Calcineurin inhibitors (CNIs) revolutionized the field of organ transplantation and remain the standard of care 40 years after the discovery of cyclosporine. The early impressive results of ...cyclosporine in kidney transplant recipients led to its subsequent use in other organ transplant recipients and for treatment of a variety of autoimmune diseases as well. In this review, we examine the discovery of CNIs, their mechanism of action, preclinical and clinical studies with CNIs, and the usage of CNIs in nontransplant recipients. We review the mechanisms of renal toxicity associated with CNIs and the recent efforts to avoid or reduce usage of these drugs. Although minimization strategies are possible, safe, and of potential long-term benefit, complete avoidance of CNIs has proven to be more challenging than initially thought.
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Local ocular delivery of cyclosporine A (CsA) is the preferred method for CsA delivery as a treatment for ocular inflammatory diseases such as uveitis, corneal healing, vernal ...keratoconjunctivitis and dry eye disease. However, due to the large molecular weight and hydrophobic nature of CsA and the natural protective mechanisms of the eye, achieving therapeutic levels of CsA in ocular tissues can be difficult. This review gives a comprehensive overview of the current products available to clinicians as well as emerging drug delivery solutions that have been developed at both the academic and industry levels.
In a randomized, controlled trial involving patients with membranous nephropathy, rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and ...was superior in maintaining proteinuria remission for up to 24 months.
Strong precorneal clearance mechanisms including reflex blink, constant tear drainage, and rapid mucus turnover constitute great challenges for eye drops for effective drug delivery to the ocular ...epithelium. In this study, cyclosporine A (CsA) for the treatment of dry eye disease (DED) was selected as the model drug. Two strategies, PEGylation for mucus penetration and cationization for potent cellular uptake, were combined to construct a novel CsA nanosuspension (NS@lipid-PEG/CKC) by coating nanoscale drug particles with a mixture of lipids, DSPE-PEG2000, and a cationic surfactant, cetalkonium chloride (CKC). NS@lipid-PEG/CKC with the mean size ∼173 nm and positive zeta potential ∼+40 mV showed promoted mucus penetration, good cytocompatibility, more cellular uptake, and prolonged precorneal retention without obvious ocular irritation. More importantly, NS@lipid-PEG/CKC recovered tear production and goblet cell density more efficiently than the commercial cationic nanoemulsion on a dry eye disease rat model. All results indicated that a combination of PEGylation and cationization might provide a promising strategy to coordinate mucus penetration and cellular uptake for enhanced drug delivery to the ocular epithelium for nanomedicine-based eye drops.
Cyclosporine A (CsA) is a well-known immunosuppressive agent that gained considerable importance in transplant medicine in the late 1970s due to its selective and reversible inhibition of ...T-lymphocytes. While CsA has been widely used to prevent graft rejection in patients undergoing organ transplant it was also used to treat several systemic and local autoimmune disorders. Currently, the neuro- and cardio-protective effects of CsA (CiCloMulsion®; NeuroSTAT®) are being tested in phase II and III trials respectively and NeuroSTAT® received orphan drug status from US FDA and Europe in 2010. The reformulation strategies focused on developing Cremophor® EL free formulations and address variable bioavailability and toxicity issues of CsA. This review is an attempt to highlight the progress made so far and the room available for further improvements to realize the maximum benefits of CsA.
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Experimental evidence suggests that cyclosporine may attenuate myocardial reperfusion injury. In a pilot trial, 58 patients with acute ST-elevation myocardial infarction were randomly assigned to ...receive an intravenous bolus of either cyclosporine or saline immediately before undergoing percutaneous coronary intervention. Creatine kinase release was significantly reduced in the patients who received cyclosporine. These results require confirmation in a larger trial.
Experimental evidence suggests that cyclosporine may attenuate myocardial reperfusion injury. In a pilot trial, creatine kinase release was significantly reduced in the patients who received cyclosporine.
Myocardial infarction is a disabling disease that is common in the United States, with more than 1.5 million new cases diagnosed each year.
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Infarct size is a major determinant of mortality in myocardial infarction.
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Limitation of infarct size has therefore been an important objective of strategies to improve outcomes. Currently, the most effective way to limit infarct size is to reperfuse the jeopardized myocardium as soon as possible with the use of coronary angioplasty or thrombolysis and to prevent reocclusion of the coronary artery with the use of antiplatelet therapy.
Although reperfusion is undoubtedly beneficial, it has detrimental . . .
Cyclosporine A (CsA) is an exceptional immunosuppressant used for the treatment of immune disorders. Niosomal vesicles are promising drug carriers that are formed by self-association of nonionic ...surfactants and cholesterol in an aqueous phase. The objective of the study was to formulate combined nonionic surfactant based vesicles and to evaluate their in vitro characterization, release studies and in vivo studies.
Five niosomal formulations (F
to F
) were prepared using the thin film hydration method. The molar ratio of cholesterol and non-ionic surfactant taken was 1:1. In formulation F
, the combination of surfactants Span 20 and Brij 35 was used. The niosomes were characterized by zeta sizer and SEM for particle size analysis, in vitro drug release and stability studies. The pharmacokinetic studies were conducted on healthy albino rabbits.
The size of niosome was found in the range of 427.1 nm to 972.3 nm. SEM image of optimized formulations F
exhibit the spherical nature of niosomal vesicles. DSC thermograms of niosomal formulations exhibited a broadened endothermic peak. The stability study exhibited that all formulations are stable and negligible change of vesicle size and entrapment was observed with time. The percentage drug release was significantly higher as compared to CsA plain dispersion for all niosomal formulations at pH 1.2 and 7.4. The release kinetic behavior showed that all preparations were best described by zero order and can release active ingredient in a sustained manner. The pharmacokinetic data showed the test formulation (F10) possessed greater bioavailability as compared to the reference formulation (CsA aqueous dispersion).
The formulation F
demonstrated a comparatively more delayed rate of release with enhanced dissolution as compared to a single surfactant scheme. The F
formulation can be a remarkable nanotechnology for prolonged delivery of CsA orally with improved dissolution profile and bioavailability.
Myocardial ischemia-reperfusion injury (MI/RI) seriously restricts the therapeutic effect of reperfusion. It is demonstrated that ferroptosis and apoptosis of cardiomyocytes are widely involved in ...MI/RI. Therefore, simultaneous inhibition of ferroptosis and apoptosis of cardiomyocytes can be a promising strategy to treat MI/RI. Besides, transferrin receptor 1 (TfR1) is highly expressed in ischemic myocardium, and apoferritin (ApoFn) is a ligand of the transferrin receptor. In this study, CsA@ApoFn was prepared by wrapping cyclosporin A (CsA) with ApoFn and actively accumulated in ischemic cardiomyocytes through TfR1 mediated endoctosis in MI/RI mice. After entering cardiomyocytes, ApoFn in CsA@ApoFn inhibited ferroptosis of ischemic cardiomyocytes by increasing the protein expression of GPX4 and reducing the content of labile iron pool and lipid peroxides. At the same time, CsA in CsA@ApoFn attenuated the apoptosis of ischemic cardiomyocytes through recovering mitochondrial membrane potential and reducing the level of reactive oxygen species, which played a synergistic role with ApoFn in the treatment of MI/RI. In conclusion, CsA@ApoFn restored cardiac function of MI/RI mice by simultaneously blocking ferroptosis and apoptosis of cardiomyocytes. ApoFn itself not only served as a safe carrier to specifically deliver CsA to ischemic cardiomyocytes but also played a therapeutic role on MI/RI. CsA@ApoFn is proved as an effective drug delivery platform for the treatment of MI/RI.
Recent studies have shown that ferroptosis is an important mechanism of myocardial ischemia-reperfusion injury (MI/RI). Therefore, simultaneous inhibition of ferroptosis and apoptosis of cardiomyocytes can be a promising strategy to treat MI/RI. Apoferritin, as a delivery carrier, can actively target to ischemic myocardium through binding with highly expressed transferrin receptor on ischemic cardiomyocytes. At the same time, apoferritin plays a protective role on ischemic cardiomyocytes by inhibiting ferroptosis. This strategy of killing two birds with one stone significantly improves the therapeutic effect on MI/RI while does not need more pharmaceutical excipients, which has the prospect of clinical transformation.
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Patients with acute STEMI undergoing PCI were assigned to cyclosporine or placebo. No significant between-group difference was seen in the rate of death, rehospitalization for heart failure, heart ...failure worsening during index hospitalization, or adverse left ventricular remodeling at 1 year.
Over the past three decades, major progress has been made in the treatment of patients with ST-segment elevation myocardial infarction (STEMI).
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Nevertheless, the rates of death, heart failure, and recurrent ischemic events occurring in the first year after infarction remain unacceptably elevated in this high-risk population. Although many advances have been made in the development of methods to reopen the culprit coronary artery and prevent reocclusion, there is currently no specific treatment that targets myocardial reperfusion injury, which is a paradoxical form of myocardial damage that occurs as a result of the restoration of vessel patency.
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Growing evidence from experimental . . .
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