RESUMO
Toxoplasmosis persists as a prevalent disease, facing challenges from parasite resistance and treatment side effects. Consequently, identifying new drugs by exploring novel protein targets is essential for effective intervention. Cyclosporin A (CsA) possesses antiparasitic activity against Toxoplasma gondii, with cyclophilins identified as possible targets. However, CsA immunosuppressive nature hinders its use as an antitoxoplasmosis agent. Here, we evaluate the potential of three CsA derivatives devoid of immunosuppressive activity, namely, NIM811, Alisporivir, and dihydrocyclosporin A to target a previously characterized cyclophilin from Toxoplasma gondii (TgCyp23). We determined the X-ray crystal structures of TgCyp23 in complex with the three analogs and elucidated their binding and inhibitory properties. The high resolution of the structures revealed the precise positioning of ligands within the TgCyp23 binding site and the details of protein-ligand interactions. A comparison with the established ternary structure involving calcineurin indicates that substitutions at position 4 in CsA derivatives prevent calcineurin binding. This finding provides a molecular explanation for why CsA analogs can target Toxoplasma cyclophilins without compromising the human immune response.
Assuntos
Ciclofilinas , Ciclosporina , Toxoplasma , Toxoplasma/efeitos dos fármacos , Ciclofilinas/química , Ciclofilinas/antagonistas & inibidores , Ciclofilinas/metabolismo , Cristalografia por Raios X , Ciclosporina/química , Ciclosporina/farmacologia , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/genética , Modelos Moleculares , Sítios de Ligação , Ciclosporinas/química , Ciclosporinas/farmacologiaRESUMO
BACKGROUND: To compare and evaluate objective and subjective clinical parameters between 0.05% cyclosporine nanoemulsion (CsN) and 0.15% hyaluronic acid (HA) administration in patients with mild-to-moderate dry eyes. METHODS: In this prospective, randomized, double-masked, single-center, and placebo-controlled parallel study, patients with mild-to-moderate dry eyes were randomly allocated to be treated with 0.05% CsN or 0.15% HA twice daily. Patients were followed-up at 4, 8, and 12 weeks. Objective and subjective parameters were evaluated during each visit. RESULTS: A total of 35 patients were enrolled in this study. Compared with baseline, tear film break-up time and fluorescein staining scores at 4, 8, and 12 weeks significantly improved in the CsN group. However, the Schirmer I test showed no statistically significant change until week 12. Using the Symptom Assessment in Dry Eye (SANDE) score, both groups gradually showed significant improvement compared with baseline values. However, the Dry Eye-Related Quality-of-life Score Questionnaire (DEQS) showed no statistically significant change during the treatment period. CONCLUSIONS: Both 0.05% CsN and 0.15% HA administration twice a day effectively improved the objective signs and subjective symptoms of patients with mild-to-moderate dry eyes. However, patients treated with 0.05% CsN experienced greater and faster improvement.
Assuntos
Ciclosporina , Síndromes do Olho Seco , Emulsões , Ácido Hialurônico , Imunossupressores , Soluções Oftálmicas , Lágrimas , Humanos , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/fisiopatologia , Ciclosporina/administração & dosagem , Ciclosporina/uso terapêutico , Soluções Oftálmicas/administração & dosagem , Feminino , Masculino , Estudos Prospectivos , Método Duplo-Cego , Pessoa de Meia-Idade , Adulto , Ácido Hialurônico/administração & dosagem , Lágrimas/metabolismo , Lágrimas/fisiologia , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Qualidade de Vida , Resultado do Tratamento , IdosoRESUMO
OBJECTIVE: To determine the effectiveness of cyclosporin A (CSA) monotherapy in treating patients with non-severe aplastic anaemia (NSAA). STUDY DESIGN: A cross-sectional observational study. Place and Duration of the Study: Department of Clinical Haematology, Armed Forces Bone Marrow Transplant Center, Rawalpindi, Pakistan, from January 2022 till December 2023. METHODOLOGY: A total of 51 patients of NSAA, classified as aplastic anaemia not satisfying criteria for severe and very severe disease as per Modified Camitta Criteria, were included. Results were evaluated in terms of survival rate (OS) and responses. Responses were assessed as complete response (CR), partial response (PR), overall response (ORR), and no response (NR) by using standard British Committee for standard Haematology (BCSH) response criteria at 3, 6, and 12 months. RESULTS: Out of 51 patients, 34 (67%) were males and 17 (33%) were females. Median age at the time of diagnosis was 25 (IQR 26) years. At follow-up of 12 months, OS was 86.3%. Overall response rates to cyclosporin monotherapy at 3, 6, and 12 months were 49%, 57%, and 59%, respectively. Baseline haemoglobin was associated with responses at 6 and 12 months and a significant association was found between transfusion dependency at 3, 6, and 12 months with overall survival (p = 0.01, 0.005, and 0.04, respectively). Responses at time-defined points also had significant impact on OS (3 months Plog-rank = 0.046, 6 months Plog-rank = 0.01, and 12 months Plog-rank = 0.008). CONCLUSION: Overall response rates at 3, 6, and 12 months indicate the potential of CSA as a viable treatment option, particularly in resource-constrained settings. Despite some patients experiencing treatment-related complications, CSA demonstrated a generally tolerable safety profile. KEY WORDS: Cyclosporin A, Non-severe aplastic anaemia, Survival rate, Response rate, Complete response, Partial response.
Assuntos
Anemia Aplástica , Ciclosporina , Imunossupressores , Humanos , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/mortalidade , Ciclosporina/uso terapêutico , Feminino , Masculino , Adulto , Estudos Transversais , Imunossupressores/uso terapêutico , Paquistão , Resultado do Tratamento , Adulto Jovem , Adolescente , Taxa de Sobrevida , Pessoa de Meia-IdadeRESUMO
Chronic spontaneous urticaria (CSU) should be on every dermatology practitioner's radar. CSU is a skin disorder marked by wheals, angioedema, or both for more than 6 weeks. Patients with CSU experience unexplained, itchy wheals that appear and disappear, traveling around the body and lasting less than 24 hours per area. Angioedema accompanies wheals for up to 48 hours in around half of cases. CSU is a diagnosis of exclusion, relying heavily on patient history to differentiate CSU symptoms from other causes of urticaria or angioedema. But reassuringly, CSU has a simple diagnostic algorithm and a clear initial treatment path. First-line strategies include non-pharmacologic approaches, and second-generation antihistamines (2gAH) administered up to 4 times their standard dose. Omalizumab and cyclosporine (off-label) are second- and third-line options, respectively. However, many patients will continue to have CSU symptoms despite consistent maximum-dose treatment. Novel therapies, including biologic agents and small molecule drugs targeting mast cell activation and inflammatory mediators, show promise in treating CSU refractory to standard therapy. However, further research is needed to establish their efficacy and safety in clinical practice. J Drugs Dermatol. 2024;23:9(Suppl 2):s5-14.Access the CME Activity.
Assuntos
Urticária Crônica , Omalizumab , Humanos , Urticária Crônica/tratamento farmacológico , Urticária Crônica/diagnóstico , Omalizumab/uso terapêutico , Omalizumab/administração & dosagem , Antagonistas dos Receptores Histamínicos/administração & dosagem , Antagonistas dos Receptores Histamínicos/uso terapêutico , Ciclosporina/uso terapêutico , Ciclosporina/administração & dosagem , Urticária/tratamento farmacológico , Urticária/diagnósticoRESUMO
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, adverse drug reaction that is notoriously complex in both its presentation and treatment. Although early diagnosis and cessation of the causative agent are universally accepted as the initial interventions for DRESS, the subsequent management lacks a standardized approach. Historically, systemic steroids have been used as first-line treatment, but there is debate about the optimal dosing and route of administration, and evidence persists on the long-term complications associated with steroid use. Novel treatment approaches with targeted therapy, cyclosporine, intravenous immunoglobulin, and plasmapheresis have been gaining interest as alternative mono- and adjuvant therapies, but their use has yet to be supported by clinical trials. This narrative review provides a summary of the current knowledge of DRESS, with a focus on clinical management. The various mono- and adjuvant therapy options are discussed, with literature-supported suggestions for their optimal use in clinical practice. The risks for relapses, viral reactivation, and long-term complications are also considered. The PubMed and Medline databases were searched for articles on DRESS, published between January 1, 2008, and May 1, 2023. 334 articles met the inclusion criteria. Based on the literature, a DRESS management tool with step-by-step guidance is provided. Further suggestions for management are woven throughout this review, giving clinicians a toolbelt of resources with which to approach diagnosis, treatment, and follow-up.
Assuntos
Síndrome de Hipersensibilidade a Medicamentos , Humanos , Síndrome de Hipersensibilidade a Medicamentos/diagnóstico , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Síndrome de Hipersensibilidade a Medicamentos/terapia , Guias de Prática Clínica como Assunto , Plasmaferese/métodos , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/uso terapêutico , Imunoglobulinas Intravenosas/efeitos adversos , Ciclosporina/uso terapêutico , Ciclosporina/efeitos adversos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêuticoRESUMO
Background/aim: To compare the efficacy of topical 0.05% cyclosporine A (CsA) and 0.1% topical cyclosporine A (CsA) over a 6-month period following pterygium surgery, specifically evaluating their effects on postoperative recurrence and clinical parameters. Material and methods: This clinical study enrolled 245 patients with pterygium who underwent surgery using the conjunctival autograft technique with mitomycin C (MMC) were enrolled. Participants were divided into three groups: Group 1 (0.05% CsA) (n = 80), Group 2 (0.1% CsA) (n = 80), and a control group (n = 85). They were examined at postoperative first day, first week, first month and sixth month. The examination included best corrected visual acuity (BCVA), intraocular pressure (IOP), presence of inflammation, and ptergium recurrence, all of which were compared across the groups. Results: The mean age of the patients was 63.22 ± 9.39 years, with 53.3% male and 46.7% female. The three groups were similar in terms of demographic characteristics and pterygium size. Inflammation in surgical area significantly regressed in all groups at 6 months postoperatively (p < 0.05). Inflammation in the first and sixth months was not different between the groups (p = 0.118, p = 0.580, and p = 0.435, respectively). The recurrence rate was not different between groups (p = 0.890). There was no statistically significant difference between groups regarding IOP (p = 0.818). A significant increase in BCVA after surgery was observed in three groups compared to preoperative levels (p < 0.05). Conclusion: This study showed that there was no difference between the efficacy of 6 month topical 0.05% CsA and 0.1% CsA application after pterygium surgery with the conjunctival autograft technique with MMC on postoperative outcomes. Including postoperative recurrence, IOP changes, BCVA changes and surgical area inflammation.
Assuntos
Ciclosporina , Pterígio , Recidiva , Humanos , Pterígio/cirurgia , Pterígio/tratamento farmacológico , Feminino , Masculino , Ciclosporina/administração & dosagem , Ciclosporina/uso terapêutico , Pessoa de Meia-Idade , Idoso , Administração Tópica , Túnica Conjuntiva/efeitos dos fármacos , Túnica Conjuntiva/transplante , Resultado do Tratamento , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Acuidade Visual/efeitos dos fármacos , Soluções Oftálmicas/administração & dosagem , Pressão Intraocular/efeitos dos fármacosRESUMO
OBJECTIVES: Ferroptosis plays a pivotal role in the pathogenesis of renal ischemia-reperfusion injury, where the processes are mediated by free ferrous ions and mitochondrial-released reactive oxygen species. However, the administration of high doses of cyclosporine A (CsA) or deferoxamine (DFO) poses a significant risk of renotoxicity. In contrast, low doses of DFO act as a ferrous iron chelator, and CsA functions as a mitochondrial reactive oxygen species blocker. This study aims to explore the potential protective effects of donor treatment with low-dose CsA, DFO, or their combination against ischemia-reperfusion injury during renal transplantation in a rat model. MATERIALS AND METHODS: In an ex vivo cold storage (CS) model utilizing renal slices, the impact of incorporating DFO, CsA, and a combination of both into the University of Wisconsin solution was assessed through the measurement of lactate dehydrogenase leakage. Additionally, their potential benefits were investigated in a rat donation after circulatory death (DCD) kidney transplant model, where the extent of damage was evaluated based on graft function, tubular necrosis, and inflammation. RESULTS: The co-administration of DFO and CsA effectively decreased the release of lactate dehydrogenase induced by CS ( P ≥ .05). In the in vivo model, this combined supplementation demonstrated a mitigating effect on reperfusion injury, evidenced by lower blood urea nitrogen levels and acute tubular necrosis scores compared to the control group (allP ≤ .05). Furthermore, the combined treatment significantly reduced apoptotic levels compared to the control group (P ≥ .05). CONCLUSIONS: The combined treatment with DFO and CsA mitigated the cold ischemia-reperfusion injury in the DCD kidney. Hence, this presents a new strategy for the CS of DCD kidney in clinical transplants.
Assuntos
Ciclosporina , Desferroxamina , Transplante de Rim , Traumatismo por Reperfusão , Animais , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/etiologia , Transplante de Rim/efeitos adversos , Desferroxamina/farmacologia , Ratos , Masculino , Rim/patologia , Rim/efeitos dos fármacos , Soluções para Preservação de Órgãos , Sinergismo Farmacológico , Isquemia Fria/efeitos adversos , Preservação de Órgãos/métodos , Modelos Animais de Doenças , Rafinose/farmacologia , AlopurinolRESUMO
The optimal treatment for patients with severe aplastic anemia (SAA) who fail an initial course of antithymocyte globulin (ATG) plus cyclosporine has not yet been established. We compared the effectiveness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) (n = 36) with repeated immunosuppressive therapy (IST) (n = 33) for relapsed/refractory SAA between 2007 and 2022. In the IST group, patients were retreated with ATG (n = 16) or high-dose cyclophosphamide (n = 17). The overall response rate was 57.6% at 6 months and 60.6% at 12 months. In the allo-HSCT group, patients received a transplant from a matched sibling donor (n = 6), matched unrelated donor (n = 7), or haploidentical donor (n = 23). All patients achieved neutrophil engraftment, and there were no cases of primary graft failure. The cumulative incidences (CIs) of grades II-IV and III-IV acute graft-versus-host disease (GVHD) were 36.1% ± 0.7% and 13.9% ± 0.3% at day +100, respectively. The 4-year CI of chronic GVHD (cGVHD) was 36.2% ± 0.7%, with moderate to severe cGVHD at 14.9% ± 0.4%. Compared with IST, HSCT recipients showed much higher hematologic recovery rate at 3, 6, and 12 months (63.9%, 83.3%, and 86.1%, respectively, p < 0.001). The estimated 4-year overall survival (OS) (79.8% ± 6.8% vs. 80.0% ± 7.3%, p = 0.957) was similar; however, the failure-free survival (FFS) was significantly better in the HSCT group (79.8% ± 6.8% vs. 56.6% ± 8.8%, p = 0.049). Of note, children in the HSCT cohort were all alive without treatment failures, exhibiting superior OS (100% vs. 50.0% ± 17.7%, p = 0.004) and FFS (100% vs. 50.0% ± 17.7%, p = 0.004) than children in the IST cohort. Subgroup analysis revealed that younger patients (age ≤ 35 years), especially children, and those with refractory SAA benefited more from HSCT. Therefore, for these patients, salvage HSCT may be more preferable than a second course of IST.
Assuntos
Anemia Aplástica , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Imunossupressores , Recidiva , Humanos , Anemia Aplástica/terapia , Anemia Aplástica/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Masculino , Feminino , Adolescente , Adulto , Doença Enxerto-Hospedeiro/etiologia , Criança , Imunossupressores/uso terapêutico , Imunossupressores/administração & dosagem , Adulto Jovem , Pré-Escolar , Pessoa de Meia-Idade , Resultado do Tratamento , Soro Antilinfocitário/uso terapêutico , Soro Antilinfocitário/administração & dosagem , Transplante Homólogo , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Terapia de Imunossupressão/métodos , Estudos Retrospectivos , Ciclosporina/uso terapêutico , Ciclosporina/administração & dosagemRESUMO
PURPOSE: Despite the importance of adherence to immunosuppressants (IMMs) after an allogeneic haematopoietic stem cell transplant (HSCT) for the treatment of acute graft-versus-host disease (aGvHD), no studies to date have reported the experiences of such patients concerning medication adherence (MA). Therefore, the aim of the study was to explore the perspective on MA to immunosuppressive oral therapy among allogeneic HSCT patients with aGvHD. METHODS: A qualitative descriptive study following a reflexive thematic analysis methodological approach was performed involving a purposive sample of 16 patients with aGvHD who were being cared for in the outpatient setting of a bone marrow transplant centre and were willing to participate. Semi-structured audio-recorded interviews were conducted, transcribed verbatim and thematically analysed; member checking was performed. COnsolidated criteria for REporting Qualitative research (COREQ) and the ESPACOMP Medication Adherence Reporting Guideline were followed. RESULTS: Participants aged 25-74 years and mostly males (62.5%) were recruited for this study; 56.2% developed grade I, 37.5% grade II and 6.3% grade III aGvHD; 56.2% were receiving treatment with both cyclosporine and prednisone. Patients' perspectives have been summarised into four themes, named: "Transiting from an external obligation to a habit"; "Being in the middle between the negative and positive effects of the IMMs"; "Failure to systematically respect the rules"; and "Adopting personal strategies to become adherent". After difficulties with the perception of feeling obliged, patients became used to adhering to IMMs. Although there were failures in systematically taking the medication correctly and there were episodes of non-adherence, the adoption of personal strategies helped patients to become adherent to their medication schedules. CONCLUSIONS: MA in patients with aGvHD is a complex behaviour and is often a challenge. These results can help healthcare professionals and centres to understand how best to design tailored strategies and behavioural interventions to maximise patients' MA to IMMs.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Imunossupressores , Adesão à Medicação , Pesquisa Qualitativa , Humanos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/psicologia , Pessoa de Meia-Idade , Masculino , Feminino , Adesão à Medicação/estatística & dados numéricos , Adulto , Idoso , Transplante de Células-Tronco Hematopoéticas/métodos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Doença Aguda , Administração Oral , Ciclosporina/administração & dosagem , Ciclosporina/uso terapêuticoRESUMO
Several studies have described increased risk ratios of certain types of malignancies in patients with severe psoriasis. Among these, the lymphoproliferative disorders, including non-Hodgkin's lymphoma, cutaneous T-cell lymphoma and non-melanoma skin cancer, have been described most frequently. In addition to traditional cancer risk factors, some psoriasis treatments may also be implicated as potential carcinogens. The aim of this study was to perform a review of current literature on the association between psoriasis, the therapies against this disease and skin cancer, focusing on both epidemiology and the potential mechanism involved. Some psoriasis treatments, such as psoralen and ultraviolet A (PUVA) therapy and cyclosporine, have been associated with increased risk of skin cancer. Variable data have been reported for anti-tumour necrosis factor (TNF) drugs, whereas other class of biologics, like anti-IL17 and IL23, as well as ustekinumab, seem not to be related to skin cancer risk, such as the case of currently available small molecules.
Assuntos
Psoríase , Neoplasias Cutâneas , Humanos , Psoríase/tratamento farmacológico , Neoplasias Cutâneas/epidemiologia , Ciclosporina/uso terapêutico , Ciclosporina/efeitos adversos , Fatores de Risco , Terapia PUVA/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , Fármacos Dermatológicos/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
AIM: The binding of integrin αvß3 with endometrial fibronectin (FN) promotes the migration of preimplantation embryos in mice. We have previously shown that cyclosporine A (CsA) improves the adhesion and invasion of mouse preimplantation embryos. In this study, we evaluated the roles of calcium ions and downstream signaling factors in the binding of integrin αvß3 to FN. METHODS: Female Institute of Cancer Research (ICR) mice were superovulated and mated, and two-cell embryos were harvested from the oviducts and cultured to the blastocyst stage The adhesion and stretching growth of hatched embryos in laminin-coated dishes were evaluated, and integrinß3 expression was determined using qPCR. Blastocytes were cultured with 0 or 1 µM cyclosporine A (CsA) and the attachment of embryonic integrin αvß3 to FN120 was observed using a fluorescent bead. To further determine the mechanism, the cells were also incubated with calcium ions and protein kinase C and calmodulin antagonists. The binding of integrin αvß3 to FN120 was examined via confocal laser scanning microscopy. RESULTS: The adhesion and stretching growth of peri-implantation embryos were greater and integrinß3 expression was higher in the 1 µM CsA group than in the 0 µM CsA group (p < 0.05). When incubated with calcium ions and protein kinase C and calmodulin antagonists, the ability of peri-implantation embryos to bind to FN decreased; CsA treatment promoted this binding. CONCLUSION: This study revealed that CsA up - regulates integrinß3 expression in peri - implantation embryos and promotes binding to FN via calcium ions, and protein kinase C, and calmodulin. These findings provide evidence supporting the beneficial effect of CsA on the peri - implantation embryo adhesion.
Assuntos
Ciclosporina , Fibronectinas , Animais , Camundongos , Fibronectinas/metabolismo , Ciclosporina/farmacologia , Feminino , Camundongos Endogâmicos ICR , Blastocisto/efeitos dos fármacos , Blastocisto/metabolismo , Integrina alfaVbeta3/metabolismoRESUMO
The therapeutic arsenal for atopic dermatitis (AD) has increased in recent years. The use of biologics or Janus kinase inhibitors (JAKi) is advocated following failure or contraindication to cyclosporine (CSA), however, it is not known whether treatment with CSA can impact the response to biologics or JAKi. The aim of this study was to evaluate the effect of previous treatment with CSA on response to biologics or JAKi in patients with AD. This was a retrospective observational study including patients with AD treated for 16 weeks with a biologic or JAKi, who had previously received cyclosporine for at least four weeks. Thirty patients with AD, with a mean age of 25.07±9.91 years, of whom 18 (60%) were women, were included. The mean duration of CSA treatment was 43.39±31.32 weeks. After 16 weeks of biologic or JAKi treatment, 17 (56.7%) patients achieved EASI75. These patients had a higher cumulative dose of CSA (3,6815 vs.76,993.33 mg; p=0.022) and a longer treatment duration (24.5 vs.57.4 weeks; p=0.003). Additionally, a negative correlation was observed between cumulative dose of CSA and EASI or SCORAD at 16 weeks. Previous cumulative dose and longer duration of CSA treatment does not appear to have a negative impact on response to biologics and JAKi in patients with AD.
Assuntos
Produtos Biológicos , Ciclosporina , Dermatite Atópica , Inibidores de Janus Quinases , Humanos , Dermatite Atópica/tratamento farmacológico , Feminino , Ciclosporina/uso terapêutico , Estudos Retrospectivos , Masculino , Inibidores de Janus Quinases/uso terapêutico , Adulto , Produtos Biológicos/uso terapêutico , Adulto Jovem , Adolescente , Índice de Gravidade de Doença , Imunossupressores/uso terapêutico , Resultado do TratamentoRESUMO
Changes to ivermectin (IVM [22,23-dihydro avermectin B1a + 22,23-dihydro avermectin B1b]) toxicokinetics (TK) with and without P-glycoprotein (P-gp) inhibition by cyclosporin A (CsA) were examined in rainbow trout (Oncorhynchus mykiss). Rainbow trout were injected with 175 µg/kg 3H-IVM (8.6 µCi/mg IVM) with or without co-administration of 480 µg/kg CsA into the caudal vasculature. Fish were sacrificed at various time points (0.25, 0.5, 1, 3, 24, 48, 96, and 168 h) for organ and tissue sampling (blood, liver, kidney, gill, intestines, brain [5 regions], eye, gonad, and fat) which were analyzed for IVM-derived radioactivity. The IVM concentration decreased over time in blood, liver, kidney, and gill, while concentrations in other tissues remained constant. The highest maximum IVM concentration (Cmax) was found in kidney, followed by liver; the lowest Cmax was found in eye, followed by brain and adipose tissue. The highest % of the administered dose was found in the blood 15 min post-IVM administration, followed by the intestine at 60 min post-IVM administration. P-gp inhibition by CsA did not significantly affect calculated TK parameters (AUC [7.33 ± 0.73 - 11.5 ± 2.5 mgâ¢h/kg], mean residence time [84.7 ± 21 - 125 ± 55 h], T1/2 [58.7 ± 15 - 86.8 ± 38 h], clearance rate [0.0152 ± 0.0033 - 0.0239 ± 0.0024 L/kgâ¢h], or volume of distribution [1.91 ± 0.47 - 2.02 ± 0.33 L/kg]), but resulted in small but significant changes in the % administered dose found in blood and medulla. These results suggest that P-gp plays a limited role in overall IVM TK, and that its role in xenobiotic protection may be much less robust in fish than it is in mammals.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Ciclosporina , Ivermectina , Oncorhynchus mykiss , Animais , Oncorhynchus mykiss/metabolismo , Ivermectina/análogos & derivados , Ivermectina/farmacocinética , Ivermectina/toxicidade , Ivermectina/sangue , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Ciclosporina/farmacocinética , Toxicocinética , Antiparasitários/farmacocinética , Distribuição TecidualRESUMO
Eltrombopag combined with immunosuppressive therapy (IST) was superior to IST alone for severe aplastic anemia (SAA) in the previous studies. But in China, horse antithymocyte globulin (hATG) is not available, instead, we use rabbit ATG (rATG). Here, we compared the efficacy and safety of IST (rATG combined with cyclosporine) combined with or without eltrombopag for the first-line treatment of SAA and very severe aplastic anemia (VSAA). A total of 371 patients in ten institutions in China from April 1, 2017 to December 1, 2022 were enrolled. The overall response (OR) rate at 3 months (54.2% vs. 41%; P = 0.046), the complete response (CR) (31.3% vs. 19.4%; P = 0.041) and OR (78.3% vs. 51.1%; P < 0.0001) rates at 6 months were significantly higher with IST combined with eltrombopag than with IST alone in SAA patients. While in VSAA patients, the addition of eltrombopag to IST only increased the CR rate at 6 months (29.8% vs. 9.43%; P = 0.010). Liver injury increased significantly in groups treated with IST combined with eltrombopag (P < 0.05). Serious treatment-related toxicities were similar (P > 0.05). In patients with SAA, 3-year failure-free survival (FFS) of eltrombopag combined with IST group was significantly higher than that of IST group (70.7 ± 5.3% vs. 50.3 ± 3.9%; P = 0.007). In patients with VSAA, the addition of eltrombopag significantly improved 3-year overall survival (OS) (82.2 ± 5.7% vs. 57.3 ± 7.2%; P = 0.020). Our findings suggested that IST combined with eltrombopag could improve the hematological recovery of newly diagnosed SAA without increasing severe toxicities. But in VSAA, the addition of eltrombopag seemed to show no other improvement to efficacy except the CR rate at 6 months.
Assuntos
Anemia Aplástica , Soro Antilinfocitário , Benzoatos , Hidrazinas , Imunossupressores , Pirazóis , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/mortalidade , Benzoatos/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Humanos , Hidrazinas/uso terapêutico , Hidrazinas/administração & dosagem , Hidrazinas/efeitos adversos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adolescente , Imunossupressores/uso terapêutico , Soro Antilinfocitário/uso terapêutico , Soro Antilinfocitário/administração & dosagem , Adulto Jovem , Idoso , Estudos Retrospectivos , Quimioterapia Combinada , Criança , Resultado do Tratamento , Índice de Gravidade de Doença , Pré-Escolar , Ciclosporina/uso terapêutico , Ciclosporina/administração & dosagem , China/epidemiologia , Taxa de SobrevidaRESUMO
The goal of this work is to investigate if the synergistic antifungal activity between cyclosporine A, CsA, and voriconazole, VRZ, increases when both drugs are encapsulated in a nanocarrier as compared when they are free. The preparation and characterization of blank and VRZ and CsA loaded polymeric based PLGA nanoparticles (PLGA, PLGA-PEG, and PLGA+PEG) was a necessary previous step. Using the more suitable NPs, those of PLGA, the antifungal susceptibility tests performed with VRZ-loaded PLGA NPs, show no significant increase of the antifungal activity in comparison to that of free VRZ. However, the synergistic behavior found for the (VRZ+CsA)-loaded PLGA NPs was fourfold stronger than that observed for the two free drugs together. On the other hand, the investigation into the suppression of C. albicans biofilm formation showed that blank PLGA NPs inhibit the biofilm formation at high NPs concentrations. However, a minor effect or even a slight biofilm increase formation was observed at low and moderate NPs concentrations. Therefore, the enhancement of the biofilm inhibition found for the three tested treatments (CsA alone, VRZ alone, and VRZ+CsA) when comparing free and encapsulated drugs, within the therapeutic window, can be attributed to the drug encapsulation approach. Indeed, polymeric PLGA NPs loaded with CsA, VRZ, or VRZ+CsA are more effective at inhibiting the C. albicans biofilm growth than their free counterparts.
Assuntos
Antifúngicos , Biofilmes , Candida albicans , Ciclosporina , Sinergismo Farmacológico , Nanopartículas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Voriconazol , Voriconazol/administração & dosagem , Voriconazol/farmacologia , Voriconazol/química , Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Antifúngicos/química , Candida albicans/efeitos dos fármacos , Nanopartículas/química , Ciclosporina/administração & dosagem , Ciclosporina/farmacologia , Ciclosporina/química , Biofilmes/efeitos dos fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Portadores de Fármacos/química , Polietilenoglicóis/química , Testes de Sensibilidade Microbiana , Ácido Láctico/químicaRESUMO
OBJECTIVE: This study aimed to compare the efficacy and safety of biologics, multitarget therapy, and standard therapy for the induction of lupus nephritis. METHODS: A systematic search of electronic databases (EMBASE, Web of Science, PubMed, Cochrane Library, and ClinicalTrials.gov) was conducted from inception to 30 August 2023. Our study included randomized controlled trials enrolling adult lupus nephritis patients treated with biologics or multitarget therapy, in comparison with standard therapy. The primary outcomes were the rates of complete renal remission (CRR) and serious adverse events (SAE). Stata 15.0 was used to conduct the network meta-analysis. RESULTS: Ten randomized controlled trials with a total of 1989 patients met the inclusion criteria. The network meta-analysis indicated that compared with standard therapy, multitarget therapy, obinutuzumab, belimumab, and voclosporin therapy demonstrated superior efficacy in achieving complete renal remission. Among these options, multitarget therapy had the greatest effect (OR = 2.78, 95% CI = 1.81-4.26). Regarding safety, it was observed that there were no significant statistical differences among the various treatment options. Cluster analysis revealed that both obinutuzumab and belimumab exhibited good efficacy and safety. CONCLUSIONS: belimumab and obinutuzumab stood out as promising treatments due to their good performance in terms of efficacy and safety. Multitarget therapy may be the most effective approach for treating lupus nephritis. However, since the study population consists exclusively of Asian patients, further research is needed to verify the efficacy of multitarget therapy in lupus nephritis patients of non-Asian descent.
Assuntos
Anticorpos Monoclonais Humanizados , Produtos Biológicos , Nefrite Lúpica , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Produtos Biológicos/uso terapêutico , Ciclosporina , Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Terapia de Alvo Molecular , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão , Resultado do TratamentoRESUMO
Immunosuppressive drugs (ISDs) are given to avoid the allograft rejection after transplantation. The concentrations of ISDs should be closely monitored owing to their wide inter-individual variability in its pharmacokinetics and narrow therapeutic window. Currently, the whole blood concentration measurement is the major approach of therapeutic drug monitoring of clinical ISDs in organ transplantation. Its correlation with the efficacy of ISDs remains elusive. While the acute rejection after transplantation may occur even when whole-blood ISDs concentrations are within the target range. Since the site of action of ISDs are within the lymphocyte, direct measurement of drug exposure in target cells may more accurately reflect the clinical efficacy of ISDs. Although several methods have been developed for the peripheral blood mononuclear cells (PBMCs) extraction and drug concentration measurement, the complex pre-processing has limited the study of the relationship between intracellular ISDs concentrations and the occurrence of rejection. In this study, the extraction of ISDs in PBMCs was carried out by the liquid-liquid extraction with low temperature purification, without centrifugation. The lower limit of quantitation were 0.2â¯ng/mL for cyclosporine A, tacrolimus and sirolimus, 1.0â¯ng/mL for mycophenolic acid, and the within-run and between-run coefficient of variations were both less than 12.4â¯%. The calibration curves of mycophenolic acid had a linear range (ng/mL): 1.0-128.0 (r2 = 0.9992). The calibration curves of other three ISDs had a linear range (ng/mL): 0.2-20.48 (r2 > 0.9956). A total of 157 clinical samples were analyzed by the UPLC-MS/MS for ISDs concentration in blood or plasma ([ISD]blood or plasma) and the concentration within PBMCs ([ISD]PBMC). Although there was strong association between [ISD]PBMC and [ISD]blood or plasma, the large discrepancies between concentration within [ISD]blood or plasma and [ISD]PBMC were observed in a small proportion of clinical samples. The developed method with short analysis time and little amounts of blood sample can be successfully applied to therapeutic drug monitoring of ISDs in PBMCs for analysis of large numbers of clinical samples and is helpful to explore the clinical value of ISDs concentration in PBMCs.
Assuntos
Monitoramento de Medicamentos , Imunossupressores , Leucócitos Mononucleares , Extração Líquido-Líquido , Espectrometria de Massas em Tandem , Humanos , Espectrometria de Massas em Tandem/métodos , Extração Líquido-Líquido/métodos , Imunossupressores/sangue , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/métodos , Tacrolimo/sangue , Ácido Micofenólico/sangue , Ácido Micofenólico/farmacocinética , Ciclosporina/sangue , Reprodutibilidade dos Testes , Limite de Detecção , Sirolimo/sangue , Espectrometria de Massa com Cromatografia LíquidaRESUMO
BACKGROUND: Different prophylactic protocols are available for preventing graft-versus-host disease (GVHD) after matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to compare the effectiveness of post-transplantation cyclophosphamide plus cyclosporine A (PT-CY/CSA) versus methotrexate plus CSA (MTX/CSA) as GVHD prophylaxis protocols in adult acute myeloid leukemia (AML) patients who received peripheral blood stem cells (PBSC) from fully matched donors. METHODS: The 1-year outcomes of 89 patients treated with PT-CY/CSA and 90 patients treated with MTX/CSA who had MSD allo-HCT for AML using unmanipulated mobilized PBSC were examined and compared. RESULTS: The cumulative incidence of acute GVHD at 100 days was considerably lower in the PT-CY/CSA group (4% vs 19.3%, p = 0.002), however there were no statistically significant difference in the cumulative incidence of chronic GVHD at 1-year (19.6% vs 37.4%, p = 0.053). Significant delays in neutrophil and platelet engraftments were reported in the PT-CY/CSA group (17 vs 12 days) and (13 vs 12 days), respectively (p < 0.001). The cumulative incidences of relapse (19.1% vs 13.7%, p = 0.470), overall survival (79.1% vs 77.3%, p = 0.986), non-relapse mortality (16.5% vs 16.8%, p = 0.837), and the GVHD and relapse-free survival (GRFS) (53.7% vs 46.6%, p = 0.478) did not differ statistically at 1-year. CONCLUSION: PT-CY/CSA demonstrated a significant decrease in the rate of acute GVHD. However, it was associated with engraftment delay.
Assuntos
Ciclofosfamida , Ciclosporina , Doença Enxerto-Hospedeiro , Leucemia Mieloide Aguda , Metotrexato , Transplante de Células-Tronco de Sangue Periférico , Transplante Homólogo , Humanos , Doença Enxerto-Hospedeiro/prevenção & controle , Ciclosporina/uso terapêutico , Ciclosporina/administração & dosagem , Masculino , Adulto , Feminino , Metotrexato/uso terapêutico , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Leucemia Mieloide Aguda/terapia , Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Adulto Jovem , Imunossupressores/uso terapêutico , Imunossupressores/administração & dosagem , Adolescente , Estudos Retrospectivos , IdosoRESUMO
ABSTRACT: A 29-year-old Korean woman with chronic aplastic anemia presented with seizures due to cyclosporine-induced posterior reversible encephalopathy syndrome, caused by unpredictable oral cyclosporine (CS) accumulation and prolonged elimination. This case demonstrates the need to monitor CS drug levels with careful dose adjustments.
Assuntos
Anemia Aplástica , Ciclosporina , Imunossupressores , Humanos , Feminino , Adulto , Ciclosporina/uso terapêutico , Ciclosporina/efeitos adversos , Ciclosporina/farmacocinética , Imunossupressores/farmacocinética , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , República da Coreia , Síndrome da Leucoencefalopatia Posterior/induzido quimicamente , Convulsões/induzido quimicamenteRESUMO
Cytokine storm syndromes (CSS) include different entities such as macrophage activation syndrome, primary and secondary hemophagocytic lymphohistiocytosis (HLH), and multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. An effective management strategy is critical in CSS. While biologics have become an essential part of CSS treatment, hematopoietic stem cell transplantation (HSCT) has changed the fate of primary HLH patients. This chapter will focus on the available alternative immunomodulatory therapies in CSS, which include corticosteroids, cyclosporine A, intravenous immunoglobulin, interleukin 18 binding protein, therapeutic plasmapheresis, HSCT, and mesenchymal stromal cell-based therapies.