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Cyclosporine Anionic and Cationic Ophthalmic Emulsions in Dry Eye Disease: A Literature Review.
Tong, L, Sun, CC, Yoon, KC, Lim Bon Siong, R, Puangsricharern, V, Baudouin, C
Ocular immunology and inflammation. 2021;(7-8):1606-1615
Abstract
Purpose: There are no clinical studies directly comparing anionic and cationic emulsions of cyclosporine for the treatment of dry eye disease (DED). We therefore conducted a literature review to evaluate the efficacy and safety of these different formulations.Methods: A literature search was performed in Embase and Medline from January 1999 to May 2019 to identify publications that evaluated clinical outcomes with either cyclosporine anionic or cationic emulsion in patients with moderate-to-severe or severe DED.Results: Thirteen publications met criteria. In patients with moderate-to-severe disease, evidence demonstrated improvement in the signs of DED with both formulations. However, improvement in symptoms was not consistently demonstrated. Studies specifically in severe DED were only identified with the cationic emulsion and showed improvement in the objective signs of DED. There were no obvious differences in tolerability between products.Conclusions: Both formulations are effective for the treatment of moderate-to-severe DED and are well tolerated.
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Molecular Dynamics Simulations and Experimental Results Provide Insight into Clinical Performance Differences between Sandimmune® and Neoral® Lipid-Based Formulations.
Warren, DB, Haque, S, McInerney, MP, Corbett, KM, Kastrati, E, Ford, L, Williams, HD, Jannin, V, Benameur, H, Porter, CJH, et al
Pharmaceutical research. 2021;(9):1531-1547
Abstract
OBJECTIVE Molecular dynamics (MD) simulations provide an in silico method to study the structure of lipid-based formulations (LBFs) and the incorporation of poorly water-soluble drugs within such formulations. In order to validate the ability of MD to effectively model the properties of LBFs, this work investigates the well-known cyclosporine A formulations, Sandimmune® and Neoral®. Sandimmune® exhibits poor dispersibility and its absorption from the gastrointestinal tract is enhanced when administered after food, whereas Neoral® disperses comparatively well and shows no food effect. METHODS MD simulations were performed of both LBFs to investigate the differences observed in fasted and fed conditions. These conditions were also tested using an in vitro experimental model of dispersion and digestion. RESULTS These MD simulations were able to show that the food effect observed for Sandimmune® can be explained by large changes in drug solubilization on addition of bile. In contrast, Neoral® is well dispersed in water or in simulated fasted conditions, and this dispersion is relatively unchanged on moving to fed conditions. These differences were confirmed using dispersion and digestion in vitro experimental model. CONCLUSIONS The current data suggests that MD simulations are a potential method to model the fate of LBFs in the gastrointestinal tract, predict their dispersion and digestion, investigate behaviour of APIs within the formulations, and provide insights into the clinical performance of LBFs.
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3.
Comparison of 0.05% cyclosporine and 3% diquafosol solution for dry eye patients: a randomized, blinded, multicenter clinical trial.
Park, CH, Lee, HK, Kim, MK, Kim, EC, Kim, JY, Kim, TI, Kim, HK, Song, JS, Yoon, KC, Lee, DH, et al
BMC ophthalmology. 2019;(1):131
Abstract
BACKGROUND This study is aim to compare the clinical effectiveness between the two most prominent dry eye disease (DED)-specific eye drops, 0.05% cyclosporine (CN) and 3% diquafosol (DQ). METHODS This is a multi-centered, randomized, masked, prospective clinical study. A total of 153 DED patients were randomly allocated to use CN twice per day or DQ six times daily. Cornea and conjunctival staining scores (NEI scale), tear break-up time (TBUT), Schirmer test scores, and ocular surface disease index (OSDI) score were measured at baseline, 4 and 12 weeks after treatment. RESULTS At 12 weeks after treatment, NEI scaled scores were significantly reduced from the baseline by - 6.60 for CN and - 6.63 for DQ group (all P < 0.0001, P = 0.9739 between groups). TBUT and Schirmer values for CN were significantly improved from the baseline at 4 and 12 weeks (P = 0.0034, P < 0.0001 for TBUT, P = 0.0418, P = 0.0031 for Schirmer test). However, for DQ, TBUT showed significant improvement at 12 weeks only (P = 0.0281). Mean OSDI score differences from the baseline to 12 weeks were improved by - 13.03 ± 19.63 for CN and - 16.11 ± 20.87 for DQ, respectively (all P < 0.0001, P = 0.854 between groups). Regarding drug compliance, the mean instillation frequency of CN was less than that of DQ (P < 0.001). There were no statistically significant intergroup differences in safety evaluation. CONCLUSIONS The level of improvement regarding NEI, TBUT, and OSDI scores were not significantly different between the two treatment groups. However, with regards to the early improvement of TBUT and patient compliance, patients using CN improved faster and with greater adherence to drug usage than did those treated with DQ. TRIAL REGISTRATION KCT0002180 , retrospectively registered on 23 December 2016.
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Efficacy of Topical Cyclosporine Nanoemulsion 0.05% Compared with Topical Cyclosporine Emulsion 0.05% and Diquafosol 3% in Dry Eye.
Park, CH, Kim, MK, Kim, EC, Kim, JY, Kim, TI, Kim, HK, Song, JS, Yoon, KC, Lee, DH, Lee, HK, et al
Korean journal of ophthalmology : KJO. 2019;(4):343-352
Abstract
PURPOSE To evaluate the efficacy and safety of cyclosporine nanoemulsion 0.05% compared to cyclosporine emulsion 0.05% and diquafosol sodium 3%. METHODS This was a multicenter, randomized, evaluator-masked, active control, parallel, phase IV study. A total of 227 patients were randomly allocated to instill cyclosporine nanoemulsion 0.05% (CN) twice daily, cyclosporine emulsion 0.05% (CE) twice daily, or diquafosol sodium 3% (DQ) six times daily. Non-inferiority of CN was analyzed by primary endpoint (cornea and conjunctival staining scores at week 12). The secondary endpoints were scores of corneal staining, conjunctival staining, tear break-up time, Schirmer test, and Ocular Surface Disease Index at weeks 4 and 12. RESULTS Primary endpoints showed statistically significant improvements in all groups. Primary endpoints were -6.60 for the CN group, -5.28 for the CE group, and -6.63 for the DQ group (National Eye Institute scale from 0 to 33), verifying the non-inferiority of CN compared to CE (95% confidence interval, -0.15 to 2.80, Δ>-2.88). In intergroup comparison between CN and CE groups, the CN group had significantly more decreased conjunctival staining score at week 12. Intergroup comparison between CN and DQ groups showed consistent statistically significant improvements in TBUT and Schirmer test in the CN group. In the DQ group, TBUT showed late statistically significant improvement at week 12 and Schirmer test showed relatively short-term statistically significant improvement at week 4. CONCLUSIONS Cyclosporine nanoemulsion 0.05% was equivalently efficient compared to cyclosporine emulsion 0.05% and diquafosol sodium 3%. In addition, CN showed significant improvements in several parameters for treatment of dry eyes.
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Positron Emission Tomography Imaging of [11 C]Rosuvastatin Hepatic Concentrations and Hepatobiliary Transport in Humans in the Absence and Presence of Cyclosporin A.
Billington, S, Shoner, S, Lee, S, Clark-Snustad, K, Pennington, M, Lewis, D, Muzi, M, Rene, S, Lee, J, Nguyen, TB, et al
Clinical pharmacology and therapeutics. 2019;(5):1056-1066
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Abstract
Using positron emission tomography imaging, we determined the hepatic concentrations and hepatobiliary transport of [11 C]rosuvastatin (RSV; i.v. injection) in the absence (n = 6) and presence (n = 4 of 6) of cyclosporin A (CsA; i.v. infusion) following a therapeutic dose of unlabeled RSV (5 mg, p.o.) in healthy human volunteers. The sinusoidal uptake, sinusoidal efflux, and biliary efflux clearance (CL; mL/minute) of [11 C]RSV, estimated through compartment modeling were 1,205.6 ± 384.8, 16.2 ± 11.2, and 5.1 ± 1.8, respectively (n = 6). CsA (blood concentration: 2.77 ± 0.24 μM), an organic-anion-transporting polypeptide, Na+ -taurocholate cotransporting polypeptide, and breast cancer resistance protein inhibitor increased [11 C]RSV systemic blood exposure (45%; P < 0.05), reduced its biliary efflux CL (52%; P < 0.05) and hepatic uptake (25%; P > 0.05) but did not affect its distribution into the kidneys. CsA increased plasma concentrations of coproporphyrin I and III and total bilirubin by 297 ± 69%, 384 ± 102%, and 81 ± 39%, respectively (P < 0.05). These data can be used in the future to verify predictions of hepatic concentrations and hepatobiliary transport of RSV.
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Randomized, open-label, comparative phase IV study on the bioavailability of Ciclosporin Pro (Teva) versus Sandimmun® Optoral (Novartis) under fasting versus fed conditions in patients with stable renal transplants.
Gäckler, A, Dolff, S, Rohn, H, Korth, J, Wilde, B, Eisenberger, U, Mitchell, A, Kribben, A, Witzke, O
BMC nephrology. 2019;(1):167
Abstract
BACKGROUND The influence of pre- or postprandial administration on pharmacokinetics of cyclosporine is supposed to be less in gel-based formulations than in microemulsions. This study was designed to investigate the influence of a high-fat meal on the pharmacokinetic profile of the two cyclosporine containing formulations Ciclosporin Pro (gel-based emulsion) and Sandimmun®Optoral (microemulsion) in renal transplant recipients. METHODS A randomized, open-label, repeated-measurement, comparative phase IV trial was conducted with two sequence groups for nutrition condition (fasting→fed, fed→fasting) and two treatment phases (Sandimmun® Optoral → Ciclosporin Pro), each covering both nutrition conditions. Primary pharmacokinetic variable of interest was the reduction of bioavailability due to high-fat food compared to fasting conditions measured by the difference D of ln-transformed bioavailability variables (AUCSS, τ, Css, max, und Css, min). RESULTS A nutrition effect was found for both study medications with respect to the parameters AUCSS, τ and CSS, max, but not to CSS, min. The reduction of bioavailability caused by high-fat food was not significantly different for Sandimmun®Optoral and Ciclosporin Pro. CONCLUSIONS An effect of high-fat breakfast prior to the morning dose on AUCSS, τ and CSS, max was found for Sandimmun® Optoral and for Ciclosporin Pro. Trough level monitoring did not capture ingestion-related variability. Conversion to Ciclosporin Pro seems to be safe with regard to intra-individual pharmacokinetic variability. TRIAL REGISTRATION EudraCT No. 2009-011354-18 (29th April 2019).
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Changes in Human Tear Proteome Following Topical Treatment of Dry Eye Disease: Cyclosporine A Versus Diquafosol Tetrasodium.
Ji, YW, Kim, HM, Ryu, SY, Oh, JW, Yeo, A, Choi, CY, Kim, MJ, Song, JS, Kim, HS, Seo, KY, et al
Investigative ophthalmology & visual science. 2019;(15):5035-5044
Abstract
PURPOSE To compare the changes in human tear proteome and clinical effects following topical cyclosporine A (CsA) 0.05% or diquafosol tetrasodium (DQS) 3% treatment of dry eye disease (DED), and to identify biomarkers for determining disease severity and treatment effectiveness in DED. METHODS A total of 18 patients were diagnosed with non-Sjögren DED. Nine patients in each group were treated with topical CsA 0.05% or DQS 3% for 4 weeks. Tear samples were collected after evaluation of tear breakup time, corneal and conjunctival erosion staining, and results of Schirmer's test 1 before and after treatment. Proteomes were characterized using liquid chromatography mass spectrometry, and proteins exhibiting a fold change >1.5 or <0.67 (P < 0.05) were considered differentially expressed (DEP). RESULTS A total of 794 proteins were identified, with no significant difference observed between pretreatment and posttreatment conditions. Proteomic analysis identified 54 and 106 DEPs between treatment groups (CsA and DQS, respectively), with gene ontology analysis indicating that both treatments enhanced innate and adaptive immune responses and cellular detoxification. Protein-network analysis showed that inflammation associated with the immune response was primarily responsible for the therapeutic process in both groups. CONCLUSIONS These results provide insight into the broad scope of changes at the ocular surface in DED and indicated that although both drugs improved the clinical parameters, the activated tear-specific biomarkers differed significantly between treatments. Our findings suggest that the DEPs identified here and those correlated with the clinical parameters might represent candidate biomarkers for DED.
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Cyclosporine A and amlodipine induced gingival overgrowth in a kidney transplant recipient: case presentation with literature review.
Nanda, T, Singh, B, Sharma, P, Arora, KS
BMJ case reports. 2019;(5)
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Abstract
Drug-induced gingival overgrowth is a condition caused by side effects of treatment with one of three types of drugs: phenytoin (used in epilepsy treatment), cyclosporine A (used in transplantology after allogenic organ transplants) and calcium channel blockers (used in the treatment of hypertension). Gingival overgrowth leads to inflammation within the gums and periodontium and can amplify the existing periodontal disease leading to tooth loss. Patients who have undergone kidney transplant are given immunosuppressants to prevent transplant rejection and mostly it is accompanied with calcium channel blockers to treat hypertension associated with kidney transplant. This article reports a case of recent gingival enlargement associated with cyclosporine A and amlodipine given to a kidney transplant patient from the past 11 years.
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Ameliorative effects of curcumin towards cyclosporine-induced genotoxic potential: an in vitro and in silico study.
Shah, AJ, Prasanth Kumar, S, Rao, MV, Pandya, HA
Drug and chemical toxicology. 2018;(3):259-269
Abstract
Several studies documented the ameliorative effects of curcumin which plays a pivotal role in radical scavenging activities. It also participates in various cellular pathways and interacts with multiple targets. In the present study, we investigated the ameliorative effect of curcumin upon chromosomal genotoxicity induced by cyclosporine, an immunosuppressant, using in vitro approaches. A plausible mechanism of how curcumin mitigates the genotoxic implications of cyclosporine was ascertained using in silico tools. We observed that the curcumin reduces the genotoxic consequences made by cyclosporine upon cell cycle checkpoints and associated chromosomal/DNA manifestations. In addition, we presented the mechanistic details of curcumin interaction with various biomacromolecule types using docking experiments which showed that the possible radical scavenging activities can only be emerged by inducing the expression of antioxidant enzymes, supported by available experimental evidences. We anticipate that the induction of antioxidant enzymes by curcumin would activate Nrf2-Keap1 pathway as the plausible mechanism to exert anti-inflammatory response as demonstrated in renal epithelial cells.
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Cyclosporine for corticosteroid-refractory acute generalized exanthematous pustulosis due to hydroxychloroquine.
Castner, NB, Harris, JC, Motaparthi, K
Dermatologic therapy. 2018;(5):e12660
Abstract
Acute generalized exanthematous pustulosis most often manifests 1-2 days following exposure to a characteristic drug, such as aminopenicillins, calcium-channel blockers, or terbinafine. Recovery is usually rapid following drug withdrawal, and systemic corticosteroids represent the historic treatment of choice. Herein, acute generalized exanthematous pustulosis incited by hydroxychloroquine is briefly reviewed: a prolonged latency and recalcitrance to corticosteroids are noteworthy. In this unique context, cyclosporine tapered over several months is an effective therapeutic option.