The effect of cyclosporine a in pterygium surgery using fibrin glue.

BACKGROUND/OBJECTIVES: To evaluate the effect of topical cyclosporine A (CsA) 0.05% in patients with pterygium surgery using fibrin glue (FG). SUBJECTS/METHODS: Patients with primary nasal pterygium were retrospectically analyzed and categorized into two groups: Group 1 with 41 eyes from 38 patients as a control group and group 2 with 39 eyes from 36 patients who received topical CsA twice a day for 6 months. Patients were assessed for recurrence rate, tear film parameters, side effects, and complications at postoperative intervals of 1-7 days; 1st, 3rd, 6th and 12th months. The follow-up period was 1 year. RESULTS: The two groups were age (p = 0.934) and sex (p = 0.996) matched. CsA drop was discontinued in one patient due to burning sensation and conjunctival hyperemia after 1 week. There was no statistically significant difference between the mean preoperative and postoperative 1st year Schirmer I and tear break-up time (TBUT) values in group 1 (p = 0.136; p = 0.069). Although the difference between the mean preoperative and postoperative 1st year TBUT values in group 2 was not statistically different (p = 0.249), Schirmer I results were higher postoperatively (p = 0.003). There was no statistically significant difference between preoperative Schirmer (p = 0.496), postoperative Schirmer (p = 0.661), preoperative TBUT (p = 0.240) and postoperative TBUT (p = 0.238) results of the two groups. Recurrence was observed in only one patient from group 1. CONCLUSION: No recurrent pterygium cases were observed in group 2. Schirmer I values were higher postoperatively in group 2; thus,topical CsA treatment may improve lacrimal secretion and be effective after pterygium surgery with FG.

Clinical, histologic, and immunologic signatures of Small Fiber Neuropathy in Systemic Lupus Erythematosus.

BACKGROUND AND OBJECTIVES: Systemic Lupus Erythematosus (SLE) often causes damage to small nerve fibers, leading to distressing painful and autonomic symptoms. Despite this, Small Fiber Neuropathy (SFN) remains an underrecognized complication for SLE patients. In this cross-sectional study, we aimed to assess SFN in patients with SLE and to explore its correlations with immunologic disease features and clinical manifestations. METHODS: We recruited 50 SLE patients (1 male to 12.5 females, aged 20-80 years) reporting painful disturbances. We conducted a comprehensive clinical and neurophysiological evaluation, using Nerve Conduction Studies and Quantitative Sensory Testing. Additionally, we carried out an extensive laboratory assessment of disease-related serological parameters. We also performed a thorough skin biopsy analysis, investigating somatic and autonomic innervation while detecting complement and inflammatory cell infiltrates within the skin. RESULTS: Out of 50 patients, 19 were diagnosed with SFN, primarily characterized by a non-length-dependent distribution; 7 had a mixed neuropathy, with both large and small fiber involvement. Patients with SFN were younger than patients with a mixed neuropathy (p = .0143); furthermore, they were more likely to have a history of hypocomplementemia (p = .0058) and to be treated with cyclosporine A (p = .0053) compared to patients without neuropathy. However, there were no significant differences in painful and autonomic symptoms between patients with and without SFN. DISCUSSION: This study highlights the relevant frequency of SFN with a non-length-dependent distribution among SLE patients experiencing painful symptoms. Indeed, SFN emerges as an early manifestation of SLE-related neuropathy and is closely associated with hypocomplementemia, suggesting a potential pathogenic role of the complement system. Moreover, SFN may be influenced by disease-modifying therapies. However, the precise role of SFN in shaping painful and autonomic symptoms in patients with SLE remains to be fully elucidated.

Plasma Venetoclax Concentrations in Patients with Acute Myeloid Leukemia Treated with CYP3A4 Inhibitors.

Venetoclax (VEN) is used in patients with acute myeloid leukemia (AML) and is primarily metabolized by CYP3A4, a major drug-metabolizing enzyme. Patients with AML simultaneously administered VEN and CYP3A4 inhibitors require a more appropriate management of drug-drug interactions (DDIs). Here, we report two cases of patients with AML (54-year-old man and 22-year-old woman) administrated VEN and CYP3A4 inhibitors, such as posaconazole, cyclosporine, or danazol. In the first case, we evaluated the appropriateness of timing for adjusting VEN dosage subsequent to the cessation of posaconazole. Consequently, modifying the VEN dosage in conjunction with the cessation of Posaconazole simultaneously may result in elevated plasma VEN levels. In the second case, plasma VEN concentrations were markedly elevated when co-administered with several CYP3A4 inhibitors. Additionally, in vitro assays were conducted for reverse translational studies to analyze CYP3A4 inhibition. CYP3A4 inhibition by combinatorial administration of cyclosporine A and danazol was demonstrated in vitro, which potentially explains the increasing plasma VEN concentrations observed in clinical settings. Although the acquisition of therapeutic effects is a major priority for patients, frequent therapeutic drug monitoring and dosage adjustments considering DDIs would be important factors in chemotherapy.

Drug-Modified Contact Lenses-Properties, Release Kinetics, and Stability of Active Substances with Particular Emphasis on Cyclosporine A: A Review.

The following review focuses on the manufacturing and parameterizing of ocular drug delivery systems (DDS) using polymeric materials to create soft contact lenses. It discusses the types of drugs embedded into contact lenses, the various polymeric materials used in their production, methods for assessing the mechanical properties of polymers, and techniques for studying drug release kinetics. The article also explores strategies for investigating the stability of active substances released from contact lenses. It specifically emphasizes the production of soft contact lenses modified with Cyclosporine A (CyA) for the topical treatment of specific ocular conditions. The review pays attention to methods for monitoring the stability of Cyclosporine A within the discussed DDS, as well as investigating the influence of polymer matrix type on the stability and release of CyA.

Preliminary study of cyclosporine A/Lifitegrast subconjunctival sustained-release drug membrane in the treatment of dry eyes.

BACKGROUND: Dry eyes can cause discomfort. To treat dry eye disease, cyclosporine A (CsA) and Lifitegrast are two eye drugs approved by the U.S. Food and Drug Administration (FDA). However, frequent use of eye drops can be challenging and lead to poor compliance, especially in elderly patients. Therefore, this study aimed to develop a drug sustained-release vector and explore its therapeutic effect in animal models of dry eye. METHODS: Firstly, drug membranes loaded with both CsA and Lifitegrast using a carrier called poly(lactate-co-ε-caprolactone) (P(LLA-CL)) were prepared and evaluated for their physicochemical properties, release behavior in vitro, and safety in vivo. Next, a rabbit dry eye model using a 0.1% benzalkonium chloride (BAC) solution was developed and treated by drug-loaded micro membranes. We observed and recorded conjunctival hyperemia, corneal staining, corneal edema, corneal neovascularization, conjunctival goblet cells and hematoxylin and eosin (H&E) staining. Finally, we detected the MUC5AC and MMP-9 by immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA). RESULTS: The composite film released both CsA and Lifitegrast for at least one month. Compared to the blank membrane group, conjunctival hyperemia, corneal fluorescein staining, corneal edema, corneal neovascularization and conjunctival goblet cells recovered faster in the drug membrane group, and the difference was statistically significant. At the molecular level, the drug membrane group showed an increase in mucin density and a significant anti-inflammatory effect. CONCLUSIONS: The implantation of CsA/Lifitegrast loaded P(LLA-CL) membrane under the subconjunctival of the rabbit eye is safe. The study suggests that this subconjunctival administration could be developed into a minimally invasive delivery system to help patients with dry eye disease who require multiple daily eyedrops but have poor compliance.

Umbilical Cord Blood and UC-MSCs Combined with Low-Dose Immunosuppressant in the Treatment of Elderly Patients with Pure Red Cell Aplastic: A Case Series.

INTRODUCTION: At present, cyclosporine (CsA) is the first-line treatment for Pure Red Cell Aplasia (PRCA), but CsA administration can be associated with a number of side effects due to its high toxicity. Therefore, it is urgent to explore a safe and effective treatment for elderly patients who cannot be treated with conventional doses of CsA, especially those with multiple complications. Allogeneic Stem Cell Transplantation (ASCT) for PRCA is a promising treatment, but reports of using umbilical cord blood (UCB) are very rare. CASE PRESENTATION: In this report, UCB and umbilical cord mesenchymal stem cells (UC-MSCs) combined with low-dose CsA (1-3mg/kg/d) were used to treat 3 elderly patients who were diagnosed with PRCA combined with multiple complications in heart, lung, and renal. The treatments were successful without complications, and 12 months after stem cell infusion, the blood tests of the patients came normal. Moreover, the function of the liver, heart, and kidney continued to be stable. CONCLUSION: This report provides an effective regimen of using UCB and UC-MSCs combined with low-dose CsA (1-3 mg/kg/d) to treat PRCA, especially for elderly patients with multiple complications who cannot use the conventional dosage.

The effect of intense pulsed light combined with topical 0.05% cyclosporin an eyedrops in the treatment of Sjögren's syndrome related dry eye.

OBJECTIVES: This study aimed to assess the effectiveness and safety of intense pulsed light (IPL) therapy plus topical 0.05% cyclosporine A (CsA) eye drops to treat Sjögren's Syndrome-related dry eyes (SS-DE). RESEARCH DESIGN AND METHODS: In this prospective, randomized trial included, 60 individuals with SS-DE symptoms were randomized to receive topical eye drops containing either 0.1% sodium hyaluronate (Group S) or 0.05% CsA (Group C) plus IPL therapy. Before the first treatment (baseline), and at 12, 16, and 20 weeks after treatment commencement, we assessed the best corrected visual acuity (BCVA), the Ocular Surface Disease Index (OSDI) score, the Schirmer I test (SIT), noninvasive tear breakup time (NBUT), corneal fluorescein staining (CFS), meibomian gland (MG) dropout, lid margin abnormality, MG expressibility, and meibum quality. RESULTS: Both groups showed significant improvements in the OSDI, NBUT, CFS, MG expressibility, and meibum quality (all p < 0.05). Group C showed a greater increase in OSDI, NBUT, MG expressibility, and meibum quality (all p < 0.05). Moreover, SIT and lid margin abnormalities significantly improved in Group C (both p < 0.05), but not in Group S. CONCLUSION: Treatment with 0.05% CsA eyedrops plus IPL therapy could significantly reduce the issues and physical discomfort of patients with SS-DE. CLINICAL TRIAL: Registered on 20 July 2021, with the registration number ChiCTR2100049059.

Hypothermia, bradycardia, and hypotension during glucocorticoid or cyclosporine A therapy in a boy with Kikuchi-Fujimoto disease.

Kikuchi-Fujimoto disease (KFD) is an inflammatory disease of unknown aetiology characterised by fever and cervical lymphadenopathy. Although KFD is a self-limiting disease, patients with severe or long-lasting course require glucocorticoid therapy. We presently report a 17-year-old boy with KFD who had seven relapses since the onset at 4 years old. He suffered from hypothermia, bradycardia, and hypotension during the treatment with prednisolone or methylprednisolone. All of his vital signs recovered after cessation of the drug in addition to fluid replacement and warming. Thus, glucocorticoid was effective but could not be continued because of the adverse event. Although hypothermia developed during the treatment with 5 mg/kg/day of cyclosporine A (CsA) at his second relapse, he was successfully treated with lower-dose CsA (3 mg/kg/day). Thereafter, he had five relapses of KFD until the age of 12 years and was treated by 1.3-2.5 mg/kg/day of CsA. Hypothermia accompanied by bradycardia and hypotension developed soon after concomitant administration of ibuprofen at his fifth and sixth relapses even during low-dose CsA therapy. Conclusively, glucocorticoid, standard dose of CsA, or concomitant use of non-steroidal anti-inflammatory drugs may cause hypothermia, bradycardia, and hypotension and needs special attention. Low-dose CsA could be a choice for such cases with KFD.

Sinus bradycardia as a rare adverse event in patients receiving cyclosporine A after allogeneic hematopoietic stem cell transplantation.

Cyclosporine A (CSA) is a commonly used immunosuppressive agent for the prophylaxis of graft-versus-host disease following allogeneic hematopoietic stem cell transplantation (alloHSCT). While tachycardia is a known adverse effect of CSA, bradycardia remains a phenomenon rarely described in the literature. We conducted a retrospective evaluation of the incidence of bradycardia in patients after alloHSCT treated with CSA between January 2020 and February 2023 at our center. Out of 206 patients, sinus bradycardia following the administration of CSA was observed in 6 (2.9%), comprising 3 women and 3 men, with the median age of 55 years (range: 20-65). The underlying diseases were myeloid malignancies in 4 and aggressive lymphoma in 2 patients. The patients received grafts from a matched unrelated (n=5) or a haploidentical family donor (n=1) following various conditioning regimens. Coexisting cardiovascular disorders were found in 5 of the 6 patients. All patients experienced symptomatic bradycardia within 1-4 days (median 2 days) after CSA introduction, which persisted until CSA withdrawal. One patient required treatment with atropine. All patients continued their immunosuppressive therapy with tacrolimus, which was well-tolerated Our study indicates CSA as a causative factor of sinus bradycardia in a small percentage of alloHSCT patients receiving CSA as graft-versus host disease (GvHD) prophylaxis. Importantly, these patients did not experience any cardiac complications when switched to tacrolimus. Although further research on the effects of CSA on heart automatation is needed, our single-center experience can help prompt diagnosis and therapeutic intervention in daily clinical practice.

Membrane-Fusing Vehicles for Re-Sensitizing Transporter-Mediated Multiple-Drug Resistance in Cancer.

Reversing the multiple drug resistance (MDR) arising from the overexpression of the efflux transporters often fails mainly due to the high toxicity or the poor water solubility of the inhibitors of these transporters. Here, we demonstrate the delivery of an inhibitor targeting three ABC transporters (ABCB1, ABCC1 and ABCG2) directly to the cell membrane using membrane-fusing vehicles (MFVs). Three different transfected MDCK II cell lines, along with parental cells, were used to investigate the inhibitory effect of cyclosporine A (CsA) in solution versus direct delivery to the cell membrane. CsA-loaded MFVs successfully reversed MDR for all three investigated efflux transporters at significantly lower concentrations compared with CsA in solution. Results showed a 15-fold decrease in the IC50 value for ABCB1, a 7-fold decrease for ABCC1 and an 11-fold decrease for ABCG2. We observed binding site specificity for ABCB1 and ABCG2 transporters. Lower concentrations of empty MFVs along with CsA contribute to the inhibition of Hoechst 33342 efflux. However, higher concentrations of CsA along with the high amount of MFVs activated transport via the H-binding site. This supports the conclusion that MFVs can be useful beyond their role as delivery systems and also help to elucidate differences between these transporters and their binding sites.

Pharmacokinetic control of orally dosed cyclosporine A with mucosal drug delivery system.

This study aimed to control the oral absorption of cyclosporine A (CsA) with the use of a mucosal drug delivery system (mDDS). Mucopenetrating nanocarriers (MP/NCs) and mucoadhesive nanocarriers (MA/NCs) were prepared by flash nanoprecipitation employing polystyrene-block-poly(ethylene glycol) and polystyrene-block-poly(N,N-dimethyl aminoethyl methacrylate), respectively. Their particle distribution in the rat gastrointestinal tract were visualized by fluorescent imaging. Plasma concentrations were monitored after oral administration of CsA-loaded MP/NCs (MP/CsA) and MA/NCs (MA/CsA) to rats. MP/NCs and MA/NCs had a particle size below 200 nm and ζ-potentials of 4 and 40 mV, respectively. The results from in vitro experiments demonstrated mucopenetration of MP/NCs and mucoadhesion of MA/NCs. Confocal laser scanning microscopic images showed diffusion of MP/NCs in the gastrointestinal mucus towards epithelial cells and localization of MA/NCs on the surface of the gastrointestinal mucus layer. In a pH 6.8 solution, rapid and sustained release of CsA were observed for MP/CsA and MA/CsA, respectively. After oral dosing (10 mg-CsA/kg) to rats, amorphous CsA powder exhibited a time to maximum plasma concentration (Tmax) of 3.4 h, maximum plasma concentration (Cmax) of 0.12 µg/mL, and bioavailability of 0.7%. Compared with amorphous CsA powder, MP/CsA shortened Tmax by 1.1 to 2.3 h and increased the bioavailability by 43-fold to 30.1%, while MA/CsA prolonged Tmax by 3.4 to 6.8 h with Cmax and bioavailability of 0.65 µg/mL and 11.7%, respectively. These pharmacokinetic behaviors would be explained by their diffusion and release properties modulated by polymeric surface modification. The mDDS approach is a promising strategy for the pharmacokinetic control of orally administered CsA.

Silk Fibroin Formed Bioadhesive Ophthalmic Gel for Dry Eye Syndrome Treatment.

PURPOSE: Dry eye syndrome (DES), arising from various etiologic factors, leads to tear film instability and ocular surface damage. Given its anti-inflammatory effects, cyclosporine A (CsA) has been widely used as a short-term treatment option for DES. However, poor bioavailability and solubility of CsA in aqueous phase make the development of a cyclosporine A-based eye drop for ocular topical application a huge challenge. METHODS: In this study, a novel strategy for preparing cyclosporine A-loaded silk fibroin nanoemulsion gel (CsA NBGs) was proposed to address these barriers. Additionally, the rheological properties, ocular irritation potential, tear elimination kinetics, and pharmacodynamics based on a rabbit dry eye model were investigated for the prepared CsA NBGs. Furthermore, the transcorneal mechanism across the ocular barrier was also investigated. RESULTS: The pharmacodynamics and pharmacokinetics of CsA NBGs exhibited superior performance compared to cyclosporine eye drops, leading to a significant enhancement in the bioavailability of CsA NBGs. Furthermore, our investigation into the transcorneal mechanism of CsA NBGs revealed their ability to be absorbed by corneal epithelial cells via the paracellular pathway. CONCLUSION: The CsA NBG formulation exhibits promising potential for intraocular drug delivery, enabling safe, effective, and controlled administration of hydrophobic drugs into the eye. Moreover, it enhances drug retention within the ocular tissues and improves systemic bioavailability, thereby demonstrating significant clinical translational prospects.

Alpha-synuclein interaction with mitochondria is the final mechanism of ferroptotic death induced by erastin in SH-SY5Y cells.

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.

Vernal Keratoconjunctivitis: Immunopathological Insights and Therapeutic Applications of Immunomodulators.

Vernal keratoconjunctivitis (VKC) is a complex and multifactorial disease process that employs Th2 cell-mediated immunologic processes, which involves the overexpression of interleukin 4 (IL-4), IL-5, IL-9, IL-13, and IL-31, and the activation of mast cells that release IL-5 and CCL-11, recruiting eosinophils to the site of inflammation. The disease primarily affects young males and is more common in regions with warm climates. VKC is characterized by persistent and recurrent conjunctival inflammation that can adversely affect the patient's quality of life, and, when inadequately treated, may lead to a host of ocular complications, such as corneal shield ulcers and scarring. The major distinct forms of VKC include limbal or palpebral, which may occur in combination. The clinicopathological features of VKC include the presence of pseudogerontoxon, limbal gelatinous hyperplasia, and perilimbal hyperpigmentation. Topical immunomodulators are effective anti-steroidal options for controlling severe and chronic cases of VKC. This review will provide a brief overview of topical immunomodulators, including cyclosporin and tacrolimus, and will highlight the clinical manifestations, pathological mechanisms, and fibroproliferative changes in the conjunctiva that can result from recurrent disease.

Short-Term Efficacy of Ophthalmic Cyclosporine: A 0.1% Cationic Emulsion in Dry Eye Patients Assessed Under Controlled Environment.

INTRODUCTION: To evaluate the short-term efficacy of cyclosporine A (CsA)-0.1% cationic emulsion (CE) in patients with dry eye disease (DED) and mitigation of the inflammatory flares triggered by desiccating stress environments. METHODS: A single-center non-randomized clinical trial was performed at a tertiary care setting. Twenty patients with DED treated with CsA 0.1% CE were exposed to a normal controlled environment (NCE) (23 °C, 50% relative humidity) and an adverse controlled environment (ACE) (23 °C, 10% relative humidity, 0.43 m/s localized airflow) during baseline and the 1- and 3-month visits. Patients underwent the following evaluations: conjunctival hyperemia and staining, corneal fluorescein staining (CFS) using the Oxford and Cornea and Contact Lens Research Unit (CCLRU) scale, meibomian gland (MG) secretion quality, Dry Eye Questionnaire-5, Symptom Assessment in Dry Eye (SANDE II), and Change in Dry Eye Symptoms Questionnaire. Multivariate models were adjusted for statistical analysis. RESULTS: Nineteen women and one man (mean age, 58.9 ± 12.3 years) completed the study. All symptom questionnaires, CFS, conjunctival hyperemia and staining, and MG secretion quality improved (p ≤ 0.003) with 1 month of treatment; improvements were maintained after 3 months (p ≤ 0.02), except for SANDE II (p ≥ 0.07). The CFS worsening (total CCLRU) after baseline ACE exposure (from 8.6 to 10.1) was higher, although not significant (p = 0.64), compared with 1 month (from 5.4 to 5.8) and 3 months (from 5.0 to 5.9) after treatment. CONCLUSION: Topical CsA-0.1% CE improved DED signs and symptoms after 1 month of treatment under controlled environmental conditions. Future studies should confirm the benefit of CsA-0.1% CE in desiccating stress environments. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04492878.

Cyclosporine a inhibits bone regeneration and induces bone loss in a rat model.

Cyclosporine A (CSA) is an immunosuppressant that has been extensively studied for its side effects on inhibiting osseointegration of titanium implants. However, the impact of CSA on bone healing in postmenopausal osteoporosis remains unknown. Therefore, this study aimed to investigate the effect of CSA on bone repair in an ovariectomized (OVX) rat model through both in vitro and in vivo experiments. We examined the interventions of CSA on osteoblast progenitor cells MC3T3-E1 and assessed their effects on biological function using RT-qPCR, CCK-8 assay, alizarin red staining, and alkaline phosphatase staining. Furthermore, we evaluated the effects of CSA on bone regeneration and bone mass in both OVX rat models and femoral diaphysis bone defect models. The results from the CCK-8 experiment indicated a positive influence of experimental doses of CSA on osteogenic differentiation of MC3T3-E1 cells. ALP expression levels and calcified nodules were also evaluated, suggesting that CSA intervention promoted osteogenic differentiation in MC3T3-E1 cells. Additionally, specific gene expressions including OPN, Runx-2, OC, and Col1a1 were up-regulated after CSA intervention. Biomechanical parameters aligned with histological analysis as well as micro-CT scans confirmed worse bone microstructure and strength following CSA intervention. Our findings preliminarily suggest that whether it is normal or osteoporotic bones, CSA has adverse effects on bone health which are associated with elevated-bone turnover.

Gene expression profile of mitogen-activated kinases and microRNAs controlling their expression in HaCaT cell culture treated with lipopolysaccharide A and cyclosporine A.

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.

Rapidly Dissolving Trans-scleral Microneedles for Intraocular Delivery of Cyclosporine A.

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.

[New and future treatment approaches for allergic conjunctivitis]. / Neue und zukünftige Therapieansätze in der Behandlung der allergischen Konjunktivitis.

BACKGROUND: In severe and recurrent ocular allergies conventional ophthalmic drugs can reach their limits, especially in chronic forms. The first novel immunomodulators and biologicals are already in clinical use and could provide relief. OBJECTIVE: Based on the immunopathophysiological mechanisms of ocular allergies, possible targets for innovative treatment approaches are presented. An overview of promising new and future immunomodulators and biologicals and their modes of action is also given. MATERIAL AND METHODS: Current reviews on ocular allergies and the treatment of systemic allergic diseases were screened. Case reports on the treatment of ocular allergy using immunomodulators and biologicals were analyzed. The clinical relevance and possible applications are presented. RESULTS: In chronic forms of ocular allergies, complex ocular surface inflammatory responses mediated via immunoglobulin E (IgE), mast cells, CD4-positive type 2 T­helper cells and eosinophilic granulocytes are predominant. Cyclosporine A 0.1% eyedrops have been approved in Europe since 2018 for children aged 4 years and older with severe vernal keratoconjunctivitis (VKC). In addition, case reports present promising data on the systemic off-label use of biologicals, such as dupilumab or omalizumab, in refractory VKC or atopic keratoconjunctivitis (AKC). CONCLUSION: A profound understanding of the immunopathophysiology of ocular allergies is necessary to detect further targets for future immunomodulators and biologicals. Currently, immunomodulatory therapy remains limited to cyclosporine A eyedrops. Other immunomodulatory agents, such as tacrolimus and biologicals can only be used off-label. Further studies on the controlled clinical use of these substances in the treatment of VKC or AKC are underway.

Impact of early cyclosporine A levels on acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation using in vivo T-cell depletion.

BACKGROUND AIMS: Cyclosporin A (CsA) remains a major component of immunosuppressive regimens applied in allogeneic hematopoietic stem cell transplantation (HSCT). The impact of CsA trough levels during the first weeks after HSCT has not yet been investigated specifically in anti-T-lymphocyte globulin (ATLG)-based HSCT from matched related and unrelated donors. METHODS: To address this issue, we have retrospectively examined 307 consecutive matched related (n = 145) and unrelated (n = 162) HSCTs, using peripheral blood stem cells or bone marrow. HSCTs for active, uncontrolled malignancies were excluded. The initial three weeks' average mean CsA trough levels were analyzed in landmark and multi-state models, using a cut-off of 200 ng/mL. RESULTS: CsA levels >200 ng/mL were associated with a reduced risk of acute graft-versus-host disease (GVHD) grade 3-4 at the first-week landmark (subdistribution hazard ratio [SHR] 0.59, P = 0.03) and the second-week landmark (SHR 0.48, P = 0.004), whereas there was no impact at the third-week landmark (HR 0.87, P = 0.69). This was supported by a multi-state model, in which week 1 (hazard ratio [HR] 0.53, P = 0.006) and week 2 (HR 0.48, P = 0.003), but not week 3 (HR 0.80, P = 0.44) CsA levels >200 ng/mL were associated with a reduced acute GVHD 3-4 risk. Relapse incidence was not significantly affected by week 1 through 3 CsA levels. Despite ATLG's inherent GVHD-preventive properties, week 1 CsA trough levels >200 ng/mL following ATLG-based HSCT (n = 220) were associated with a significantly reduced risk of non-relapse mortality (SHR 0.52, P = 0.02) and improved overall survival (HR 0.61, P = 0.02). CONCLUSIONS: Our findings emphasize the continuing importance of ensuring CsA levels ≥200 ng/mL immediately post-transplant in the setting of ATLG-based HSCT.