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Purpose To compare the effectiveness of using Cyclosporine A (CsA) eye drops with a concentration of 0.05% alone versus using eye drops containing both CsA of 0.05% concentration combined with autologous serum (AS) of 20% used together for treating vernal keratoconjunctivitis (VKC) which were moderate to severe. Methods A prospective comparative noninterventional case series was carried out at the Ophthalmology Department at Kafrelsheik University, involving 40 individual patients with moderate to severe VKC sorted into two groups; 20 patients using CsA 0.05% eye drops as group A and 20 patients in group B using eye drops of CsA 0.05% combined with AS eye drop of 20% concentration for treating VKC for 12 weeks, 4 times daily. Results According to the scores recorded for symptoms and signs, the difference detected statistically was of no significance among the two involved study groups as regards the baseline score (P=0.783, and 0.137, respectively). While the scores reported for the symptoms and signs were statistically lower significantly among group B other than observed among group A as determined at the 4th week (P=0.015, and 0.004, respectively), 8th week (P<0.001, for both), and 12th week (P=0.001, and 0.002, respectively). Regarding side effects of treatment, 12 patients had a burning sensation, eight of them in group A and four patients in group B, with not reach to significant level between the studied groups during the follow-up visits (P=0.382) Conclusions We concluded a higher efficacy of using combined eye drops of CsA 0.05% and AS 20% for treating VKC than CsA 0.05% eye drops alone. [ABSTRACT FROM AUTHOR]

Objective(s): Selenium Nanoparticles can modulate the function of the immune system and improve immunity. We investigate the expression of toll-like receptor-7 (TLR-7), myeloid differentiation primary response 88 (MyD88), Nuclear factor kappa B (NF-κB), and TNF receptor associated factor 6 (TRAF6) genes in thymus of Wistar rats following treatment with cyclosporine A (CsA) and Nano-selenium (Nano-Se) supplementation. Materials and Methods: Twenty-four male Wistar rats (200-220 grams) were divided into 3 groups of control (n=8), CsA (n=8), and CsA+Nano-Se (n=8). Rats in CsA and CsA+Nano-Se group's received cyclosporine A and olive oil solution by subcutaneous injection for 10 days at a dose of 5 mg/kg/day. Nano-Se with a dose of 2.5 mg/kg of body weight was gavaged to the CsA+Nano-Se group once a day and 3 times a week. Real-time PCR were used for gene expression of TLR-7, MyD88, NF-kB, and TRAF6 at thymus. Results: The result of this study show that CsA significantly decreased expressions of TLR-7, MyD88, NF-kB, and TRAF6 at thymus compared to control group (P<0.05). However, expressions of TLR-7, MyD88, NF-kB, and TRAF6 at thymus in CsA+ Nano-Se group was significantly increased compared to CsA group (P<0.05). Conclusion: Nano-Se supplementation significantly regulated the expression of TLR-7, MyD88, NF-kB and TRAF6 genes in the thymus of rats treated with cyclosporine A. Therefore, Nano-Se supplementation can be recommended to boost immune function after using immunosuppressive drugs. However, more research is needed in the future. [ABSTRACT FROM AUTHOR]

Abstract Objective To compare outcomes in patients with repeated implantation failure undergoing Intracytoplasmic Sperm Injection/In vitro fertilization (IVF/ICSI) plus immunosuppressants such as prednisolone, prednisone, or cyclosporine A versus the use of IVF/ICSI alone. Data source Databases were systematically searched in PubMed, Cochrane, and Embase databases in September 2023. Study Selection Randomized clinical trials and observational studies with the outcomes of interest were included. Data collect We computed odds ratios (ORs) for binary endpoints, with 95% confidence intervals (CIs). Heterogeneity was assessed using I2 statistics. Data were analyzed using Review Manager 5.4.The main outcomes were live birth, miscarriage, implantation rate, clinical pregnancy, and biochemical pregnancy. Data synthesis Seven studies with 2,829 patients were included. Immunosuppressive treatments were used in 1,312 (46.37%). Cyclosporine A improved implantation rate (OR 1.48; 95% CI 1.01-2.18) and clinical pregnancy (1.89, 95% CI 1.14-3.14). Compared to non-immunosuppressive treatment, prednisolone and prednisone did not improve live birth (OR 1.13, 95% CI 0.88-1.46) and miscarriage (OR 1.49, 95% CI 1.07-2.09). Prednisolone showed no significant effect in patients undergoing IVF/ICSI, clinical pregnancy (OR 1.34; 95% CI 0.76-2.36), or implantation rate (OR 1.36; 95% CI 0.76-2.42). Conclusion Cyclosporine A may promote implantation and clinical pregnancy rates. However, given the limited sample size, it is important to approach these findings with caution. Our results indicate that prednisolone and prednisone do not have any beneficial effects on clinical outcomes of IVF/ICSI patients with repeated implantation failure. PROSPERO CRD42023449655

Abstract Background The glomerulus is a highly complex system, composed of different interdependent cell types that are subjected to various mechanical stimuli. These stimuli regulate multiple cellular functions, and changes in these functions may contribute to tissue damage and disease progression. To date, our understanding of the mechanobiology of glomerular cells is limited, with most research focused on the adaptive response of podocytes. However, it is crucial to recognize the interdependence between podocytes and parietal epithelial cells, in particular with the progenitor subset, as it plays a critical role in various manifestations of glomerular diseases. This highlights the necessity to implement the analysis of the effects of mechanical stress on renal progenitor cells. Methods Microgravity, modeled by Rotary Cell Culture System, has been employed as a system to investigate how renal progenitor cells respond to alterations in the mechanical cues within their microenvironment. Changes in cell phenotype, cytoskeleton organization, cell proliferation, cell adhesion and cell capacity for differentiation into podocytes were analyzed. Results In modeled microgravity conditions, renal progenitor cells showed altered cytoskeleton and focal adhesion organization associated with a reduction in cell proliferation, cell adhesion and spreading capacity. Moreover, mechanical forces appeared to be essential for renal progenitor differentiation into podocytes. Indeed, when renal progenitors were exposed to a differentiative agent in modeled microgravity conditions, it impaired the acquisition of a complex podocyte-like F-actin cytoskeleton and the expression of specific podocyte markers, such as nephrin and nestin. Importantly, the stabilization of the cytoskeleton with a calcineurin inhibitor, cyclosporine A, rescued the differentiation of renal progenitor cells into podocytes in modeled microgravity conditions. Conclusions Alterations in the organization of the renal progenitor cytoskeleton due to unloading conditions negatively affect the regenerative capacity of these cells. These findings strengthen the concept that changes in mechanical cues can initiate a pathophysiological process in the glomerulus, not only altering podocyte actin cytoskeleton, but also extending the detrimental effect to the renal progenitor population. This underscores the significance of the cytoskeleton as a druggable target for kidney diseases.

Abstract Background The management of post-refractive surgery dry eye disease (DED) can be challenging in clinical practice, and patients usually show an incomplete response to traditional artificial tears, especially when it is complicated with ocular pain. Therefore, we aim to investigate the efficacy of combined topical 0.05% cyclosporine A and 0.1% sodium hyaluronate treatment in post-refractive surgery DED patients with ocular pain unresponsive to traditional artificial tears. Methods We enrolled 30 patients with post-refractive surgery DED with ocular pain who were unresponsive to traditional artificial tears. Topical 0.05% cyclosporine A and 0.1% sodium hyaluronate were used for 3 months. They were evaluated at baseline and 1 and 3 months for dry eye and ocular pain symptoms and objective parameters, including Numerical Rating Scale (NRS), Neuropathic Pain Symptom Inventory modified for the Eye (NPSI-Eye), tear break-up time (TBUT), Schirmer I test (SIt), corneal fluorescein staining (CFS), corneal sensitivity, and corneal nerve morphology. In addition, tear levels of inflammatory cytokines and neuropeptides were measured using the Luminex assay. Results After 3 months of treatment, patients showed a statistically significant improvement in the ocular surface disease index (OSDI), TBUT, SIt, CFS, and corneal sensitivity (all P

Objectives: Cyclosporine A promotes gingival fibrosis by enhancing the proliferation of gingival fibroblasts, leading to gingival overgrowth. The population of gingival fibroblasts is regulated by cell cycle machinery, which balances cell growth and inhibition. Cells that detect DNA damage pause at the G1/S checkpoint to repair the damage instead of progressing to the S phase. Previous studies have linked drug-induced gingival overgrowth to the response of fibroblasts to lipopolysaccharide (LPS) and cyclosporine A. This research investigates the effects of cyclosporine A on the G1/S checkpoint and its mediators in LPS-treated gingival fibroblasts to clarify the mechanisms behind cyclosporine-A-induced gingival overgrowth. Methods: Semi-confluent human gingival fibroblasts were treated with LPS or cyclosporine A in DMEM. Cell proliferation was evaluated by counting the total number of cells. The distribution of the cell cycle phases was analyzed using flow cytometry. Additionally, the expression levels of mRNAs and proteins related to cell cycle regulators were quantified by reverse-transcription quantitative PCR and Western blotting, respectively. Results: Cyclosporine A treatment significantly enhanced cell proliferation and the G1-S cell cycle transition. It increased the mRNA levels of CDC25A and CYCLIN D while decreasing those of RB1, SMAD3, and SMAD4. Additionally, it upregulated the protein levels of CDC25A, CYCLIN D, CDK4, CDK6, and pRB and downregulated the protein levels of SMAD3 and SMAD4. Conclusions: Gingival overgrowth induced by cyclosporine A could be attributed to these alterations.

Abstract Background The aberrant formation of neutrophil extracellular traps (NETs) has been implicated in ulcerative colitis (UC), a chronic recurrent intestinal inflammation. Cyclosporine A (CsA) is now applied as rescue therapy for acute severe UC. In addition, it has been certained that CsA inhibits the formation of NETs in vitro and the mechanism of which was still vague. The study aimed to explore the mechanism CsA inhibits the NETs formation of colitis in vivo and in vitro. Methods NETs enrichment in clinical samples was analyzed using databases from Gene Expression Omnibus and verified in our center. Dextran sulfate sodium (DSS)-induced acute colitis mice model was used to investigate the effect of CsA on NETs of colonic tissue expression. To clarify the mechanism, intracellular energy metabolites were examined by Liquid Chromatograph Mass Spectrometer, and reactive oxygen species (ROS) levels were examined by fluorescence intensity in neutrophils treated with CsA after LPS stimulation. The transcriptional level and activity of G6PD of neutrophils were also assessed using qRT-PCR and WST-8. RNA Sequencing was used to detect differentially expressed genes of neutrophils stimulated by LPS with or without CsA. The expression levels of related proteins were detected by western blot. Results NETs enrichment was especially elevated in moderate-to-severe UC patients compared to HC. NETs expression in the colon from DSS colitis was decreased after CsA treatment. Compared with neutrophils stimulated by LPS, NETs formation and cellular ROS levels were decreased in LPS + CsA group. Cellular ribulose 5-phosphate and NADPH/NADP + related to the pentose phosphate pathway (PPP) were reduced in LPS + CsA group. In addition, CsA could decrease G6PD activity in neutrophils stimulated with LPS, and the results were further verified by inhibiting G6PD activity. At last, P53 protein was highly expressed in LPS + CsA group compared with the LPS group. Intracellular G6PD activity, ROS level and NETs formation, which were downregulated by CsA, could be reversed by a P53 inhibitor. Conclusion Our results indicated CsA could alleviate the severity of colitis by decreasing the formation of NETs in vivo. In vitro, CsA reduced ROS-dependent NETs release via downregulating PPP and cellular ROS levels by decreasing G6PD activity directly by activating the P53 protein.

Abstract Background Pharmaceutical companies do not sell formulations for all diseases; thus, healthcare workers have to treat some diseases by concocting in-hospital preparations. An example is the high-concentration 2% cyclosporine A (CyA) ophthalmic solution. Utilizing a filter in sterility operations is a general practice for concocting in-hospital preparations, as is the case for preparing a 2% CyA ophthalmic solution. However, whether filtering is appropriate concerning the active ingredient content and bacterial contamination according to the post-preparing quality control of a 2% CyA ophthalmic solution is yet to be verified. Methods We conducted particle size, preparation concentration, and bacterial contamination studies to clarify aforementioned questions. First, we measured the particle size of CyA through a laser diffraction particle size distribution. Next, we measured the concentration after preparation with or without a 0.45-µm filter operation using an electrochemiluminescence immunoassay. Finally, bacterial contamination tests were conducted using an automated blood culture system to prepare a 2% CyA ophthalmic solution without a 0.45 μm filtering. Regarding the pore size of the filter in this study, it was set to 0.45 μm with reference to the book (the 6th edition) with recipes for the preparation of in-hospital preparations edited by the Japanese Society of Hospital Pharmacists. Results CyA had various particle sizes; approximately 30% of the total particles exceeded 0.45 μm. The mean ± standard deviation of filtered and non-filtered CyA concentrations in ophthalmic solutions were 346.51 ± 170.76 and 499.74 ± 76.95ng/mL, respectively (p = 0.011). Regarding bacterial contamination tests, aerobes and anaerobes microorganisms were not detected in 14 days of culture. Conclusions Due to the results of this study, the concentration of CyA may be reduced by using a 0.45-µm filter during the preparation of CyA ophthalmic solutions, and furthermore that the use of a 0.45-µm filter may not contribute to sterility when preparing CyA ophthalmic solutions.

Abstract Background Dry eye disease (DED) is a disorder characterized by loss of tear film homeostasis that causes ocular surface inflammation and damage. The incidence of DED increases with age. Cyclosporine ophthalmic solution 0.09% (CEQUA®; OTX-101), cyclosporine ophthalmic emulsion 0.05% (Restasis®; CsA), and lifitegrast ophthalmic solution 5% (Xiidra®; LFT) are anti-inflammatory agents indicated for DED. This analysis compared treatment patterns in patients with DED receiving OTX-101, CsA, or LFT. Methods This real-world, retrospective, longitudinal cohort study utilized Symphony Health Integrated Dataverse claims from July 2019 to June 2021. The dataset included all patients with OTX-101 claims and patients with CsA or LFT claims randomly selected 2:1 to OTX-101. Patients were sorted into 3 cohorts based on index treatment. Index date was that of first treatment claim, and follow-up period was from index date to end of clinical activity or data availability. Time to treatment discontinuation (TTD), probability of discontinuation, and treatment persistence were assessed for OTX-101 vs. CsA, then OTX-101 vs. LFT. Subgroup analysis was performed based on age and prior DED treatment. Kaplan-Meier analysis and log-rank test were used to examine TTD. A logistic model evaluated association between index treatment and discontinuation. Unadjusted and adjusted odds ratios, 95% confidence intervals, and P-values were reported, with statistically significant associations based on P-values

Background: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a sensitive method with high specificity. However, its routine use in the clinical laboratory is hampered by its high complexity and lack of automation. Studies demonstrate excellent analytical performance using the first fully automated LC-MS/MS for 25-hydroxy vitamin D and immunosuppressant drugs (ISD) in hospital routine laboratories. Objectives: Our objectives were (1) to verify the suitability of an automated LC-MS/MS in a commercial laboratory, which differs from the needs of hospital laboratories, and (2) examine its usability among operators with various professional backgrounds. Methods: We assessed the analytical assay performance for vitamin D and the ISDs cyclosporine A and tacrolimus over five months. The assays were compared to an identical analyzer in a hospital laboratory, to in-house LC-MS/MS methods, and to chemiluminescent microparticle immunoassays (CMIA). Nine operators evaluated the usability of the fully automated LC-MS/MS system by means of a structured questionnaire. Results: The automated system exhibited a high precision (CV

Background and Purpose: Atherosclerosis induced by cyclosporine A (CsA), an inhibitor of the calcineurin/nuclear factor of activated T cells (NFAT) pathway, is a major concern after organ transplantation. However, the atherosclerotic mechanisms of CsA remain obscure. We previously demonstrated that calcineurin/NFAT signalling inhibition contributes to atherogenesis via suppressing microRNA‐204 (miR‐204) transcription. We therefore hypothesised that miR‐204 is involved in the development of CsA‐induced atherosclerosis. Experimental Approach: ApoE−/− mice with macrophage‐miR‐204 overexpression were generated to determine the effects of miR‐204 on CsA‐induced atherosclerosis. Luciferase reporter assays and chromatin immunoprecipitation sequencing were performed to explore the targets mediating miR‐204 effects. Key Results: CsA alone did not significantly affect atherosclerotic lesions or serum lipid levels. However, it exacerbated high‐fat diet‐induced atherosclerosis and hyperlipidemia in C57BL/6J and ApoE−/− mice, respectively. miR‐204 levels decreased in circulating monocytes and plaque lesions during CsA‐induced atherosclerosis. The upregulation of miR‐204 in macrophages inhibited CsA‐induced atherosclerotic plaque formation but did not affect serum lipid levels. miR‐204 limited the CsA‐induced foam cell formation by reducing the expression of the scavenger receptors SR‐BII and CD36. SR‐BII was post‐transcriptionally regulated by mature miR‐204‐5p via 3′‐UTR targeting. Additionally, nuclear‐localised miR‐204‐3p prevented the CsA‐induced binding of Ago2 to the CD36 promoter, suppressing CD36 transcription. SR‐BII or CD36 expression restoration dampened the beneficial effects of miR‐204 on CsA‐induced atherosclerosis. Conclusion and Implications: Macrophage miR‐204 ameliorates CsA‐induced atherosclerosis, suggesting that miR‐204 may be a potential target for the prevention and treatment of CsA‐related atherosclerotic side effects. [ABSTRACT FROM AUTHOR]

Ferroptosis has been characterized as a form of iron-dependent regulated cell death accompanied by an accumulation of reactive oxygen species and lipid oxidation products along with typical morphological alterations in mitochondria. Ferroptosis is activated by diverse triggers and inhibited by ferrostatin-1 and liproxstatin-1, apart from iron chelators and several antioxidants, and the process is implicated in multiple pathological conditions. There are, however, certain ambiguities about ferroptosis, especially regarding the final executioner of cell death subsequent to the accumulation of ROS. This study uses a typical inducer of ferroptosis such as erastin on SH-SY5Y cells, and shows clearly that ferroptotic death of cells is accompanied by the loss of mitochondrial membrane potential and intracellular ATP content along with an accumulation of oxidative stress markers. All these are prevented by ferrostatin-1 and liproxstatin-1. Additionally, cyclosporine A prevents mitochondrial alterations and cell death induced by erastin implying the crucial role of mitochondrial permeability transition pore (mPTP) activation in ferroptotic death. Furthermore, an accumulation of α-synuclein occurs during erastin induced ferroptosis which can be inhibited by ferrostatin-1 and liproxstatin-1. When the knock-down of α-synuclein expression is performed by specific siRNA treatment of SH-SY5Y cells, the mitochondrial impairment and ferroptotic death of the cells induced by erastin are markedly prevented. Thus, α-synuclein through the involvement of mPTP appears to be the key executioner protein of ferroptosis induced by erastin, but it needs to be verified if it is a generalized mechanism of ferroptosis by using other inducers and cell lines. [ABSTRACT FROM AUTHOR]

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Objective To study the effect of Bailing capsule on renal function and other organ systems in 60 patients after renal transplantation in No. 910 Hospital of Joint Logistics Support Force. Methods 60 patients with renal allograft in 2018−2020 were divided into 2 groups according to different immunosuppressive regimens. In the control group, 35 cases were treated with MMF + CsA or FK506; in the treatment group, 25 cases were treated with MMF + CsA or FK506 + Bailing capsule. Blood and urine routine, liver and renal function and uric acid were measured after operation. The dosage of immunosuppressive drugs was recorded in stages at 48 weeks.Results The urinary red and white blood cell counts, blood aspartate transaminase and alanine transaminase, serum uric acid, total bilirubin and direct bilirubin in the treatment group were significantly less than those in the control group, while the serum total protein and albumin were significantly higher than those in the control group. The number of red blood cells and white blood cells in the treatment group was significantly higher than that in the control group at 12-48 weeks after kidney transplantation, and that in the lymphocyte group was significantly higher than that in the control group at 24-48 weeks after kidney transplantation. The dosage of CsA and FK506 in the treatment group was significantly lower than that in the control group after 48 weeks. Conclusion Bailing capsule could protect liver and kidney, stimulate hematopoiesis, improve hypoalbuminemia and reduce the dosage of immunosuppressant, which could be an ideal immunomodulator. [ABSTRACT FROM AUTHOR]

Studies indicate that mitogen-activated protein kinases (MAPKs) are activated and overexpressed in psoriatic lesions. The aim of the study was to assess changes in the expression pattern of genes encoding MAPKs and microRNA (miRNA) molecules potentially regulating their expression in human adult low-calcium high-temperature (HaCaT) keratinocytes exposed to bacterial lipopolysaccharide A (LPS) and cyclosporine A (CsA). HaCaT cells were treated with 1 µg/mL LPS for 8 h, followed by treatment with 100 ng/mL cyclosporine A for 2, 8, or 24 h. Untreated cells served as controls. The molecular analysis consists of microarray, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay analyses. The statistical analysis of the obtained results was performed using Transcriptome Analysis Console and STATISTICA 13.5 PL with the statistical significance threshold of p < 0.05. Changes in the expression profile of six mRNAs: dual-specificity phosphatase 1 (DUSP1), dual-specificity phosphatase 4 (DUSP4), mitogen-activated protein kinase kinase 2 (MAP2K2), mitogen-activated protein kinase kinase 7 (MAP2K7), mitogen-activated protein kinase kinase kinase 2 (MAP3K2) and mitogen-activated protein kinase 9 (MAPK9) in cell culture exposed to LPS or LPS and the drug compared to the control. We observed that under the LPS and cyclosporine treatment, the expression o/ miR-34a, miR-1275, miR-3188, and miR-382 changed significantly (p < 0.05). We demonstrated a potential relationship between DUSP1 and miR-34a; DUSP4 and miR-34a, miR-382, and miR-3188; MAPK9 and miR-1275, MAP2K7 and mir-200-5p; MAP3K2 and mir-200-5p, which may be the subject of further research in the context of psoriasis. [ABSTRACT FROM AUTHOR]

Cyclosporine A (CsA) is a cyclic peptide immunosuppressant drug that is beneficial in the treatment of various ocular diseases. However, its ocular bioavailability in the posterior eye is limited due to its poor aqueous solubility. Conventional CsA formulations such as a solution or emulsion permeate poorly across the eye due to various static and dynamic barriers of the eye. Dissolvable microneedle (MN)-based patches can be used to overcome barrier properties and, thus, enhance the ocular bioavailability of CsA in the posterior eye. CsA-loaded dissolvable MN patches were fabricated using polyvinylpyrrolidone (PVP) and characterized for MN uniformity and sharpness using SEM. Further characterization for its failure force, penetration force, and depth of penetration were analyzed using a texture analyzer. Finally, the dissolution time, ex vivo permeation, and ocular distribution of cyclosporine were determined in isolated porcine eyes. PVP MNs were sharp, uniform with good mechanical properties, and dissolved within 5 min. Ocular distribution of CsA in a whole porcine eye perfusion model showed a significant increase of CsA levels in various posterior segment ocular tissues as compared to a topically applied ophthalmic emulsion (Restasis®) (P < 0.001). Dissolving MNs of CsA were prepared, and the MN arrays can deliver CsA to the back of the eye offering potential for treating various inflammatory diseases. [ABSTRACT FROM AUTHOR]

Summary: During the early stages of human pregnancy, successful implantation of embryonic trophoblast cells into the endometrium depends on good communication between trophoblast cells and the endometrium. Abnormal trophoblast cell function can cause embryo implantation failure. In this study, we added cyclosporine A (CsA) to the culture medium to observe the effect of CsA on embryonic trophoblast cells and the related mechanism. We observed that CsA promoted the migration and invasion of embryonic trophoblast cells. CsA promoted the expression of leukaemic inhibitory factor (LIF) and fibroblast growth factor (FGF). In addition, CsA promoted the secretion and volume increase in vesicles in the CsA-treated group compared with the control group. Therefore, CsA may promote the adhesion and invasion of trophoblast cells through LIF and FGF and promote the vesicle dynamic process, which is conducive to embryo implantation. [ABSTRACT FROM AUTHOR]

Background: The management of post-refractive surgery dry eye disease (DED) can be challenging in clinical practice, and patients usually show an incomplete response to traditional artificial tears, especially when it is complicated with ocular pain. Therefore, we aim to investigate the efficacy of combined topical 0.05% cyclosporine A and 0.1% sodium hyaluronate treatment in post-refractive surgery DED patients with ocular pain unresponsive to traditional artificial tears. Methods: We enrolled 30 patients with post-refractive surgery DED with ocular pain who were unresponsive to traditional artificial tears. Topical 0.05% cyclosporine A and 0.1% sodium hyaluronate were used for 3 months. They were evaluated at baseline and 1 and 3 months for dry eye and ocular pain symptoms and objective parameters, including Numerical Rating Scale (NRS), Neuropathic Pain Symptom Inventory modified for the Eye (NPSI-Eye), tear break-up time (TBUT), Schirmer I test (SIt), corneal fluorescein staining (CFS), corneal sensitivity, and corneal nerve morphology. In addition, tear levels of inflammatory cytokines and neuropeptides were measured using the Luminex assay. Results: After 3 months of treatment, patients showed a statistically significant improvement in the ocular surface disease index (OSDI), TBUT, SIt, CFS, and corneal sensitivity (all P < 0.01) using linear mixed models. As for ocular pain parameters, the NRS and NPSI-Eye scores were significantly reduced (both P < 0.05) and positively correlated with the OSDI and CFS scores. Additionally, tear IL-1β, IL-6, and TNF-α levels were improved better than pre-treatment (P = 0.01, 0.03, 0.02, respectively). Conclusion: In patients with post-refractive surgery DED with ocular pain, combined topical 0.05% cyclosporine A and 0.1% sodium hyaluronate treatment improved tear film stability, dry eye discomfort, and ocular pain, effectively controlling ocular inflammation. Trial registration: Registration number: NCT06043908. [ABSTRACT FROM AUTHOR]

Background: Acute graft-versus-host disease (aGvHD) is a major cause of death for patientsfollowing allogeneic hematopoietic stem cell transplantation (HSCT). Effective management of moderate to severe aGvHD remains challenging despite recent advances in HSCT, emphasizing the importance of prophylaxis and risk factor identification. Methods: In this study, we analyzed data from 1479 adults who underwent HSCT between 2005 and 2017 to investigate the effects of aGvHD prophylaxis and time-dependent risk factors on the development of grades II–IV aGvHD within 100days post-HSCT. Results: Using a dynamic longitudinal time-to-event model, we observed a nonmonotonic baseline hazard overtime with a low hazard during the first few days and a maximum hazard at day 17, described by Bateman function with a mean transit time of approximately 11days. Multivariable analysis revealed significant time-dependent effects of white blood cell counts and cyclosporine A exposure as well as static effects of female donors for male recipients, patients with matched related donors, conditioning regimen consisting of fludarabine plus total body irradiation, and patient age in recipients of grafts from related donors on the risk to develop grades II–IV aGvHD. Additionally, we found that higher cumulative hazard on day 7 after allo-HSCT are associated with an increased incidence of grades II–IV aGvHD within 100days indicating that an individual assessment of the cumulative hazard on day 7 could potentially serve as valuable predictor for ater grades II–IV aGvHD development. Using the final model, stochastic simulations were performed to explore covariate effects on the cumulative incidence over time and to estimate risk ratios. Conclusion: Overall, the presented model showed good descriptive and predictive performance and provides valuable insights into the interplay of multiple static and time-dependent risk factors for the prediction of aGvHD. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel diseases (IBDs) have several treatment modalities including immunoregulators, like cyclosporine A, an immunosuppressant that interacts with cytoplasmic cyclophilin A, and probiotics. Aims: This study explored and compared the possible role of syndecan-1 in the IBD pathogenic process as well as the effectiveness of cyclophilin A, cyclosporine A, and their combination in the management of IBDs in the presence of probiotics. Methodology: IBD was induced in a total of 112 mice equally divided between syndecan-1 knock-out (KO) and Balb/c wild-type mice, using 2% dextran sulfate sodium (DSS) followed by intraperitoneal treatment with cyclosporine A, cyclophilin A, or a combination of both. In addition, a daily dose of probiotics was given in their drinking water. The animals were monitored for clinical signs and symptoms and checked for gross pathologies in the abdomen after 3 weeks. Descending and sigmoid colon biopsies were collected and fixed for routine microscopy or frozen for protein extraction and molecular testing for IL-6, CD3, CD147, and beta 1 integrins as well as pAkt expression. Results: The data showed that the induction of IBD in the syndecan-1 KO mice was more severe at the clinical, histological, and molecular levels than in the wild type. The combined CypA-CyA treatment showed no added inhibitory effect compared to single-drug treatment in both strains. Probiotics added to the combination was more effective in the wild type and, when used alone, its inhibition of IL-6 was the highest. As for the CD147 marker, there were more suppressions across the various groups in the KO mice except for the probiotics-alone group. Concerning CD3, it was significantly increased by the CypA-CyA complex, which led to more inflammation in the KO mice. Probiotics had little effect with the combination. In relation to beta 1 integrins, the CypA-CyA combination made no significant difference from CyA alone, and adding probiotics to the combination resulted in higher beta 1 integrin expression in the KO mice. As for pAkt, it was very well expressed and upregulated in both strains treated with DSS, but the effect was much larger in the KO mice. In brief, the CypA-CyA complex showed a decrease in the expression of pAkt, but there was no added effect of both drugs. Probiotics along with the complex had a similar reduction effects in both strains, with a greater effect in the wild-type mice, while probiotics alone led to a similar reduction in pAkt expressions in both strains. Conclusions: The differential effects of CyA, CypA, probiotics, and their combinations on the various inflammatory markers, as well as the histological alterations and clinical signs and symptoms, speak in favor of a clear role of syndecan-1 in reducing inflammation. However, probiotics need to be considered after more explorations into the mechanisms involved in the presence of CypA and CyA especially since pAkt is less active in their presence. [ABSTRACT FROM AUTHOR]

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are key determinants of drug–drug interactions (DDIs). Various drugs including the calcineurin inhibitor (CNI) cyclosporine A (CsA) exert preincubation-induced trans-inhibitory effects upon OATP1B1 and/or OATP1B3 (abbreviated as OATP1B1/3) by unknown mechanism(s). OATP1B1/3 are phosphoproteins; calcineurin, which dephosphorylates and regulates numerous phosphoproteins, has not previously been investigated in the context of preincubation-induced trans-inhibition of OATP1B1/3. Herein, we compare the trans-inhibitory effects exerted on OATP1B1 and OATP1B3 by CsA, the non-analogous CNI tacrolimus, and the non-CNI CsA analogue SCY-635 in transporter-overexpressing human embryonic kidney (HEK) 293 stable cell lines. Preincubation (10–60 min) with tacrolimus (1–10 µM) rapidly and significantly reduces OATP1B1- and OATP1B3-mediated transport up to 0.18 ± 0.03- and 0.20 ± 0.02-fold compared to the control, respectively. Both CsA and SCY-635 can trans-inhibit OATP1B1, with the inhibitory effects progressively increasing over a 60 min preincubation time. At each equivalent preincubation time, CsA has greater trans-inhibitory effects toward OATP1B1 than SCY-635. Preincubation with SCY-635 for 60 min yielded IC50 of 2.2 ± 1.4 µM against OATP1B1, which is ~18 fold greater than that of CsA (0.12 ± 0.04 µM). Furthermore, a proteomics-based screening for protein interactors was used to examine possible proteins and processes contributing to OATP1B1/3 regulation and preincubation-induced inhibition by CNIs and other drugs. A total of 861 and 357 proteins were identified as specifically associated with OATP1B1 and OATP1B3, respectively, including various protein kinases, ubiquitin-related enzymes, the tacrolimus (FK506)-binding proteins FKBP5 and FKBP8, and several known regulatory targets of calcineurin. The current study reports several novel findings that expand our understanding of impaired OATP1B1/3 function; these include preincubation-induced trans-inhibition of OATP1B1/3 by the CNI tacrolimus, greater preincubation-induced inhibition by CsA compared to its non-CNI analogue SCY-635, and association of OATP1B1/3 with various proteins relevant to established and candidate OATP1B1/3 regulatory processes. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial permeability transition pore (mPTP) opening plays a crucial role in cell death during ischemia-reperfusion injury (IRI). Cyclosporine A (CsA) inhibits mPTP opening. This study aimed to investigate the effects of CsA treatment during cardioplegia on the mitochondrial function and cardiac IRI. Methods: Landrace pigs (52.9 ± 3.7 kg) were subjected to midline sternotomy, cardiopulmonary bypass at 34°C and 90 minutes of cardiac arrest. They received either a single shot of standard 4°C cold histidine-tryptophan-α-ketoglutarate (HTK)-Bretschneider solution (n = 11) or HTK-Bretschneider plus 1.2 mg/L CsA (histidine-tryptophan-α-ketoglutarate plus cyclosporine A (HTK/CsA); n = 11). During reperfusion global left-ventricular function was assessed and myocardial biopsies were harvested at baseline, during ischemia and 45 minutes following reperfusion. High-resolution respirometry and hydrogen peroxide production were measured. Immunohistochemical stainings for apoptosis-inducing factor and hypoxia-inducible factor-1α as well as a flow cytometry-based JC-1 mitochondrial membrane potential assay were performed. Results: Hemodynamic parameters were comparable between both groups. The cytochrome C release (HTK: 930.3 ± 804.4 pg/mg, HTK/CsA: 699.7 ± 394.0 pg/mg, p = 0.457) as well as PGC1α content (HTK: 66.7%, HTK/CsA: 33.3%, p = 0.284) was lower in the HTK/CsA group. Respiratory measurements revealed that the oxygen flux under basal respiration was higher in the HTK/CsA group (8.2 ± 1.3 pmol·O2·s−1·mg−1·ww) than in the HTK group (3.8 ± 1.4 pmol·O2·s−1·mg−1·ww, p = 0.045). There were no significant differences regarding histological surrogates of apoptosis and necrosis. Conclusions: Supplementing cardioplegic solutions with CsA enhances the basal mitochondrial respiration thereby exerting a cardioprotective effect and diminishing IRI-induced damage. CsA seems to preserve mitochondrial function via non-ROS related pathways. [ABSTRACT FROM AUTHOR]

Neutrophils are an essential component of the innate immune system; however, uncontrolled neutrophil activity can lead to inflammation and tissue damage in acute and chronic diseases. Despite inclusion of neutrophil presence and activity in clinical evaluations of inflammatory diseases, the neutrophil has been an overlooked therapeutic target. The goal of this program was to design a small molecule regulator of neutrophil trafficking and activity that fulfilled the following criteria: (a) modulates neutrophil epithelial transmigration and activation, (b) lacks systemic exposure, (c) preserves protective host immunity, and (d) is administered orally. The result of this discovery program was ADS051 (also known as BT051), a low permeability, small molecule modulator of neutrophil trafficking and activity via blockade of multidrug resistance protein 2 (MRP2)‐ and formyl peptide receptor 1 (FPR1)‐mediated mechanisms. ADS051, based on a modified scaffold derived from cyclosporine A (CsA), was designed to have reduced affinity for calcineurin with low cell permeability and, thus, a greatly reduced ability to inhibit T‐cell function. In cell‐based assays, ADS051 did not inhibit cytokine secretion from activated human T cells. Furthermore, in preclinical models, ADS051 showed limited systemic absorption (

Background: In animal studies, minocycline (Mcy) has been proven to have antidepressant effects. In addition to modulating peripheral and central pro-inflammatory pathways, Mcy may regulate the hypothalamic-pituitary-adrenal (HPA) axis and the mechanistic target of rapamycin (mTOR) signaling pathway. This study aims to evaluate the antidepressant-like effect of Mcy in mice following injection of dexamethasone (Dex) or cyclosporine-A (CsA). Methods: Male NMRI mice were randomly divided into eight groups of 6, including control, Dex 0.25 mg/kg, CsA 20 mg/kg, Mcy 40 mg/kg, Dex+Mcy, Dex+fluoxetine 20 mg/kg, CsA+Mcy, and CsA+fluoxetine. All drugs were injected intraperitoneally (except for Dex, which was subcutaneous injection) once daily for 3 days. The locomotor activity, forced swimming test (FST), and sucrose preference (SP) test were performed on day 4. Results: Mcy alone reduced immobility time in the FST (27.0±6.4 s) compared to the control group (104±3.9 s) (P

Background: Pharmaceutical companies do not sell formulations for all diseases; thus, healthcare workers have to treat some diseases by concocting in-hospital preparations. An example is the high-concentration 2% cyclosporine A (CyA) ophthalmic solution. Utilizing a filter in sterility operations is a general practice for concocting in-hospital preparations, as is the case for preparing a 2% CyA ophthalmic solution. However, whether filtering is appropriate concerning the active ingredient content and bacterial contamination according to the post-preparing quality control of a 2% CyA ophthalmic solution is yet to be verified. Methods: We conducted particle size, preparation concentration, and bacterial contamination studies to clarify aforementioned questions. First, we measured the particle size of CyA through a laser diffraction particle size distribution. Next, we measured the concentration after preparation with or without a 0.45-µm filter operation using an electrochemiluminescence immunoassay. Finally, bacterial contamination tests were conducted using an automated blood culture system to prepare a 2% CyA ophthalmic solution without a 0.45 μm filtering. Regarding the pore size of the filter in this study, it was set to 0.45 μm with reference to the book (the 6th edition) with recipes for the preparation of in-hospital preparations edited by the Japanese Society of Hospital Pharmacists. Results: CyA had various particle sizes; approximately 30% of the total particles exceeded 0.45 μm. The mean ± standard deviation of filtered and non-filtered CyA concentrations in ophthalmic solutions were 346.51 ± 170.76 and 499.74 ± 76.95ng/mL, respectively (p = 0.011). Regarding bacterial contamination tests, aerobes and anaerobes microorganisms were not detected in 14 days of culture. Conclusions: Due to the results of this study, the concentration of CyA may be reduced by using a 0.45-µm filter during the preparation of CyA ophthalmic solutions, and furthermore that the use of a 0.45-µm filter may not contribute to sterility when preparing CyA ophthalmic solutions. [ABSTRACT FROM AUTHOR]

Glycyrol (GC) is one natural active product. Imiquimod-induced psoriasis-like Balb/c mouse models were established. The model mice were intraperitoneally injected with cyclosporine A (CsA) and GC for 8 days followed by a series of biological detections. GC had little toxicity according to the levels of peripheral blood cells, hemoglobin, blood urea nitrogen (BUN), and serum creatinine (CRE), while CsA significantly increased the levels of BUN and CRE. GC decreased the splenic index and reduced the expressions of IL-6, IL-23, and CXCL-3 in the model mice and IL-6, CXCL-1, and CXCL-2 in the inflammatory HaCaT cells. The half inhibition concentration (IC50) of GC on HaCaT cells was 29.72 μmol/L, resulting in improved apoptosis, enhanced expressions of p21, BAX, and BIK, and reduced expressions of BCL-2. GC is an immunosuppressive agent against psoriasis-like symptoms by anti-inflammatory effects, which provides a strategy for the discovery of anti-psoriatic natural products. [ABSTRACT FROM AUTHOR]

Objective: This study was to assess the safety and effectiveness of immunosuppressive agents, specifically Voclosporin, when used in conjunction with mycophenolate mofetil (MMF) induction therapy for the management of lupus nephritis (LN). Methods: A systematic review and network meta-analysis (NMA) was conducted on randomized controlled trials investigating the efficacy of immunosuppressant-induced therapy for LN. The random effects model was used in the analysis. I² was used to evaluate the heterogeneity of the model. Odds ratios (OR) and 95% credible intervals (CrI) were computed to assess and compare the relative effectiveness and safety of various treatment protocols. Results: The study included a total of 16 randomized controlled trials (RCTs) involving 2444 patients with LN. The analysis results indicated that there was no significant difference in terms of partial remission (PR) between the drugs. However, when considering complete remission (CR), the combination of Voclosporin with MMF showed the highest remission rate, followed by Tacrolimus (TAC). Unfortunately, Voclosporin in combination with MMF had the highest risk of infection and serious infection, indicating a lower safety profile. Conclusions: Voclosporin in combination with MMF demonstrated the highest efficacy as an induction therapy for LN. However, it should be noted that the risk of infection and serious infection was found to be high with this regimen. On the other hand, TAC not only showed efficacy but also had a lower risk of infection and serious infection, making it a favorable option in terms of safety. This study did' not include results on other adverse events. [ABSTRACT FROM AUTHOR]

In order to facilitate therapeutic drug monitoring of tacrolimus and cyclosporine A in clinical practice, a simple, rapid, robust, sensitive and specific LC–MS/MS assay was developed and validated for the simultaneous determination of tacrolimus and cyclosporine A in human whole blood. Erythrocytes were destroyed using internal standard solution with 10% (w/v) zinc sulfate in water. The analytes were extracted from 100 μl of whole blood by protein precipitation with acetonitrile. Chromatographic separation was conducted on a Kinetex PFP column (60°C) by a gradient elution with a flow rate of 0.450 ml/min in 2.5 min. Quantitative analysis was performed using electrospray ionization and multiple reaction monitoring in positive ionization mode. The method was fully validated as per current guidelines on bioanalytical methodologies of the US Food and Drug Administration and European Medicines Agency. The method developed was applied successfully in analyzing clinical samples from patients administered tacrolimus or cyclosporine A. The sample treatment procedure was rationalized and improved to fulfill the complete target extraction. The chromatography conditions were optimized to achieve rapid and accurate quantification of both analytes. This method may be beneficial as a constructive input for the therapeutic drug monitoring of tacrolimus and cyclosporine A in obtaining individualized therapy. [ABSTRACT FROM AUTHOR]

Background: Dry eye disease (DED) is a disorder characterized by loss of tear film homeostasis that causes ocular surface inflammation and damage. The incidence of DED increases with age. Cyclosporine ophthalmic solution 0.09% (CEQUA®; OTX-101), cyclosporine ophthalmic emulsion 0.05% (Restasis®; CsA), and lifitegrast ophthalmic solution 5% (Xiidra®; LFT) are anti-inflammatory agents indicated for DED. This analysis compared treatment patterns in patients with DED receiving OTX-101, CsA, or LFT. Methods: This real-world, retrospective, longitudinal cohort study utilized Symphony Health Integrated Dataverse claims from July 2019 to June 2021. The dataset included all patients with OTX-101 claims and patients with CsA or LFT claims randomly selected 2:1 to OTX-101. Patients were sorted into 3 cohorts based on index treatment. Index date was that of first treatment claim, and follow-up period was from index date to end of clinical activity or data availability. Time to treatment discontinuation (TTD), probability of discontinuation, and treatment persistence were assessed for OTX-101 vs. CsA, then OTX-101 vs. LFT. Subgroup analysis was performed based on age and prior DED treatment. Kaplan-Meier analysis and log-rank test were used to examine TTD. A logistic model evaluated association between index treatment and discontinuation. Unadjusted and adjusted odds ratios, 95% confidence intervals, and P-values were reported, with statistically significant associations based on P-values < 0.05. Results: Overall, 7102 patients (OTX-101 n = 1846; CsA n = 2248; LFT n = 3008) were eligible. Median TTD was 354 days for patients receiving OTX-101 vs. 241 days for CsA and 269 days for LFT. Log-rank test indicated TTD was significantly longer for patients on OTX-101 vs. CsA (P = 0.033). Patients on CsA were 35% more likely to discontinue treatment than patients on OTX-101; OTX-101 and LFT groups had similar discontinuation rates. After 360 days, 49.8% of patients receiving OTX-101 remained on treatment vs. 39.4% of patients on CsA (P = 0.036) and 44.0% of patients on LFT (P = 0.854). Conclusions: Patients receiving OTX-101 remained on treatment significantly longer and were significantly less likely to discontinue treatment than patients on CsA. Older patients remained on OTX-101 significantly longer than CsA. These findings highlight treatment pattern differences in patients with DED receiving these anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

In this study, the extra-fine dry powder inhalers (DPIs) with chitosan (CS) as carrier were successfully prepared by ionic gel method combined with spray drying technique for deep pulmonary drug delivery of Cyclosporine A (CsA), using sodium hyaluronate (SHA) and sodium polyglutamate (SPGA) as polyanions. The CsA-loaded DPIs of CS-SHA-CsA and CS-SPGA-CsA were spherical particles with wrinkles on the surface, which were more conducive to improving the aerosol properties. The aerodynamic evaluation of CS-SHA-CsA and CS-SPGA-CsA showed that the fine particle fraction (FPF) reached up to 79.22 ± 2.12% and 81.55 ± 0.43%, while the emitted fraction (EF) reached 77.15 ± 1.46% and 78.29 ± 2.10%. In addition, the mass median aerodynamic diameter (MMAD) was calculated as 1.58 ± 0.04 μm and 1.94 ± 0.02 μm for CS-SHA-CsA and CS-SPGA-CsA, indicating that they were all extra-fine particles (d < 2 μm). These in vitro aerodynamic results showed that CS-SHA-CsA and CS-SPGA-CsA could reach the smaller airways, further improving therapeutic efficiency. The cell viability on A549 cell line results showed that CS-SHA-CsA and CS-SPGA-CsA were safe to deliver CsA to lungs. The in vivo pharmacokinetics consequence proved that inhalation administration of CS-SHA-CsA and CS-SPGA-CsA could significantly improve the bioavailability of CsA in vivo compared with oral administration of Neoral®, effectively reducing the risk of a series of adverse effects caused by systemic overexposure. In addition, the safety and compatibility of DPIs using SHA, SPGA, and CS as carriers for pulmonary drug delivery was verified by in vivo repeated dose inhalation toxicity. From these findings, the extra-fine DPIs with CS as carrier could be a viable delivery option for the deep pulmonary drug delivery of CsA relative to orally administered drug. [Display omitted] • CS nanoparticles were successfully prepared in a short reaction time. • CsA loaded CS DPIs had fine aerosol characteristics and could be delivered into the deep lungs. • Inhalable DPIs could significantly improve the bioavailability of CsA in vivo compared with oral administration of Neoral®. • Repeated dose inhalation toxicity assessment in vivo proved the safety and tolerability of DPIs in the lungs. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is an idiopathic, chronic, relapsing disease. In most cases, only the distal colon is affected, and the colonic stasis or fast colonic transit through the inflamed colon usually results in reduced exposure of the distal inflamed colon. Although the immunosuppressant cyclosporine A (CsA) has been used in patients with severe colitis who do not respond to corticosteroids, the clinical application of CsA remains limited due to the systemic toxicities and insufficient accumulation at the site of action for the intravenous and oral routes. In this study, we loaded CsA into the amphipathic poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) micelles and then embedded them in hydrogels consisting of chitosan, poloxamer 188, and poloxamer 407 to construct a thermosensitive and mucoadhesive hydrogel drug delivery system (PLCP). The PLCP presented a high drug-loading capacity and showed a stable and rapid gelation rate after rectal administration into the body. Compared to CsA-loaded micelles and Sandimmun (Neoral®), the developed thermosensitive gel exhibited prolonged retention on the inflamed colon, as seen from in vitro adhesion and in vivo distribution experiments. It also fast mitigated colitis symptoms in TNBS-treated mice by regulating the expression levels of proinflammatory cytokines (TNF-α, IL-1β, COX-2, and iNOS2), anti-inflammatory cytokines (IL-10, Nrf2, NQO1, and HO-1), and other relevant biochemical factors. Our results suggested that CsA-loaded micelle thermal hydrogel system could be a promising strategy by enhancing the retention in the diseased colon and promoting the relief and recovery of UC. [ABSTRACT FROM AUTHOR]

AIM: To systematically evaluate the safety and efficacy of 0.05% cyclosporine A(CsA)in the treatment of dry eye.METHODS: PubMed, Web of Science, Cochrane Library, Embase, Chinese Bio-Medical Literature Database, CNKI, VIP, and Wan Fang Database were retrieved. Randomized controlled trials related to the treatment of dry eye with 0.05%CsA from January 1, 2016 to March 28, 2022 in each database were included. The CsA group was treated with 0.05% CsA eye drops, and the control group was treated with artificial tears and placebo. ReMan 5.3 was used for Meta-analysis of post-treatment Schirmer Ⅰ test(SⅠt), break up time(BUT), corneal fluorescein staining(CFS), ocular surface disease index(OSDI)and adverse effects.RESULTS: A total of 13 literatures were included, which included 1 164 cases(2 057 eyes). Compared with the control group, the SIt in the CsA group was prolonged(MD=2.04, 95%CI: 1.75～2.33, P

Background Dry eye disease (DED) is a common ophthalmic disorder which affects 5–50% of the global population. Aim The aim of this study was to compare the effects of topical application of cyclosporine A (CsA) to prednisolone in patients with DED. Patients and methods The study included 40 patients diagnosed with DED. They were randomly divided into two groups: group A patients received treatment with topical 0.05% CsA twice a day, and group B patients received treatment with topical 1% prednisolone four times a day for 1 month. All patients were examined at three visits: before treatment, after 2 weeks, and 1 month after the intervention to show the effect of the two drugs on the tear break-up time (TBUT), Schirmer’s score, ocular surface disease index (OSDI), and surface stain, in addition to assessment of the patient’s DED-related symptoms. Results In the prednisolone group, the pretreatment Schirmer’s test results were 3.05±1.57 and 2.35±1.57 mm for the right (OD) and left eyes (OS), respectively. It improved to 5.65±2.30 and 5.85±2.43 mm, respectively 2 weeks after discontinuation of treatment (posttreatment). Similarly, the pretreatment values for the CsA group were 1.35±1.57 and 2.0±1.52 mm and became 5.65±2.30 and 5.85±2.434 mm, respectively after treatment. There was a statistically significant difference between the two groups regarding the pretreatment (P=0.001) and posttreatment (P=0.026) Schirmer’s test results. In the prednisolone group, the pretreatment TBUT was 4.20±1.61 and 3.85±1.09 s and improved to 6.60±1.31 and 6.85±1.42 s, respectively after treatment. Similarly, in the CsA group the pretreatment values were 2.65±1.81 and 3.30±1.38 s and became 8.65±1.69 and 9.30±1.42 s, respectively, posttreatment. In addition, there was a statistically significant difference between the studied groups regarding the pretreatment (P=0.007) and posttreatment TBUT (P0.05). The surface stain improved in both groups after treatment, with the prednisolone group showing the greatest improvement at 2 weeks (P=0.002). However, there was no statistically significant difference between the two groups at 1 month (P>0.05). Conclusion Both topical CsA and prednisolone demonstrated effectiveness in treating moderate to severe DED cases and were comparable. Prednisolone showed a greater improvement in OSDI (that assesses the DED-related symptoms) and surface stain, while CsA was associated with more improvement in Schirmer’s test and TBUT.

PURPOSE: The purpose is to compare the effects of cyclosporine (CsA) on the steroid-refractory mixed-type dry eye (MTDE) and aqueous deficient dry eye (ADDE). MATERIALS AND METHODS: We retrospectively enrolled 71 patients with levels 3 and 4 dry eye that were refractory to artificial tears and topical steroids. The effects were analyzed using the ocular surface disease index (OSDI) and standard patient evaluation of eye dryness (SPEED) questionnaires, Schirmer test II, blink patterns, lipid layer thickness (LLT), meibomian gland expressibility (MGE) and extent of meibomian gland (MG) dropout (meiboscale). RESULTS: MTDE patients (LLT ≤60 nm, n = 38) were younger than those in ADDE (LLT >60 nm, n = 33). Before CsA treatment, they had higher Schirmer scores, less MGE, and a thinner LLT. There was no statistically significant difference in OSDI/SPEED scores between groups. CsA improved the OSDI in the ADDE group but not in the MTDE group. CsA treatment decreased the severity of superficial punctate keratitis (SPK) in both groups, but it significantly decreased partial blinks, total blinks, and partial blink rates in the ADDE group only. CsA did not increase the Schirmer score, LLT, MGE, or meiboscale grade in both groups. CsA could significantly improve subjective symptoms, SPK, and blink patterns in dry eyes refractory to topical steroids, which were more pronounced in ADDE than in MTDE. CONCLUSION: In MTDE cases, concurrent MG treatment modalities, such as intense pulse light and/or thermal pulsation, could be considered to maximize the effects of CsA treatment.

Cyclosporine A (CsA) is a secondary cyclopeptide metabolite produced by Tolypocladium inflatum that is widely used clinically as an immunosuppressant. CsA production and mycelial growth differed when T. inflatum was cultured in different carbon source media. During early fermentation, CsA was preferred to be produced in fructose medium, while the mycelium preferred to accumulate in sucrose medium. On the sixth day, the difference was most pronounced. In this study, high-throughput comparative proteomics methods were applied to analyze differences in protein expression of mycelial samples on day 6, revealing the proteins and mechanisms that positively regulate CsA production related to carbon metabolism. The differences included small molecule acid metabolism, lipid metabolism, organic catabolism, exocrine secretion, CsA substrate Bmt synthesis, and transcriptional regulation processes. The proteins involved in the regulation of mycelial growth related to carbon metabolism were also revealed and were associated with waste reoxidation processes or coenzyme metabolism, small molecule synthesis or metabolism, the stress response, genetic information or epigenetic changes, cell component assembly, cell wall integrity, membrane metabolism, vesicle transport, intramembrane localization, and the regulation of filamentous growth. This study provides a reliable reference for CsA production from high-efficiency fermentation. This study provides key information for obtaining more CsA high-yielding strains through metabolic engineering strategies.

The objective of present study is to identify the adverse effects of cyclosporine A drug and the protective role of garlic in cytotoxicity test, including sperms deformation and histological changes in testes tissues of male albino rats. The study recorded significant increase p≥0.05 in sperms head and tail deformation rates in groups that were administrated cyclosporine and cyclosporine + garlic for two weeks compared with control groups which were administrated olive oil and garlic. The study reported significant decrease p≥0.05 in sperms head and tail deformation rates in the group that was administrated cyclosporine + garlic compared with group that was administrated cyclosporine only. In addition, the study also indicated histological changes in testes tissues including degenerative changes represented by depletion of the spermatogonial cells (some seminiferous tubules appeared with one or two layers of spermatogonia) in the group that was administrated cyclosporine compared with the control group which was administrated olive oil. The study reported slight histological changes in testes tissues from normal testes architecture, somniferous tubules with maturation of spermatogony and sperms inside the lumen in group that was administrated cyclosporine + garlic for two weeks compared with the control group which was administrated olive oil and garlic. Finally, the findings showed reduction in histological changes of testes tissues in group which was administrated cyclosporine + garlic for two weeks compared with group which was administrated cyclosporine only. [ABSTRACT FROM AUTHOR]

One strategy to prevent islet rejection is to create a favorable immune-protective local environment at the transplant site. Herein, we utilize localized cyclosporine A (CsA) delivery to islet grafts via poly(lactic-co-glycolic acid) (PLGA) microparticles to attenuate allograft rejection. CsA-eluting PLGA microparticles were prepared using a single emulsion (oil-in-water) solvent evaporation technique. CsA microparticles alone significantly delayed islet allograft rejection compared to islets alone (p < 0.05). Over 50% (6/11) of recipients receiving CsA microparticles and short-term cytotoxic T lymphocyte-associated antigen 4-Ig (CTLA4-Ig) therapy displayed prolonged allograft survival for 214 days, compared to 25% (2/8) receiving CTLA4-Ig alone. CsA microparticles alone and CsA microparticles + CTLA4-Ig islet allografts exhibited reduced T-cell (CD4+ and CD8+ cells, p < 0.001) and macrophage (CD68+ cells, p < 0.001) infiltration compared to islets alone. We observed the reduced mRNA expression of proinflammatory cytokines (IL-6, IL-10, INF-γ, and TNF-α; p < 0.05) and chemokines (CCL2, CCL5, CCL22, and CXCL10; p < 0.05) in CsA microparticles + CTLA4-Ig allografts compared to islets alone. Long-term islet allografts contained insulin+ and intra-graft FoxP3+ T regulatory cells. The rapid rejection of third-party skin grafts (C3H) in islet allograft recipients suggests that CsA microparticles + CTLA4-Ig therapy induced operational tolerance. This study demonstrates that localized CsA drug delivery plus short-course systemic immunosuppression promotes an immune protective transplant niche for allogeneic islets. [ABSTRACT FROM AUTHOR]

The purpose of this study was to prepare large hollow particles (LHPs) by spray drying for pulmonary delivery of cyclosporine A (CsA), using L-Leucine (LEU) and hydroxypropyl methylcellulose (HPMC) as excipients and ammonium bicarbonate (AB) as a porogen. The prepared LHPs were spherical particles composed of both CsA and LEU on the surface and HPMC on the inner layer. The formulation of CsA-LEU-0.8HPMC-AB as typical LHPs showed excellent in vitro aerodynamic performance with a minimum mass median aerodynamic diameter (MMAD) of 1.15 μm. The solubility of CsA-LEU-0.8HPMC-AB was about 5.5-fold higher than that of raw CsA, and the dissolution of CsA-LEU-0.8HPMC-AB suggested that the drug was released within 1 h. The cell viability of the A549 cell line showed that CsA-LEU-0.8HPMC-AB was safe for delivering CsA to the lungs. In addition, inhalation administration of CsA-LEU-0.8HPMC-AB with the Cmax and AUC0–∞ increasing by about 2-fold and 2.8-fold compared with the oral administration of Neoral® could achieve therapeutic drug concentrations with lower systemic exposure and significantly improve the in vivo bioavailability of CsA. From these findings, the LHPs, with the advantage of avoiding alveolar macrophage clearance, could be a viable choice for delivering CsA by inhalation administration relative to oral administration. [ABSTRACT FROM AUTHOR]

Pachymaran (PCP), the major medicinal constituent of Poria cocos, has a regulatory effect on immunosuppressive lung injury, but its mechanism of action with respect to gut microorganisms and their metabolites is not clear. The aim of this study was to investigate the protective effect of PCP against immunosuppressive lung injury caused by cyclosporine A (CsA), and to reveal its possible mechanism of action via the comprehensive analysis of 16S rRNA and LC-MS. We demonstrated that PCP was effective at alleviating CsA-induced immunosuppressive lung injury by restoring the organ indices and lung tissue morphology and structure. PCP significantly altered the composition of the gut and lung microbiota in mice with CsA-induced immunosuppressive lung injury by increasing the number of beneficial bacteria from the Eubacterium nodatum group, Eubacterium ventriosum group, Akkermansia, and Ruminococcus, and reducing the pathogenic Rikenellaceae RC9 gut group to fulfill its immunomodulatory role. In lung tissue microecology, PCP intervention significantly reduced the abundance of Chryseobacterium, Lawsonella, Paracoccus, and Sediminibacterium and increased the abundance of Alloprevotella. The LC-MS results showed that PCP alleviated the CsA-induced immunosuppression of lung tissue injury. The model serum metabolite Americine decreased the expression of PC(O-18:1(4Z)/0:0). Our results suggest that PCP may be involved in regulating the composition, function, and metabolism of the gut and lung microbiota to reverse CsA-induced immunosuppressive lung injury. [ABSTRACT FROM AUTHOR]

Cyclosporine A (CsA) is used for the treatment of dry eye (DE) with good clinical results, improving tear secretion and decreasing subjective symptoms. These effects are attributed to the improved tear film dynamics, but there are no data on the effect of CsA on the abnormal sensory nerve activity characteristic in DE. Our purpose was to evaluate the CsA effect on the enhanced activity of corneal cold thermoreceptors in a tear-deficient DE animal model using in vitro extracellular recording of cold thermoreceptors nerve terminal impulses (NTIs) before and in the presence of CsA. NTI shape was also analyzed. Blinking frequency and tearing rate were also measured in awake animals before and after topical CsA. CsA increased the tearing and blinking of treated animals. CsA significantly decreased the peak response to cold of cold thermoreceptors. Neither their spontaneous NTIs discharge rate nor their cooling threshold were modified. CsA also seemed to reverse some of the changes in NTI shape induced by tear deficiency. These data suggest that, at least in part, the beneficial clinical effects of CsA in DE can be attributed to a direct effect on sensory nerve endings, although the precise mechanisms underlying this effect need further studies to be fully clarified. [ABSTRACT FROM AUTHOR]

The mitochondrial permeability transition pore (mPTP) is a channel in the mitochondrial inner membrane that is activated by excessive calcium uptake. In this study, we used a whole-mitoplast patch-clamp approach to investigate the ionic currents associated with mPTP at the level of the whole single mitochondrion. The whole-mitoplast conductance was at the level of 5 to 7 nS, which is consistent with the presence of three to six single mPTP channels per mitochondrion. We found that mPTP currents are voltage dependent and inactivate at negative potential. The currents were inhibited by cyclosporine A and adenosine diphosphate. When mPTP was induced by oxidative stress, currents were partially blocked by the adenine nucleotide translocase inhibitor bongkrekic acid. Our data suggest that the whole-mitoplast patch-clamp approach is a useful method for investigating the biophysical properties and regulation of the mPTP. [ABSTRACT FROM AUTHOR]

Cyclosporine A (CsA) is an immunosuppressant primarily used at a higher dosage in transplant medicine and autoimmune diseases with a higher success rate. At lower doses, CsA exhibits immunomodulatory properties. CsA has also been reported to inhibit breast cancer cell growth by downregulating the expression of pyruvate kinase. However, differential dose–response effects of CsA in cell growth, colonization, apoptosis, and autophagy remain largely unidentified in breast cancer cells. Herein, we showed the cell growth-inhibiting effects of CsA by preventing cell colonization and enhancing DNA damage and apoptotic index at a relatively lower concentration of 2 µM in MCF-7 breast cancer cells. However, at a higher concentration of 20 µM, CsA leads to differential expression of autophagy-related genes ATG1, ATG8, and ATG9 and apoptosis-associated markers, such as Bcl-2, Bcl-XL, Bad, and Bax, indicating a dose–response effect on differential cell death mechanisms in MCF-7 cells. This was confirmed in the protein–protein interaction network of COX-2 (PTGS2), a prime target of CsA, which had close interactions with Bcl-2, p53, EGFR, and STAT3. Furthermore, we investigated the combined effect of CsA with SHP2/PI3K-AKT inhibitors showing significant MCF-7 cell growth reduction, suggesting its potential to use as an adjuvant during breast cancer therapy. [ABSTRACT FROM AUTHOR]

Neutrophils are an essential component of the innate immune system; however, uncontrolled neutrophil activity can lead to inflammation and tissue damage in acute and chronic diseases. Despite inclusion of neutrophil presence and activity in clinical evaluations of inflammatory diseases, the neutrophil has been an overlooked therapeutic target. The goal of this program was to design a small molecule regulator of neutrophil trafficking and activity that fulfilled the following criteria: (a) modulates neutrophil epithelial transmigration and activation, (b) lacks systemic exposure, (c) preserves protective host immunity, and (d) is administered orally. The result of this discovery program was ADS051 (also known as BT051), a low permeability, small molecule modulator of neutrophil trafficking and activity via blockade of multidrug resistance protein 2 (MRP2)‐ and formyl peptide receptor 1 (FPR1)‐mediated mechanisms. ADS051, based on a modified scaffold derived from cyclosporine A (CsA), was designed to have reduced affinity for calcineurin with low cell permeability and, thus, a greatly reduced ability to inhibit T‐cell function. In cell‐based assays, ADS051 did not inhibit cytokine secretion from activated human T cells. Furthermore, in preclinical models, ADS051 showed limited systemic absorption (<1% of total dose) after oral administration, and assessment of ADS051 in human, cell‐based systems demonstrated inhibition of neutrophil epithelial transmigration. In addition, preclinical toxicology studies in rats and monkeys receiving daily oral doses of ADS051 for 28 days did not reveal safety risks or ADS051‐related toxicity. Our results to date support the clinical development of ADS051 in patients with neutrophil‐mediated inflammatory diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] Although the efficacy of Cyclosporine A (CsA) in the management of ocular inflammation is well-demonstrated, ocular delivery remains challenging due to its hydrophobic nature. The semifluorinated alkane, perfluorobutylpentane (F4H5) has previously been suggested as an efficient vehicle for preparation of CsA eyedrops. Here we evaluated the influence of drop volume and the formulation aid, ethanol (EtOH), on ocular penetration of CsA and compared it to that of the commercial eyedrop, Ikervis, ex vivo and in vivo. Moreover, conjunctival and corneal tolerability after EtOH addition were evaluated ex vivo. The F4H5/EtOH vehicle was well tolerated and resulted in better corneal CsA penetration (AUC (0 – 4h) : 63,008 ± 3,946 ng.h.g−1) than Ikervis (AUC (0 – 4h) : 10,328 ± 1,462 ng.h.g−1) or F4H5 alone (AUC (0 – 4h) : 50,734 ± 3,472 ng.h.g−1) ex vivo. Interestingly, in vivo the CsA concentration in cornea, conjunctiva and lacrimal glands observed after administration of the F4H5 formulation (AUC (0.133-24h) : 7,741 ± 1,334 ng.h.g−1, 1,313 ± 291 ng.h.g−1, 48.2 ± 26.3 ng.h.g−1) and F4H5/EtOH, both at a reduced dose of 11 µl (AUC (0.133-24h) : 9,552 ± 1,738 ng.h.g−1, 1,679 ± 285 ng.h.g−1, 50.3 ± 21.1 ng.h.g−1) was similar or even greater than that observed on administration of 50 µl Ikervis (AUC (0.133-24h) : 9,943 ± 1,413 ng.h.g−1, 2,069 ± 263 ng.h.g−1, 30.6 ± 18.4 ng.h.g−1). Thus, F4H5-based eyedrops were shown to deliver CsA more efficiently to anterior ocular tissues at a reduced dose in comparison to Ikervis, reducing dose wastage and minimizing any potential systemic side effects. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to determine the therapeutic efficacy of 0.05% topical cyclosporine A (CsA) for chronic ocular surface disease (OSD) in patients using benzalkonium chloride (BAK)-preserved antiglaucoma eye drops. Methods: A prospective, randomized, paired-eye, controlled clinical trial was conducted with participants who had been instilling at least one BAK-preserved topical antiglaucoma drug in both eyes for at least 6 months. Topical CsA was only applied in randomly selected unilateral eyes. Visual field (VF) indices, ocular surface parameters, tear meniscus height (TMH), and matrix metalloproteinase-9 (MMP-9) immunoassay were evaluated at baseline and at 2 and 4 months. Results: Seventy eyes from 35 participants were included in the study. The Schirmer I, tear breakup time, and TMH increased by 4.5 ± 8.6 mm (P < 0.01), 5.0 ± 5.3 s (P < 0.001), and 85.4 ± 159.0 μm (P < 0.01) in the treated eyes at 4 months from baseline, respectively. The ocular staining score and MMP-9 positivity in the treated eyes decreased by 2.2 ± 1.3 (P < 0.001) and 0.7 ± 0.9 points (P < 0.001), respectively, at 4 months. In untreated eyes, only TMH increased by 41.4 ± 92.1 μm (P = 0.016) from baseline to 4 months. In VF indices, the tracking failure frequency was 19.09% ± 21.62%, and the test duration was 336.0 ± 79.5 s in the treated eyes at 4 months, which were lower than 34.37% ± 23.13% (P < 0.001) and 375.9 ± 70.7 s (P < 0.05) in the nontreated eyes. Conclusion: Application of topical 0.05% CsA significantly improved the OSD parameters and the reliability indices of VF tests. This study was registered with the Clinical Research Information Service (CRIS) (number KCT0007124). [ABSTRACT FROM AUTHOR]

Purpose: To assess the efficacy and safety of dupilumab combined with cyclosporine A in patients with atopic dermatitis. Methods: This retrospective study enrolled 100 patients with atopic dermatitis who received treatment at Beijing Luhe Hospital between November 2020 and November 2022. The patients were randomly divided into two groups, namely, treatment group and comparison group, with 50 cases in each group. Comparison group received cyclosporine A, while the treatment group received dupilumab in addition to cyclosporine A. The various fficacy scores and adverse reactions between the two groups were recorded and compared. Results: After treatment, skin lesion area and severity, EASI score, NRS score, SCORAD score, POEM score and DLQI score in the treatment group were significantly lower than those in the comparison group (p < 0.05). Conclusion: The combination of dupilumab and cyclosporine A significantly alleviates the symptoms of acne and pruritis, as well as reduce the area of skin lesions in patients with atopic dermatitis. This treatment also enhances the quality of life of the patients. However, further but larger clinical trials are required prior to adoption of this combination treatment in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Cyclosporine A (CsA)-induced cardiac interstitial fibrosis and cardiac hypertrophy are highly known phenomena; however, the basic mechanisms of CsA cardiotoxicity are unclear. The present study evaluated the role of the Transforming growth factor-beta (TGF-β)/Smad3/miR-29b signaling pathway and CaMKIIδ isoforms gene expression in cardiac remodeling under CsA exposure alone or combined with moderate exercise. Methods: A total of 24 male Wistar rats were divided into control, cyclosporine (30 mg/kg BW), and cyclosporine-exercise groups. Results: After 42 days of treatment, the findings revealed a significant decline in miR-29 and miR-30b-5p gene expression and an increase in gene expression of Smad3, calcium/calmodulin-dependent protein kinaseIIδ (CaMKIIδ) isoforms, Matrix Metalloproteinases (MMPs), protein expression of TGF-β, heart tissue protein carbonyl and oxidized LDL (Ox-LDL), and plasma LDL and cholesterol levels in the CsA-treated group compared to the control group. The CsA group presented greater histological heart changes such as fibrosis, necrosis, hemorrhage, infiltrated leukocyte, and left ventricular weight/heart weight than the control group. Moreover, combined moderate exercise and CsA relatively improved gene expression changes and histological alternations compared to the CsA group. Conclusion: TGF-β-Smad3-miR-29 and CaMKIIδ isoforms may mainly contribute to the progression of heart fibrosis and hypertrophy due to CsA exposure, providing new insight into the pathogenesis and treatment of CsA-induced side effects on the heart tissue. [ABSTRACT FROM AUTHOR]