluate macroscopic, microscopic, metabolic, laboratory effects and side effects of the use of topical tacrolimus ointment, in different concentrations, in the prevention of hypertrophic scars. METHODS: Twenty-two rabbits were submitted to the excision of 2 fragments of 1 cm of each ear, 4 cm apart, down to cartilage. The left ear of the animals was standardized as control and Vaseline applied twice a day. The right ear received tacrolimus ointment, at concentrations of 0.1% on the upper wound and 0.03% on the lower wound, also applied twice a day. Macroscopic, microscopic, laboratory criteria and the animals' weight were evaluated after 30 days of the experiment. RESULTS: Wounds treated with tacrolimus, at concentrations of 0.1% and 0.03%, when compared to control, showed a lower average degree of thickening (p = 0.048 and p <0.001, respectively). The average of scar thickness and lymphocyte, neutrophil and eosinophil concentrations are lower in the treated wounds compared to the control (p <0.001, p=0.022, p=0.007, p=0.044, respectively). The mean concentration of lymphocytes is lower in wounds treated with a higher concentration of the drug (p=0.01). STUDY LIMITATIONS: experiment lasted only 30 days. CONCLUSIONS: Tacrolimus at the 2 concentrations evaluated reduced the severity of inflammatory changes and positively altered the macroscopic aspect of the scar in the short term. Its use was shown to be safe, with no evidence of systemic or local adverse effects.

Impact of calcineurin inhibitors on rat glioma cells viability / 영남의대학술지

BACKGROUND: Although kidney transplantation outcomes have improved dramatically after using calcineurin inhibitors (CNIs), CNI toxicity continues to be reported and the mechanism remains uncertain. Here, we investigated the neurotoxicity of CNIs by focusing on the viability of glioma cells.METHODS: Glioma cells were treated with several concentrations of CNIs for 24 hours at 37℃ and their cell viability was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.RESULTS: Exposure to 0, 0.25, 0.5, 2.5, 5.0, and 10.0 mM concentrations respectively showed 100%, 64.3%, 61.3%, 68.1%, 62.4%, and 68.6% cell viability for cyclosporine and 100%, 38.6%, 40.8%, 43.7%, 37.8%, and 43.0% for tacrolimus. The direct toxic effect of tacrolimus on glioma cell viability was stronger than that of cyclosporine at the same concentration.CONCLUSION: CNIs can cause neurological side effects by directly exerting cytotoxic effects on brain cells. Therefore, we should carefully monitor the neurologic symptoms and level of CNIs in kidney transplant patients.

Efficacy and Utility of Wet Wrap Dressing for Patients with Pediatric Atopic Dermatitis / 대한피부과학회지

BACKGROUND: Management of atopic dermatitis (AD) involves the regular use of emollients together with topical steroids or calcineurin inhibitors for acute flares. However, the long-term use of oral medications in young children may have certain limitations. Wet wrap dressing (WWD) is an interesting alternative therapy for the short-term control of severe or refractory flares, thus avoiding the use of systemic treatments. OBJECTIVE: This study aimed to compare the efficacy between WWD and topical steroid agents and to control and estimate the utility of WWD in pediatric AD. METHODS: A total of 40 patients with mild-to-severe AD (eczema area and severity index of ≥3) aged <13 years were included in this study. Twenty patients were treated with WWD using two layers of cotton bandages or garments (Tubifast™), and the remaining were applied with topical steroid agents without cotton bandages. Improvement in severity of atopic dermatitis was evaluated using the eczema area and severity index (EASI). Improvement in skin barrier dysfunction was evaluated by measuring the transepidermal water loss (TEWL). We compared the two groups after 1 week of treatment using analysis of covariance and t-test. Furthermore, we surveyed the study groups using a questionnaire to estimate the utility of WWD and its adverse effects as well as to evaluate subjective outcomes of WWD. RESULTS: There were significant reductions in the mean EASI (−6.3, 95% confidence interval [CI]: −7.5 to −5.1, p=0.013) and TEWL (−26.7, 95% CI: −31.2 to −22.3, p=0.002) after 1 week of WWD treatment compared with the mean EASI (−4.0, 95% CI: −5.2 to −2.9) and TEWL (−15.4, 95% CI: −19.8 to −10.9) of the control group. Results of patient self-assessment and scores in the visual analogue scale (VAS) for pruritus were improved in both groups, but the differences were not statistically significant. Usefulness of WWD as an alternative therapy for the conventional therapy was satisfactory. CONCLUSION: This study is meaningful in that it estimates both the subjective and objective efficacy of WWD. In view of these findings, WWD showed superior therapeutic effects than conventional steroid application in the treatment of AD in children, with good compliance of patients and parent-caregivers.

Effect of conversion from calcineurin inhibitors to everolimus on hepatitis C viremia in adult kidney transplant recipients / Efeitos da conversão de inibidores da calcineurina para Everolimo na viremia por hepatite C em receptores adultos de transplantes renais

ABSTRACT Introduction: Currently, there is no specific immunosuppressive protocol for hepatitis C (HCV)-positive renal transplants recipients. Thus, the aim of this study was to evaluate the conversion effect to everolimus (EVR) on HCV in adult kidney recipients. Method: This is an exploratory single-center, prospective, randomized, open label controlled trial with renal allograft recipients with HCV-positive serology. Participants were randomized for conversion to EVR or maintenance of calcineurin inhibitors. Results: Thirty patients were randomized and 28 were followed-up for 12 months (conversion group, Group 1 =15 and control group, Group 2 =13). RT-PCR HCV levels reported in log values were comparable in both groups and among patients in the same group. The statistical analysis showed no interaction effect between time and group (p value G*M= 0.852), overtime intra-groups (p-value M=0.889) and between group (p-value G=0.286). Group 1 showed a higher incidence of dyslipidemia (p=0.03) and proteinuria events (p=0.01), while no difference was observed in the incidence of anemia (p=0.17), new onset of post-transplant diabetes mellitus (p=1.00) or urinary tract infection (p=0.60). The mean eGFR was similar in both groups. Conclusion: Our study did not show viral load decrease after conversion to EVR with maintenance of antiproliferative therapy.

RESUMO Introdução: Atualmente não há um protocolo imunossupressor específico para os receptores de transplantes renais portadores de hepatite C (HCV). Assim, o objetivo deste estudo foi avaliar o efeito da conversão a Everolimo (EVR) na HCV em receptores adultos de transplantes renais. Método: Trata-se de um estudo unicêntrico, prospectivo, randomizado, exploratório, controlado, aberto em receptores de aloenxertos renais com sorologia positiva para HCV. Os participantes foram randomizados para conversão a EVR ou manutenção dos inibidores da calcineurina. Resultados: Trinta pacientes foram randomizados e 28 foram acompanhados por um período de 12 meses (grupo de conversão, Grupo 1 = 15 e grupo controle, Grupo 2 =13). Níveis de RT-PCR HCV descritos em valores logarítmicos foram comparáveis entre os grupos e entre pacientes em um mesmo grupo. A análise estatística não mostrou efeitos de interação entre tempo e grupo (valor p G*M= 0,852), ao longo do tempo em cada grupo (valor p M=0,889) e entre grupos (valor p G=0,286). O Grupo 1 apresentou uma maior incidência de eventos de dislipidemia (p=0,03) e proteinúria (p=0,01); não houve diferença na incidência de anemia (p=0,17), diabetes mellitus de início pós-transplante (p=1,00) ou infecção do trato urinário (p=0,60). A TFGe média foi semelhante nos dois grupos. Conclusão: Nosso estudo não mostrou redução da carga viral após conversão a EVR com manutenção do tratamento antiproliferativo.

Treatment of Atopic Dermatitis / 대한피부과학회지

Atopic dermatitis (AD) is a common, chronic, relapsing, inflammatory skin disease that affects both children and adults. AD is the cause of considerable morbidity including severe pruritus and impaired quality of life. Treatments for active disease include avoidance of triggering factors, barrier repair, topical medications including topical corticosteroids (TCs) and topical calcineurin inhibitors (TCIs), phototherapy, antibacterial agents, and systemic immunosuppressants including cyclosporine. Until recently, the only Food and Drug Administration (FDA)-approved systemic treatment options for patients with moderate-to-severe AD were steroids and cyclosporine. Systemic steroids are not recommended by current guidelines and are commonly associated with disease rebound. Instead, clinicians choose from several off-label immunosuppressants. In 2018, the Korean FDA approved dupilumab for adults with moderate-to-severe AD whose disease is not adequately controlled with topical therapies. The implementation of treatment guidelines for AD is challenging. Herein, we review the several treatment modalities for AD and recommend a treatment algorithm.