Impact Of Cyclosporine A Research Articles

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.

Treatment with the calcineurin inhibitor and immunosuppressant cyclosporine A impairs sensorimotor gating in Dark Agouti rats

RationaleCalcineurin is a protein regulating cytokine expression in T lymphocytes and calcineurin inhibitors such as cyclosporine A (CsA) are widely used for immunosuppressive therapy. It also plays a functional role in distinct neuronal processes in the central nervous system. Disturbed information processing as seen in neuropsychiatric disorders is reflected by deficient sensorimotor gating, assessed as prepulse inhibition (PPI) of the acoustic startle response (ASR).ObjectivePatients who require treatment with immunosuppressive drugs frequently display neuropsychiatric alterations during treatment with calcineurin inhibitors. Importantly, knockout of calcineurin in the forebrain of mice is associated with cognitive impairments and symptoms of schizophrenia-like psychosis as seen after treatment with stimulants.MethodsThe present study investigated in rats effects of systemic acute and subchronic administration of CsA on sensorimotor gating. Following a single injection with effective doses of CsA, adult healthy male Dark Agouti rats were tested for PPI. For subchronic treatment, rats were injected daily with the same doses of CsA for 1 week before PPI was assessed. Since calcineurin works as a modulator of the dopamine pathway, activity of the enzyme tyrosine hydroxylase was measured in the prefrontal cortex and striatum after accomplishment of the study.ResultsAcute and subchronic treatment with the calcineurin inhibitor CsA disrupted PPI at a dose of 20 mg/kg. Concomitantly, following acute CsA treatment, tyrosine hydroxylase activity was reduced in the prefrontal cortex, which suggests that dopamine synthesis was downregulated, potentially reflecting a stimulatory impact of CsA on this neurotransmitter system.ConclusionsThe results support experimental and clinical evidence linking impaired calcineurin signaling in the central nervous system to the pathophysiology of neuropsychiatric symptoms. Moreover, these findings suggest that therapy with calcineurin inhibitors may be a risk factor for developing neurobehavioral alterations as observed after the abuse of psychomotor stimulant drugs.

Patient and physician perspectives on the use of cyclosporine ophthalmic emulsion 0.05% for the management of chronic dry eye.

Dry eye disease (DED) is a multifactorial disease of the ocular surface and is one of the most common reasons for patients to visit an eye care provider. Cyclosporine A (CsA) is an immune modulating drug that was approved in the US for topical use in the treatment of DED in 2003, which led to a paradigm change in our understanding and treatment of DED, turning attention to control of inflammation for treatment. This review summarizes the literature to date regarding the impact of CsA on the treatment of DED. A special focus is given to the patient and physician perspectives of CsA, including dry eye symptom improvement, medication side effects, and overall patient satisfaction. Studies evaluating CsA in DED have considerable heterogeneity making generalized conclusions about the effect of CsA difficult. However, most studies have demonstrated improvement in at least some symptoms of dry eye in CsA-treated patients. Side effects, most commonly ocular burning on administration of CsA, are common. The literature is sparse regarding long-term follow-up of patients treated with CsA, optimal duration of treatment, and identifying which patients may receive the most benefit from CsA.

Cyclosporine A (CSA) Significantly Reduces the Cytotoxic Effects of In Vitro Expanded NK Cells: Implications for Adoptive NK Cell Therapy in the Setting of Allogeneic Hematopoietic Stem Cell Transplantation (HCT).

The ability to expand NK cells in vitro has led to the recent initiation of protocols incorporating adoptive NK cell infusions after HCT. Calcineurin inhibitors such as CSA are commonly used to prevent graft versus host disease (GVHD) in HCT recipients. Recently, Hong et al found the phenotype and function of fresh NK cells cultured in vitro with CSA was altered, with CSA treated NK cell cultures having enhanced cytotoxicity against tumor targets. However, the impact of CSA on in vitro expanded NK cell function and phenotype has not been explored. We analyzed cell proliferation, IFN-gamma production, cell surface immunofluorescent staining and cytotoxicity against K562 and renal cell carcinoma cell lines by in vitro expanded vs freshly isolated NK cells cultured in physiological doses of CSA (40ng/ml, 200ng/ml, 1000ng/ml for 18hrs). Fresh NK cells were obtained from the PBMC of healthy donors using immunomagnetic beads to isolate CD56+/ CD3− cells. NK cells were expanded in vitro using irradiated EBV transformed B cells as feeder cells in media containing IL-2 [500U/ml] for 12–14 days. Comparing CSA containing cultures to controls, there was a significant reduction in IL-2 stimulated fresh NK cell proliferation (stimulation index 0.51± 0.1) and TRAIL expression (MFI 10.4 vs 3.01). Furthermore, an ELISA assay showed fresh NK cells treated with CSA had a significant reduction in IL-2 induced IFN-g production compared to controls (median 231 vs 57 pg/ml, p=0.025). In contrast, in vitro expanded NK cells cultured in CSA showed no significant reduction of proliferation or TRAIL expression. At the highest doses of CSA (1000ng/ml), minimal inhibition of K562 killing of freshly isolated NK cells was observed. In contrast, expanded NK cells cultured in CSA for 18 hours compared to controls had a significant reduction in the killing of K562 cells (E:T=10:1, median 66 vs 43% lysis, p=0.011) and RCC tumor cells (E:T=20:1, 14.8 vs 8.8%, p=0.043). [Display omitted] These data confirm CSA alters the phenotype and function of CD3−/CD56 + NK cells. Importantly, CSA appears to have a deleterious effect on expanded NK cell tumor cytotoxicity that was not observed with fresh NK cells. These finding suggest the anti-tumor effects of in vitro expanded NK cells could be hindered when adoptively infused in HCT patients receiving CSA.

A Review of the Immunosuppressive Activity of Cyclosporine Metabolites:New Insights into an Old Issue

Cyclosporine A (CsA) is metabolized into a vast spectrum of metabolites. The potential immunosuppressive action of CsA's metabolites has been studied extensively in the early 1990's, with conflicting and inconclusive results. Since then, the pharmacological and clinical consensus guidelines recommend the use of specific monoclonal assays for measurement of CsA's concentrations thus avoiding metabolite interference. Nevertheless, clinical benefit or superiority of these assays was never convincingly demonstrated. We provide a review of the performed in vivo, in vitro and animal studies and their conclusions. During the last years, many transplantation centres have employed the C(2) monitoring of CsA (2 hours post-dose concentration). The metabolites / parent drug ratio two hours post dose is completely different from trough levels (predose concentration). Cyclosporine exerts its immunosuppressive action by inhibiting the enzyme calcineurin phosphatase (CaN). Currently, our laboratory, among others, is working on determination of the enzyme's inhibition and its potential use as a pharmacodynamic biomarker. Utilizing this novel pharmacodynamic approach, we have performed in vitro and in vivo studies investigating the immunosuppressive impact of CsA's metabolites on C2 monitoring and on various monitoring assays (mono-/polyclonal). Interestingly, even though we have estimated in vivo that the potential immunosuppressive action of metabolites is less than 10% of the parent drug, we have found assays that take metabolites into consideration to correlate stronger with calcineurin phosphatase inhibition. We believe that the old controversial issue of metabolite induced immunosuppressive action examined under the light of newer pharmacodynamic approaches is still intriguing. Instead of a priori neglecting CsA's metabolites maybe we should investigate the potential of utilizing them as an additional tool towards better therapeutic drug monitoring of cyclosporine.

The potential of cyclosporin a as an anti-tumour agent

Cyclosporin A (CsA) has become established as the agent of choice for the prevention of organ allograft rejection and has shown considerable promise in the clinical management of certain autoimmune disorders. The impact of CsA as an immunotherapeutic agent of major importance is attributable to its powerful, selective inhibitory action on T-lymphocyte activation and proliferation. Moreover, CsA lacks the myelotoxic and other major side effects associated with cytotoxic immunosuppressive agents, such as cyclophosphamide or azathioprine. It is now clear that CsA has a potential therapeutic role in the treatment of malignancies, especially T-cell cancers. Recent studies suggest that there may be several areas of application for CsA, either as a direct antiproliferative agent or in combination with other drugs, including inhibitors of polyamine biosynthesis or cytotoxic anti-tumour agents, including vincristine and adriamycin. In addition, CsA and non-immunosuppressive analogues have been shown to restore multi-drug sensitivity in cancer cells with acquired drug resistance. A further application of CsA may be to prevent the induction of human immune responses to therapeutic mouse monoclonal antibodies directed against tumour antigens, thereby enhancing the efficiency and safety of this form of cancer immunotherapy. Due to our incomplete understanding of the antiproliferative properties of CsA, further exploration of its potential as an anti-tumour agent must be accompanied by detailed studies aimed at elucidating its action on subcellular molecular events in both normal and malignant cells.