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Ocular surface inflammatory disorder (OSID) is a chronic ocular disease caused by systemic disorders or involving the local immune system.OSID induces persistent inflammatory reaction in the ocular adnexal connective tissues which in turn give rise to tear hypertonicity and ocular surface epithelial damage, leading to dry eye formation or progression.Common immune-related ocular surface diseases include vernal keratoconjunctivitis, Sj?gren syndrome, graft versus host disease, dry eye and immune-related corneal disease, all of which can significantly impact the visual function and quality of life of patients.Current treatments including the use of artificial tears and glucocorticoid eye drops are not always effective and have the risk of adverse events.Cyclosporine A (CsA) is a commonly utilized immunosuppressant that has a strong immunomodulatory effect, but its clinical application is somewhat limited due to the low permeability of its current ophthalmic dosage form.The development of CsA ophthalmic agents has changed the treatment strategy for OSID.The development of 0.1% CsA cationic emulsion has significantly improved the efficacy and safety of topical CsA treatment, which is worth the attention.In order to rationally apply 0.1% CsA cationic emulsion to OSID, ophthalmologists should fully understand the immune-related pathogenesis of each OSID and comprehend the curative effect, indication, application methods and adverse events of topical CsA treatment.
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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<0.00001), BUT was longer(MD=1.32, 95%CI: 0.87～1.76, P<0.00001), CFS decreased(MD=-0.79, 95%CI: -1.20～-0.39, P=0.0001)and OSDI decreased(MD=-5.52, 95%CI: -9.14～-1.91, P=0.003). However, the CsA group had more adverse reactions(OR=1.69, 95%CI: 1.06～2.72, P=0.03).CONCLUSION: 0.05% CsA can improve the subjective symptoms and various objective indicators of dry eye patients. However, 0.05% CsA seems to produce more adverse effects, like ocular burning sensation when compared to drugs such as artificial tears.
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OBJECTIVE To compare the efficacy， safety and economy of tacrolimus （TAC）， cyclosporin A （CsA）， cyclophosphamide （CTX） and rituximab （RTX） in the treatment of membranous nephropathy （MN）. METHODS Retrieved from Pubmed， the Cochrane Library， Wanfang data， CNKI and health technology assessment （HTA） official website， HTA reports， systematic reviews/meta-analysis and pharmacoeconomic studies about TAC， CsA， CTX and RTX combined with glucocorticoid in the treatment of MN were collected during the inception and Mar. 2022. After data extraction and quality evaluation， descriptive analysis was performed on the results of the included studies. RESULTS A total of 15 articles were included， involving 13 systematic reviews/meta-analysis and 2 pharmacoeconomic studies. In terms of efficacy， TAC and CsA showed significant advantages in increasing the response rate， and could improve the levels of urine protein， serum albumin， serum creatinine and serum total cholesterol. In terms of safety， the incidence of adverse reaction induced by TAC， CsA and RTX was low and the symptoms were mild. In terms of economics， CTX cost lower but caused severe adverse reaction； TAC cost higher but showed higher remission rate and good safety. CONCLUSIONS TAC combined with glucocorticoid may be the recommended scheme for MN.
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ABSTRACT Purpose: The aim of this study was to compare the effects of topical cyclosporine 0.1% and bevacizumab on experimentally induced corneal neovascularization in a rat model. Methods: A total of 30 adult Sprague-Dawley rats were used in this experimental study. The central cornea of the rats was cauterized chemically. The rats were randomly enrolled into three groups as follows: Group 1 received bevacizumab 1%, Group 2 received cyclosporine 0.1%, and Group 3 received isotonic saline twice a day for 28 days. Slit-lamp examination of all rats was performed at the 3rd and 28th day. The rats were then sacrificed, and the corneas were excised. The number of blood vessels, state of inflammation, and collagen formation were evaluated histopathologically in the corneal sections. Results: Corneal opacity and edema grades were significantly lower in Group 2 than in Group 3 (p=0.04 and 0.00, respectively). In the histopathological examination, Group 2 demonstrated significantly lesser number of blood vessels than Group 3 (p=0.001). Regarding collagen formation, Group 2 exhibited more regular collagen formation than Groups 1 and 3 (p=0.03). Inflammation grades were significantly lower in Groups 1 and 2 than in Group 3 (p=0.014 and 0.001, respectively). Conclusion: Topical bevacizumab is effective in inhibiting newly formed corneal neovascularization. The topical cyclosporine 0.1% treatment appears to be more effective than the topical bevacizumab treatment.
RESUMO Objetivo: Comparar os efeitos da ciclosporina tópica 0,1% e do bevacizumabe na neovascularização da córnea produzida experimentalmente em um modelo com ratos. Métodos: Trinta ratos Sprague-Dawley adultos foram usados neste estudo experimental. A córnea central dos ratos foi cauterizada quimicamente. Os ratos foram distribuídos aleatoriamente em três grupos. O grupo 1 recebeu bevacizumabe a 1%, o grupo 2 recebeu ciclosporina tópica a 0,1% e o grupo 3 recebeu solução salina isotônica duas vezes ao dia durante 28 dias. O exame de lâmpada de fenda de todos os ratos foi realizado no terceiro e no vigésimo oitavo dias. Os ratos foram então sacrificados e as córneas excisadas. Nos cortes da córnea, o número de vasos sanguíneos, o estado de inflamação e a formação de colágeno foram avaliados em uma análise anatomopatológica. Resultados: No Grupo 2, os graus de opacidade e de edema da córnea foram significativamente menores que no Grupo 3 (p=0,04 e 0,00, respectivamente). No exame histopatológico, o Grupo 2 apresentou um número significativamente menor de vasos sanguíneos do que o Grupo 3 (p=0,001). Em relação à avaliação da formação de colágeno, esta mostrou-se mais regular no Grupo 2 que no Grupo 1 e no Grupo 3 (p=0,03). Os graus de inflamação foram significativamente menores no Grupo 1 e no Grupo 2 em comparação com o Grupo 3 (p=0,014 e 0,001, respectivamente). Conclusão: O bevacizumabe tópico é eficaz na inibição da neovascularização da córnea recém-formada. O tratamento tópico com ciclosporina a 0,1% parece ser mais eficaz em comparação ao tratamento tópico com bevacizumabe.
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Cyclosporine A is widely used in organ transplantation and autoimmune diseases . Due to the obvious differences in metabolism between individuals ，the dosage should be adjusted according to the patient ’s blood concentration during clinical use . But the blood concentration does not reflect accurately its clinical prognosis . This article focuses on the four laboratory examination indexes following aspects ：the cyclosporine A concentration of peripheral blood mononuclear cells ，calcineurin activity ，T cell function and metabolite concentration of cyclosporine A . The relationship between them and the pharmacokinetics of cyclosporine and clinical prognosis were reviewed . It’s found that the above indicators have a certain predictive effect on the clinical prognosis of patients receiving cyclosporine A ，which can make up for the insufficiency of blood drug concentration monitoring ，and the clinical practicability needs to be further improved .
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Objectives:To establish a candidate reference measurement procedure based on isotope dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) for cyclosporin A, tacrolimus, sirolimus, and everolimus measurements in human whole blood.Methods:The isotope labeled cyclosporine A, tacrolimus, sirolimus, and everolimus were selected as the internal standards. Samples were accurately weighed while protein precipitation and solid phase extraction were selected for the sample preparation. The standard curve method was applied for quantification. The ultra-high liquid chromatography coupled with triple quadrupole mass spectrometer was used for analysis. The specificity, matrix effect, detection limit, quantification limit, precision, accuracy, and uncertainty of the method were evaluated.Results:The method showed good selectivity and specificity. No apparent interferences or matrix effects were found in the target analyte measurements. The detection limits and quantification limits of cyclosporin A, tacrolimus, sirolimus and everolimus met clinical requirements. Intra-batch coefficients of variation ( CV) were from 1.4% to 1.8% for CSA, from 1.7% to 2.8% for TAC, from 1.3% to 3.7% for SRL and from 2.3% to 3.2% for EVR, and total CVs were from 1.8% to 2.9% for CSA, from 1.7% to 3.8% for TAC, from 2.6% to 4.7% for SRL and from 3.5% to 4.6% for EVR. The relative recoveries were from 97.9% to 100.3% for CSA, from 98.4% to 103.1% for TAC, from 99.4% to 102.0% for SRL and from 98.3% to 99.4% for EVR, and the relative expanded uncertainties at four concentrations were from 4.2% to 4.4% for CSA, from 1.5% to 2.4% for TAC, from 4.4% to 4.9% for SRL and from 2.2% to 2.7% for EVR. Conclusion:A candidate reference measurement procedure for the cyclosporine A, tacrolimus, sirolimus, and everolimus in human whole blood was established by ID-LC-MS/MS.
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The main purpose of our study was to evaluate the efficacy and safety of eltrombopag plus cyclosporine A (CsA) in transfusion-dependent non-severe aplastic anemia(TD-NSAA). The clinical characteristics of 13 TD-NSAA patients who received initial treatment of eltrombopag plus CsA from 2019 to 2021 were retrospectively analyzed. The 3-month overall hematological response (OR) rate was 12/13. Until the end of follow-up, 12 patients responded, among whom 2 patients reached complete response (CR) and 9 patients reached partial response (PR) and 1 with HR. Paroxysmal nocturnal hemoglobinuria (PNH) developed in one patient at 6 months after treatment. Five of thirteen patients reported mild adverse reactions, which were all manageable. Compared with historical data, the combination of eltrombopag with CsA is an effective regimen in patients with TD-NSAA.
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OBJECTIVE@#To investigate the effects of topical administration of cyclosporine A (CsA) on salivary secretion and inflammation of the submandibular glands in non-obese diabetic (NOD) mice.@*METHODS@#Female NOD mice, 21 aged 14 weeks and 18 aged 21 weeks were selected and randomly divided into low-dose group, high-dose group and control group on average. CsA was injected into submandibular glands. One week later the saliva stimulated by pilocarpine was collected and measured. The submandibular glands were collected to make paraffin sections. The lymphocyte infiltration in submandi-bular gland was observed by microscope after hematoxylin-eosin (HE) staining. The number of lymphocyte infiltration foci was counted to calculate the focus sore and the ratio of lymphocyte infiltration area to total gland area was figured up by Leica image analysis system. The expressions of inflammatory cytokines tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-4 (IL-4), IL-13, IL-17F, IL22 and IL-23a in the submandibular glands of the NOD mice were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell apoptosis in the submandibular gland was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). The levels of serum creatinine (Scr), blood urea nitrogen (BUN), uric acid (UA), alanine aminotransferase (ALT), aspertate aminotransferase (AST), alkaline phosphatase (ALP), albumin (ALB) and γ-glutamyl transferase (GGT) were measured by automatic biochemical analyzer to evaluate liver and kidney functions.@*RESULTS@#After topical injection of CsA in the submandibular gland, the stimulated salivary flow rate of the 14- and 21-week-old NOD mice significantly increased compared with the control group (P < 0.01 or P < 0.05), and the number and area of lymphocyte infiltration foci in the 14-week-old NOD mice low-dose group significantly decreased compared with the control group (P < 0.01). Low and high dose of CsA had similar effects on reducing inflammation and improving salivary secretion. The overall level of inflammatory cytokines in the submandibular gland did not decrease significantly. The number of cell apoptosis of submandibular gland in the NOD mice treated with CsA decreased compared with the control group, but there was no statistically significant difference. Topical injection of CsA had no adverse effect on liver and kidney function in the NOD mice.@*CONCLUSION@#Topical injection of CsA can reduce lymphocyte infiltration in submandibular gland of NOD mice and improve salivary secretion.
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Animals , Female , Mice , Cyclosporine , Diabetes Mellitus, Experimental/drug therapy , Disease Models, Animal , Inflammation , Mice, Inbred NOD , Saliva , Sjogren's Syndrome , Submandibular GlandABSTRACT
Accurate determination of drug concentration in blood samples is a necessary prerequisite for therapeutic drug monitoring (TDM) and the implementation of precise drug treatment, and it is also one of the important tasks of clinical laboratories.TDM plays an important role in clinical treatment in immunosuppressants (cyclosporine A, tacrolimus), psychotropic drugs (valproic acid, carbamazepine) and other drugs that require monitoring of drug concentration. There are many types of methods used for TDM for the detection of drug concentration in blood samples. At present, only a few immuno-assay methods were approved for marketing with detection systems and kits, most methods used for TDM are high performance liquid chromatography or liquid chromatography-tandem mass spectrometry which belong to laboratory developed tests (LDTs). Detection of TDM samples has many problems, such as incomparable testing results and large bias between different testing systems, including the biasbetween both different methods and different laboratories using the same method. There are several reasons:(1) the traceability chain has not been established, (2) the methods have not yet been standardized, (3) the coverage of the EQA plan is insufficient, (4) the awareness of TDM laboratories to participate in the EQA plan is insufficient, (5) TDM standardization is still in its infancy. These problems restrict the clinical application of TDM and the development of related research work. In order to solve these problems, it is necessary to: (1) Establish a reference system to realize the traceability of the test results; (2) While gradually increasing the TDM EQA plan items, the Trueness evaluation plan should be carried out as soon as possible; (3) Standardized TDM sample testing Technology; (4) Strengthen laboratory management and establish a complete quality management system.
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Type 1 diabetes (T1D) is a chronic autoimmune disordercharacterized by specific immune destruction of the insulinproducing pancreatic β-cells. The loss of β cells involves bothgenetic and ill-defined environmental factors. The highest riskHLA-DR3/4 DQ8 genotype has been shown to be highlyassociated with β-cell autoimmunity and benign insulinitis.Subsequently; catalysts viz. viruses transform predisposedsubjects into overt diabetics. Such autoimmunity is herald byautoantibodies and subsequently low C-peptide production.Hence, there is no ideal autoimmune therapy for T1D sincepatients are genetically predisposed. Previous autoimmunemeasures to suppress early transformations were crippled bylong-term complications of medications. In our case report; welimited the use of Cyclosporine A to 1 year in a patient and itwas cost effective.
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OBJECTIVE: To establish a method for simultaneous quantitative determination of 14 bile acids in human plasma by liquid chromatograohy-tandem mass spectrometry (LC-MS/MS) and to explore the correlation between the hepatotoxicity induced by cyclosporine A and bile acids. METHODS: Plasma samples were extracted by protein precipitation and bile acids were separated on a Waters ACQUITY UPLC HSS T3(2.1 mm×150 mm,1.8 μm) column with a flow rate of 0.3 mL•min-1. The mobile phase was water (containing 4 mmol•L-1 ammonium acetate) and 95% acetonitrile using gradient elution in 15 min. The detection system used an electrospray ion source in negative ion mode. RESULTS: Fourteen bile acids had a good linear relationship, the intra-and inter-assay RSD values were less than 15%, the accuracy was between 87% and 116%, and the extraction recovery rates of the quality was between 101% and 120%. The concentration of cholic acid (CA) was well correlated with cyclosporine A and suggested that bile acids may be associated with the hepatotoxicity induced by cyclosporine A. CONCLUSION: This LC-MS/MS method for quantitatively determining various bile acids in human plasma is convenient, accurate and sensitive and can be used for further basic research in hepatotoxicity caused by cyclosporine A.
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Coronavirus mainly causes local infection in birds and mammals. In recent decades, there has been an evidence that it can infect humans. Highly pathogenic coronavirus, including severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), are fatal zoonotic viruses, which have posed a major threat to public health. Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2, COVID-19) has also seriously endangered the health and safety of the human beings. These coronaviruses transmit through close contact between people, resulting in the development of acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF) and having a higher morbidity and mortality. This article reviews the structure, epidemiology, immunology and treatment of the coronavirus, hoping to provide reference for the prevention, control and treatment of the disease.
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@#AIM: To analyze the efficacy of sodium hyaluronate and cyclosporine A eye drops in treating patients with mixed dry eye disease. <p>METHODS: Among patients diagnosed with dry eye who presented to our hospital between February 2018 to February 2019, 60(120 eyes)cases were divided into 30(60 eyes)in each control and treatment group by random number table method. Both groups received routine treatment with the methods of eyelid hot compress cleaning and meibomian gland massage. The treatment group received combined application of sodium hyaluronate eye drop(0.3%)and cyclosporine A eye drop(1%), while control group received carbomer eye drops used alone at four times daily. And dry eye symptom score, Schirmer I test(SⅠt), tear film break-up time(BUT)and corneal fluorescein staining(CFS)results were obtained before treatment, at the 1 and 3mo after initiation of treatment. <p>RESULTS: No statistically differences were observed in any of the indexes between the control group(dry eye symptom score: 13.52±2.15, SⅠt: 5.22±2.23, BUT: 5.02±1.58, CFS:2.82±0.81)and the treatment group(dry eye symptom score: 13.75+3.05, SⅠt: 5.54+2.89, BUT: 5.14+1.84, CFS: 2.73±0.45)before initiating treatment. One month later, the dry eye symptom score of the control group(12.22±2.64)and the treatment group(11.42±2.06)improved after treatment; the SⅠt of the control group(7.94±2.15)and the treatment group(8.63±2.78)also improved after treatment, and result of the treatment group was better than that of the control group, and the difference was statistically significant; the BUT of the control group(5.32±1.34)and the treatment group(5.46±1.45)were better after treatment, but the difference was not statistically significant. After 3mo treatment, the dry eye symptom score, SⅠt, BUT and CFS of the control group were 11.57±2.98, 8.44±2.35, 5.92±1.75, 1.92±0.44, respectively, and the dry eye symptom score, SⅠt, BUT and CFS of the control group were 9.23±2.34, 10.45±2.65, 5.92±1.75, 8.69±1.78, 1.59±0.79, respectively(<i>P</i><0.05).<p>CONCLUSIONS: Combination therapy of sodium hyaluronate eye drop and cyclosporine A eye drops treatments are effective for the treatment of mixed dry eye syndrome.
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@#AIM: To analyze the efficacy of sodium hyaluronate and cyclosporine A eye drops in treating patients with mixed dry eye disease. <p>METHODS: Among patients diagnosed with dry eye who presented to our hospital between February 2018 to February 2019, 60(120 eyes)cases were divided into 30(60 eyes)in each control and treatment group by random number table method. Both groups received routine treatment with the methods of eyelid hot compress cleaning and meibomian gland massage. The treatment group received combined application of sodium hyaluronate eye drop(0.3%)and cyclosporine A eye drop(1%), while control group received carbomer eye drops used alone at four times daily. And dry eye symptom score, Schirmer I test(SⅠt), tear film break-up time(BUT)and corneal fluorescein staining(CFS)results were obtained before treatment, at the 1 and 3mo after initiation of treatment. <p>RESULTS: No statistically differences were observed in any of the indexes between the control group(dry eye symptom score: 13.52±2.15, SⅠt: 5.22±2.23, BUT: 5.02±1.58, CFS:2.82±0.81)and the treatment group(dry eye symptom score: 13.75+3.05, SⅠt: 5.54+2.89, BUT: 5.14+1.84, CFS: 2.73±0.45)before initiating treatment. One month later, the dry eye symptom score of the control group(12.22±2.64)and the treatment group(11.42±2.06)improved after treatment; the SⅠt of the control group(7.94±2.15)and the treatment group(8.63±2.78)also improved after treatment, and result of the treatment group was better than that of the control group, and the difference was statistically significant; the BUT of the control group(5.32±1.34)and the treatment group(5.46±1.45)were better after treatment, but the difference was not statistically significant. After 3mo treatment, the dry eye symptom score, SⅠt, BUT and CFS of the control group were 11.57±2.98, 8.44±2.35, 5.92±1.75, 1.92±0.44, respectively, and the dry eye symptom score, SⅠt, BUT and CFS of the control group were 9.23±2.34, 10.45±2.65, 5.92±1.75, 8.69±1.78, 1.59±0.79, respectively(<i>P</i><0.05).<p>CONCLUSIONS: Combination therapy of sodium hyaluronate eye drop and cyclosporine A eye drops treatments are effective for the treatment of mixed dry eye syndrome.
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Alzheimer's disease (AD) is one of the most common dementia causes especially in elders. Black raisins (Vitis vinifera) have memoryenhancing effects. This study was designed to investigate the effect of oral administration of black raisins (V. vinifera) on aluminumchloride (AlCl3) induced AD in male albino rats. Forty adult male Albino rats were equally and randomly divided into five groups, 8 rats ineach. The rats of the first group received a vehicle and served as controls. The animals of the second group received raisin (5 g per rat/day)orally for 8 weeks. The rats in the third group were treated with AlCl3 (model of AD) (100 mg/kg BW/day) for 8 weeks. The animals of thefourth group were treated with AlCl3 (100 mg/kg BW/day) and raisin. The animals of the fifth group received rivastigmine (0.3 mg/kgBW/day) and AlCl3 (100 mg/kg BW/day) orally for 8 weeks. After eight weeks, the behavioral test (maze learning test) was performed on allrats to assess learning and memory. Moreover, acetylcholinesterase (AchE) activity, some neurotransmitter levels [dopamine (DA),norepinephrine (NE), gamma-aminobutyric acid (GABA)], and oxidative stress [reduced glutathione (GSH), superoxide dismutase (SOD),oxidase glutathione (GSSG), and lipid peroxidation (LPO)] were estimated in the cortex and hippocampus homogenate. Thehistopathological studies were also made in the hippocampus area. The results showed that aluminum exposure significantly decreased thelearning and memory in the maze-learning test as revealed by increase in elapsed time and error number in the maze. Significant increaseof cortex and hippocampus homogenate levels of AchE and LPO, but a significant decrease in DA, NE, GABA, GSH, GSSG, and SOD wereobserved in rats subjected to AlCl3. Histopathological evaluations of hippocampus sections of rats treated with AlCl3 showed severealterations including the increase of degenerated cells with structural damage. The treatment of rats with raisin or rivastigmine for 8 weeksshowed a pronounced attenuation on the damage caused by AlCl3 associated with the improvement of behavioral, biochemical, andhistopathological alterations. This study suggested that chronic oral administration of black raisin had neuroprotective effects andimproved learning and memory in AD animal models. These actions were done due to the antioxidant constituents of raisin.
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Background: Hepatotoxicity induced by Cyclosporine A (CsA) remains one of the major side effects. The aim of this studywas to determine the protective effects of beet root (Beta Vulgaris L) extract and silymarin against hepatotoxicity induced byCyclosporine A in rats. Methods: Sixty male albino rats, were divided into 6 groups (n=10). Group I control group. GroupII CsA-treated and received (50mg/kg weight, orally). Group III received (500mg/kg b.wt) beet root extract orally. Group IVreceived beet root extract and CsA as in group II and III. Group V was received (100 mg/kg b.wt) silymarin orally. Group VIreceived CsA and silymarin as in group II and V. Serum levels of (ALT, AST, ALP) and bilirubin (Total and Direct) weremeasured. Oxidative stress biomarkers, antioxidant status, damage to DNA, apoptosis and inflammatory mediators weremeasured in the tissues of the liver. Result: CsA administration significantly increased serum levels of the liver enzymesALT, AST, ALP and bilirubin. In addition, significant increase in MDA, Nitrite, 8-OHdG, caspase3, NF-κB, TNF-α andsignificant decrease of GST in liver tissues was noticed. Furthermore, histopathological changes occurred in CsA treatedrats exhibited disruption of normal liver architecture, congested central vein, vacuolated cytoplasm and inflammatory cellsinfiltration. Co-administration of beet root extract or silymarin +CsA ameliorated all these parameters. Conclusion: Thepresent study suggests that beet root extract and silymarin have beneficial effect in reducing hepatotoxicity induced by CsAvia decreasing oxidative stress, inflammation, DNA damage, apoptosis and repairing the histopathological changes
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OBJECTIVE： To systematically evaluate the correlation between CYP3A5 6986A＞G gene polymorphism and blood concentration of Cyclosporine A （CsA） in Chinese renal transplant recipients. METHODS： Retrieved from Cochrane Library， PubMed， Embase， CBM， CNKI， VIP and Wanfang database， case-control or cohort studies about Chinese patients receiving CsA immunosuppressive therapy and blood concentration monitoring after kidney transplantation were collected. After literature screening and data extracting， the quality of literature was evaluated with Newcastle Ottawa scale， and Meta-analysis was performed by using Rev Man 5.3 software. RESULTS： Eight literatures with a total of 890 patients were involved in cohort study. Meta-analysis showed that the trough concentration after dosage correction （C0/D） of CsA in CYP3A5*1/*1 genotype was significantly lower than CYP3A5*1/*3 genotype[MD＝－6.97，95％CI （－13.18，－0.76），P＝0.03]. The subgroup analysis showed that the C0/D of CsA in CYP3A5*1/*1 genotype was significantly lower than CYP3A5*1/*3 genotype when test time≤1 month after renal transplant [MD＝－8.50，95％CI（－12.57，－4.43），P＜0.000 1] and ＞1-＜6 months after renal transplant [MD＝－14.02，95％CI（－26.28， －1.76），P＝0.02]. C0/D of CsA in CYP3A5*1/*3 genotype was significantly lower than CYP3A5*3/*3 genotype [MD＝－6.04，95％CI（－8.99，－3.09），P＜0.000 1]. The subgroup analysis showed that C0/D of CsA in CYP3A5*1/*3 genotype was significantly lower than CYP3A5*3/*3 genotype when test time ≤1 month after renal transplant [MD＝－6.94，95％CI（－10.21， －3.68），P＜0.000 1]. C0/D of CsA in CYP3A5*1/*1 genotype was significantly lower than CYP3A5*3/*3 genotype [MD＝－12.64，95％CI（－21.09，－4.20），P＝0.003]. The subgroup analysis showed that C0/D of CsA in CYP3A5*1/*1 genotype was significantly lower than CYP3A5*3/*3 genotype when test time ≤1 month after renal transplant [MD＝－16.69，95％CI（－24.03，－9.36），P＜0.000 01] and ＞1-＜6 months after renal transplant [MD＝－16.78，95％CI（－28.63，－4.93），P＝0.006]. There was no statistical significance in CsA of peak concentration after dose correction between CYP3A5*1/*1 genotype and CYP3A5*1/*3 genotype， CYP3A5*1/*3 genotype and CYP3A5*3/*3 genotype， CYP3A5*1/*1 genotype and CYP3A5*3/*3 genotype. CONCLUSIONS： CYP3A5 6986A＞G gene polymorphism is associated with C0/D of CsA in Chinese renal transplantation recipients. The sequence of C0/D when test time ≤1 month after renal transplantation is as follows as CYP3A5*1/*1 genotype＜CYP3A5*1/*3 genotype＜CYP3A5*3/*3 genotype； during＞1-＜6 months after renal transplantation， C0/D of CsA in CYP3A5*1/*1 genotype＜CYP3A5*1/*3 genotype and CYP3A5*1/*1 genotype＜CYP3A5*3/*3 genotype.
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Understanding the effect of immunosuppressive agents on intestinal microbiota is important to reduce the mortality and morbidity from orthotopic liver transplantation (OLT). We investigated the relationship between the commonly used immunosuppressive agent cyclosporine A (CSA) and the intestinal microbial variation in an OLT model. The rat samples were divided as follows: (1) N group (normal control); (2) I group (isograft LT, Brown Norway [BN] rat to BN); (3) R group (allograft LT, Lewis to BN rat); and (4) CSA group (R group treated with CSA). The intestinal microbiota was assayed by denaturing gradient gel electrophoresis profiles and by using real-time polymerase chain reaction. The liver histopathology and the alanine/aspartate aminotransferase ratio after LT were both ameliorated by CSA. In the CSA group, the numbers of rDNA gene copies of Clostridium cluster I, Clostridium cluster XIV, and Enterobacteriaceae decreased, whereas those of Faecalibacterium prausnitzii increased compared with the R group. Cluster analysis indicated that the samples from the N, I, and CSA groups were clustered, whereas the other clusters contained the samples from the R group. Hence, CSA ameliorates hepatic graft injury and partially restores gut microbiota following LT, and these may benefit hepatic graft rejection.
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The poor solubility of cyclosporine A (CsA) in water limits its oral absorption. We prepared CsA/ Soluplus/SDS complex, which can form CsA/Soluplus/SDS supersaturated micelles (CSS-SM) after hydration. Then, We further prepared CSS-SM osmotic pump tablets (CSS-SM-T). CSS-SM had a particle size of 156 nm, where in encapsulation efficiency and drug loading efficiency of CsA were 89.0% and 17.5%, respectively. CSS-SM-T achieved zero-level drug release in vitro. Pharmacokinetic data from Beagle dogs (all animal experiments were conducted under the guidelines approved by the Institutional Animal Care and Use Committee of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences) indicated that CsA in the ordinary osmotic pump tablets was hardly absorbed after orally administered; despite slightly lower bioavailability [relative bioavailability: (85.1 ± 47.4) %] than that of Sandimmum Neoral, CSS-SM-T displayed lower fluctuations in CsA plasma concentration and obvious sustained-release characteristics in vivo, implying lower toxicity. Therefore, CSS-SM-T provides a new research idea for the design and development of oral sustained- and controlled-release preparations of poorly water-soluble drugs.
ABSTRACT
Objective To investigate the corneal permeability of cyclosprin A (CsA) loaded on polymeric vector after topical application.Methods The grafted copolymer chitosan-graft-cyclodextrin (CS-g-CD) was synthesized,and the physicochemical structures of the polymer were investigated using nuclear magnetic resonance spectroscopy (NMR) and fourier transform infrared spectroscopy (FT-IR).A novel CsA eye drop was prepared using the grafted copolymer as carrier material.The physicochemical properties of eye drop,including drug-loading content,osmotic pressure and viscosity were investigated by high performance liquid chromatography-mass spectrometry (HPLC-MS),osmotic pressure gauge and viscometer,respectively.New Zealand albino rabbits were randomly divided into intact cornea CsA group,epithelium debrided CsA group and epithelium debrided control group.The corneal epithelia of the left eyes was debrided in the cornea epithelium debrided group.Cornea irritation test was performed on New Zealand albino rabbits.The aqueous humor was taken and the corneas were collected at 0.5 hour and 1 hour after instilled.The concentration of CsA was measured by HPLC-MS.Cy5 labeled vector loaded with Coumarin 6 served as model copolymers system,the penetration capabilities of the double fluorescent labeling copolymers system were monitored in vivo using two-photon scanning fluorescence microscopy on murine corneas after topical application.The use and care of the animals complied with Regulations for the Administration of Affair Concerning Experimental Animals by State Science and Technology Commission.Results The polymer of CS-g-CD was successfully synthesized and confirmed using NMR and FT-IR.The drug loading of CsA in eye drop solution was 0.06 ％;the osmotic pressure was 305 mOsmol/kg and the viscosity was 36.5 cP.The CsA drug delivery system had a reversible temperature-sensitive drug release behavior and had no obvious irritation on the eyes of New Zealand rabbits.One hour after treatment,the concentration of CsA in the cornea and aqueous humor of epithelium debrided CsA group was (5.88 ± 1.46) μg/g and (149.19 ± 3.93) ng/ml,respectively,which was significantly higher than (3.98 ±0.95) μg/g and (30.25± 11.43) ng/ml in epithelium debrided control group (both at P＜0.05);the concentration of CsA in the aqueous humor of intact cornea CsA group was (7.23 ± 1.31)ng/ml,which was significantly lower than that in epithelium debrided CsA group (P＜0.05).Polymer vectors were mainly retained in the corneal epithelium,and coumarin 6 gradually diffused into the deep corneal stroma with time.Conclusions The grafted copolymer can load CsA,and the eye drop can effectively overcome the corneal barrier and increase the corneal permeability of CsA.