Oral Cyclosporin A Research Articles

Two-photon fluorescence probe for quantification of cyclosporine.

A novel ratiometric fluorescent sensor was fabricated for the fast and facile determination of cyclosporine A (CsA). Due to the narrow therapeutic index of CsA, its desired therapeutic effects are evident within a limited range of blood concentration, indicating the fundamental role of therapeutic drug monitoring in CsA pharmacological response. In this study, a two-photon fluorescence probe based on the zeolitic imidazolate framework (ZIF-8) and norepinephrine-capped silver nanoparticles (AgNPs@NE) was employed for the quantification of the CsA in human plasma samples. In the presence of CsA, the fluorescent emission intensity of ZIF-8-AgNPs@NE was quenched. Under the optimum conditions, the proposed probe determines CsA in plasma samples in two linear ranges of 0.01 to 0.5 μg mL-1 and 0.5 to 10 μg mL-1. The developed probe demonstrates the advantages of a facile and fast platform with limit of detection as low as 0.007 μg mL-1. At last, this method was applied to find CsA concentration in four patients receiving oral CsA regimen which indicates it as a promising method for on-site detection applications.

Effect of posaconazole on the concentration of intravenous and oral cyclosporine in patients undergoing hematopoietic stem cell transplantation.

This study aimed to investigate the interactions between posaconazole (POS) and intravenously/orally administered cyclosporine A (CsA) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We included 118 allogeneic HSCT patients who received CsA and POS simultaneously between January 2017 and June 2020 in this study. The ratio of CsA blood concentration (ng/mL) to dosage (mg/day) (C/D) before and after POS initiation was compared. After the initiation of POS, the level of CsA increased 1 to 2 times in 66% (78/118) of patients compared to those without POS. However, the CsA C/D ratio increased by more than threefold in 6% (7/118) of patients after POS initiation, with an increase of more than fourfold in two patients. The median C/D ratio of CsA increased from 0.89 to 1.23 (P < 0.001) and 0.78 to 1.22 (P < 0.001) after POS initiation when CsA was administered intravenously and orally, respectively. In patients who received POS at the time of transition from intravenous to oral CsA, the value increased from 1.01 to 1.38 (P = 0.001). The route of administration had no significant effect on the change in the CsA C/D ratio (P = 0.615). Additionally, we observed the time required for the C/D ratio to reach a plateau after POS initiation was similar on days 13, 8, and 15 under various scenarios. POS treatment increased blood CsA levels. A large variability was found in the fold-change in the CsA C/D ratio. Therefore, CsA doses should be adjusted by closely monitoring the blood levels of CsA after POS initiation.

A pilot study on oral cyclosporine A in association with fulguration for the treatment of interstitial cystitis with Hunner's lesions.

To evaluate the efficacy and safety of lesion fulguration in combination with cyclosporine A (CyA) as a maintenance therapy in patients with interstitial cystitis/bladder pain syndrome (IC/BPS) with Hunner's lesion (HL). Retrospective observational study of refractory patients with HL treated with daily 1.5 mg/kg or less of oral CyA following lesion fulguration. Pain severity, subjective improvement, urinary symptoms, and adverse events were used to assess long-term treatment efficiency and safety. Among the 22 patients, median follow-up under CyA was 27 months. Patients reported sustained significant reduction compared to pretreatment in pain (0/10 vs. 8/10; p < 0.001), urinary frequency per 24 h (9.5 vs. 20.8; p < 0.001), and nocturia (2.3 vs. 7.6; p < 0.001). Subjective improvement rate (SIR) and patient global impression of improvement were of 90% and 1 ("very much better"), respectively, including four patients who considered themselves cured (SIR: 100%). Three patients needed an additional procedure due to pain relapse. Minor increase in creatinine was observed and three patients developed or worsened their arterial hypertension. CyA dosage was decreased to 1.2 mg/kg or less for long-term relief (n = 8), creatinine increase (n = 5), and neutropenia (n = 1) with subsequent improvement in renal function without symptom deterioration. Oral CyA seems to allow a sustained long-term relief following HL fulguration by alleviating pain, decreasing urinary symptoms, and procuring great subjective improvement. The daily low dose of 1.5 mg/kg or less appears to have limited adverse events while preventing repeated procedures. Larger trials are warranted.

The Effect of Particle Size on the Absorption of Cyclosporin A Nanosuspensions.

BackgroundCyclosporin A (CsA) is a hydrophobic drug widely used as an immunosuppressant and anti-rejection drug in solid organ transplantation. On the market, there are two oral CsA formulations available containing polyoxyethylene castor oil, which can cause serious allergic reactions and nephrotoxicity. In order to eliminate polyoxyethylene castor oil, CsA was formulated into a nanosuspension. This study aimed to design an oral cyclosporin A nanosuspensions (CsA-NSs) and investigate the effect of particle size on absorption of CsA-NSs.MethodsCsA-NSs were prepared using a wet bead milling method. Particle size, morphology and crystallinity state of CsA-NSs were characterized. The in vitro dissolution, the intestinal absorption properties and pharmacokinetic study of CsA-NSs were investigated.ResultsCsA-NSs with sizes of 280 nm, 522 nm and 2967 nm were prepared. The shape of CsA-NSs with smaller size was similar to that of spheres. The crystallinity of CsA in nanocrystals was reduced. The dissolution rate of CsA-NSs (280 nm) was greater than that of CsA-NSs (522 nm) and CsA-NSs (2967 nm). CsA-NSs (280 nm) showed higher absorption rate constants (Kα) and effective permeability coefficients (Peff) of different intestinal segments compared with that of CsA-NSs (522 nm) and CsA-NSs (2967 nm). AUC0-48h of 280 nm CsA-NSs was about 1.12-fold of that of 522 nm CsA-NSs, and about 1.51-fold of that of 2967 nm CsA-NSs. In particular, the particle size of CsA-NSs was nanoscale, and their bioavailability was bioequivalent with marked self-microemulsion (Sandimmun Neoral®).ConclusionIt is feasible to prepare CsA-NSs. The dissolution rate, gastrointestinal transport properties and the oral absorption of CsA-NSs were promoted by reducing size. Considering the cost, efficiency and energy consumption, there should be an optimal particle size range in industrial production.

Development of softgel capsules containing cyclosporine a encapsulated pine essential oil based self-microemulsifying drug delivery system

In this study, a new self-microemulsifying drug delivery system (SMEDDS) based on pine essential oil has been designed and successfully developed to load cyclosporine A (CsA), a poorly water-soluble immunosuppressant, for oral CsA softgel manufacturing. SMEDDS were prepared from pine essential oil and Capmul MCM as oily phases, Kolliphor RH 40 as surfactant, polyethylen glycol 400 as co-surfactant/co-solvent and none volatized co-solvent utilizing the pseudo-ternary phase diagrams. CsA SMEDDS loading 9.09% of CsA, dispersed in aqueous environments (water, pH 1.2, 4.5 and 6.8 buffers), presented an average droplet size of about 160 nm with polydispersity index (PdI) below 0.25, and were stable after 6 h of self-emulsification. Cytotoxicity of CsA SMEDDS on LLC-PK1 cells demonstrated that CsA SMEDDS had an IC50 value greater than that of the reference product, suggesting product safety against nephrotoxicity. CsA SMEDDS was filled into oval-5 soft gelatin capsules (softgels) containing 0.5% glycine which could avoid the cross-linking process. Additionally, CsA SMEDDS softgels presented the in vitro release profiles equivalent to that of Sandimmun Neoral® at pH 1.2, 4.5 and 6.8. Therefore, the pine essential oil based SMEDDS was considered to be potential and suitable for developing softgels to enhance the oral bioavailability of CsA.

Effects of diurnal variation of bile acids by meal on cyclosporine A absorption.

Stabilizing blood levels with microemulsified cyclosporine A (CsA), administered in many pediatric kidney diseases, is important for effective immunosuppression and reduced nephrotoxicity. CsA is affected by total bile acids (TBAs); however, no reports have simultaneously measured both. We aimed to elucidate the hypothesized relationship between TBA levels and diurnal variation in CsA in children. We retrospectively reviewed the medical records of children who were taking oral CsA for the treatment of kidney diseases between January 2016 and July 2021. They consumed four balanced meals and snacks during the day. CsA and TBA were measured twice, in pairs, before and at 0.5, 1, 1.5, 2, 3, and 4 h after oral administration in the morning and evening, and the four-h area under curve (AUC)0-4 of CsA and trough-to-peak ratio (TPR) of TBA were compared. Fifty-eight pairs were measured in total; 12 children had idiopathic nephrotic syndrome and 4 children had immunoglobulin A vasculitis with nephritis. The median age at measurement was 7.5 years and the dose of CsA was 3.8 mg/kg/day. The AUC0-4 (ng·h/mL) was significantly lower in the evening than in the morning (1,669 vs. 1,451, P < 0.001). The TPR of TBA was significantly higher in the evening than in the morning (0.14 vs. 0.25, P < 0.001). The low AUC0-4 and slow TBA secretion observed in the evening may be due to pediatric-specific dietary rhythms; thus, snack timing should be considered in children for stabilizing CsA levels.

Drug delivery formulation impacts cyclosporine efficacy in a humanised mouse model of acute graft versus host disease

Acute graft versus host disease (aGvHD) is an allogeneic T cell mediated disease which manifests as a severe inflammatory disease affecting multiple organs including the liver, skin, lungs and gastrointestinal tract. Existing prophylactic and therapeutic approaches in aGvHD include the use of cyclosporine A (CyA), however the currently approved CyA formulations which were designed to optimise systemic CyA bioavailability can have a number of side effects including nephrotoxicity as well as the potential to attenuate the beneficial Graft-versus-Leukemia (GvL) effect. An added complication with CyA is that it has a narrow therapeutic window, and following oral administration is absorbed only from the small intestine, with variable cytochrome P450 metabolism contributing to intra- and inter-patient variability. This study sought to investigate the efficacy of a novel CyA oral formulation enabled by the integrated SmPill® oral drug delivery platform in a humanised mouse model of aGvHD. The study compared the approved optimised CyA (Neoral®) with SmPill®-enabled CyA and a systemic intravenous CyA formulation. Our findings clearly demonstrate superior efficacy of the novel SmPill® CyA in prolonging survival in a clinically relevant humanised aGvHD model. SmPill® CyA significantly reduced pathological score in the small intestine, colon, liver and lung of aGvHD mice. In addition, SmPill® CyA significantly reduced the levels of pro-inflammatory cytokines in all the GvHD target tissues examined. Notably, SmPill® CyA was significantly more potent in reducing GvHD associated pathology and inflammatory cytokine production compared to the optimised approved oral CyA formulation, Neoral®.

An investigation of the effectiveness of oral cyclosporine on perioperative myocardial injury (PMI) in patients who undergo the surgical procedure of coronary artery bypass graft (CABG): A Randomized Controlled Clinical Trial.

Background:Routine clinical strategies for the prevention of myocardial infarction (MI) during the surgical procedure of CABG include cross-clamp fibrillation and cardioplegia have failed to decrease the risk of perioperative myocardial injury (PMI). Cyclosporine-A (CsA) might be able to prevent mitochondrial dysfunction and PMI.Methods:In the present clinical trial, patients were divided into two groups (Case receive 2.5 mg/kg CsA and Control receive a placebo) randomly. Moreover, patients were controlled by placebo through a double-blind, single-center trial 4-12 h before anesthesia. Perioperative blood tests include bilirubin, complete blood count, the amount of hemoglobin in whole blood, liver transaminases, and glomerular filtration rate (GFR). Blood samples were taken before surgery and at 24, 48, and 72 h after surgery and serum Troponin-I and CK-MB levels were determined in all blood samples using ELISA.Results:There were no significant differences between the two groups in the results of routine pre-operative blood results, intraoperative variables, and baseline characteristics (P > 0.05). There are significant correlations between cross clamp time and cTnI and CKMB levels in patients taking CsA. In patients with both diabetes and hypertension, postsurgical cTnI and CKMB levels decrease significantly in CsA compared to placebo group on 24, 48, and 72 h (P < 0.05). Moreover, patients with old MI, both postsurgical cTnI and CKMB levels decrease significantly in CsA compared to placebo group on 24 h and 48 h (P < 0.05).Conclusions:In patients with a long cross-clamping period, using an oral CSA single dose before conducting CABG surgery, the risk of PMI could be decreased. Also, oral CsA has protective effect for CABG in diabetic patients with hypertension.

Dextran sulfate sodium-induced colitis and ginseng intervention altered oral pharmacokinetics of cyclosporine A in rats

Ethnopharmacological relevanceApplication of cyclosporine A (CsA) as a rescue treatment in acute severe ulcerative colitis (UC) is limited by its narrow therapeutic window and great interpatient variability. As a substrate of cytochrome P450 3A enzyme (CYP3A) and P-glycoprotein (P-gp), the oral pharmacokinetics of CsA is susceptible to disease status and concomitant medications. Combined treatment with ginseng, a famous medicinal herb frequently prescribed for ameliorating abnormal immune response in many diseases including UC, showed immunologic safety in CsA-based immunosuppression. Aim of the studySince the therapeutic levels of CsA can be achieved within 24 h, this study first assessed the impact of acute colitis and ginseng intervention on the single oral dose pharmacokinetics of CsA and explored the underlying mechanisms in dextran sulfate sodium (DSS)-induced colitis rats and Caco-2 cells. Materials and methodsRats received drinking water (normal group), 5% DSS (UC group), or 5% DSS plus daily oral ginseng extract (GS+UC group). On day 7, GS+UC group only received an oral dose of CsA (5 mg/kg), while animals of normal or UC group received an oral, intravenous (1.25 mg/kg), or intraperitoneal dose of CsA (1.25 mg/kg), respectively. Blood, liver/intestine tissues and fecal samples were collected for determining CsA and main hydroxylated metabolite HO-CsA or measuring hepatic/intestinal CYP3A activity. Caco-2 cells were incubated with gut microbial culture supernatant (CS) of different groups or ginseng (decoction or polysaccharides), and then CYP3A, P-gp and tight junction (TJ) proteins were determined. ResultsOral CsA exhibited enhanced absorption, systemic exposure and tissue accumulation, and lower fecal excretion, while intravenous or intraperitoneal CsA showed lower systemic exposure and enhanced distribution, in colitis rats. Diminished intestinal and hepatic P-gp expression well explained the changes with DSS-induced colitis. Moreover, blood exposures of HO-CsA in both normal and colitis after oral dosing were significantly higher than intravenous/intraperitoneal dosing, supporting the dominant role of intestinal first-pass metabolism. Interestingly, colitis reduced CYP3A expression in intestine and liver but only potentiated intestinal CYP3A activity, causing higher oral systemic exposure of HO-CsA. Oral ginseng mitigated colitis-induced down-regulation of CYP3A and P-gp expression, facilitated HO-CsA production, biliary excretion and colonic sequestration of CsA, while not affected CsA oral systemic exposure. In Caco-2 cells, gut microbial CS from both colitis and GS+UC group diminished P-gp function, while ginseng polysaccharides directly affected ZO-1 distribution and suppressed TJ proteins expression, explaining unaltered oral CsA systemic exposure. ConclusionsDSS-induced colitis significantly altered oral CsA disposition through regulating intestinal and hepatic P-gp and CYP3A. One-week ginseng treatment enhanced colonic accumulation while not altered the systemic exposure of CsA after single oral dosing, indicating pharmacokinetic compatibility between the two medications.

MP07-05 DESCRIPTIVE ANALYSIS OF PATIENTS WITH HUNNER LESION TREATED WITH FULGURATION OR INTRALESIONAL TRIAMCINOLONE INJECTIONS IN ASSOCIATION WITH CYCLOSPORINE A

You have accessJournal of UrologyInfections/Inflammation/Cystic Disease of the Genitourinary Tract: Interstitial Cystitis (MP07)1 Apr 2020MP07-05 DESCRIPTIVE ANALYSIS OF PATIENTS WITH HUNNER LESION TREATED WITH FULGURATION OR INTRALESIONAL TRIAMCINOLONE INJECTIONS IN ASSOCIATION WITH CYCLOSPORINE A Frederique Bouchard*, Raphaëlle Brière, Annie-Kim Gareau Labelle, and Le Mai Tu Frederique Bouchard*Frederique Bouchard* More articles by this author , Raphaëlle BrièreRaphaëlle Brière More articles by this author , Annie-Kim Gareau LabelleAnnie-Kim Gareau Labelle More articles by this author , and Le Mai TuLe Mai Tu More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000827.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Lesion fulguration or intralesional triamcinolone injections are the recommended efficient treatments for interstitial cystitis-bladder pain syndrome (IC-BPS) with Hunner lesions (IC-HL). However, repeated procedures due to symptom recurrence are frequent. Limited number of studies reported cyclosporine A (CyA) as an effective treatment for IC-HL, but adverse events (AE) are common thus making CyA a last-line option. Our objective was to assess the efficacy and safety of lesion fulguration or triamcinolone injections in association with oral CyA in patients with refractory IC-HL. We hypothesized that low-dose CyA could allow a sustained symptom alleviation therefore decreasing the need for repeated procedures and preventing occurrence of AE. METHODS: This was a retrospective observational study of 20 refractory IC-HL patients treated with daily 1.5 mg/kg of CyA following fulguration (n=16) or triamcinolone injection (n=4) between 2007 and 2019. Primary outcomes, assessed at the last follow-up, were pain severity (0 to 10 scale), flares and subjective improvement (assessed via Subjective Improvement Rate [SIR] and Patient Global Impression of Improvement [PGI-I]). Urinary frequency (UF), nocturia and CyA safety were evaluated as secondary outcomes. RESULTS: Median follow-up was 16.5 months. Among the 20 patients, the median pain score was 0/10 (8/10 pre-treatment) and only 2 patients still reported flares. Median SIR and PGI-I were 82.5% and 1/7 respectively, including 6 patients who considered themselves cured (SIR 100%). Post-treatment UF and nocturia also significantly improved (table 1). Following the procedure, 4 patients experienced symptoms relapse and required additional procedures while continuing CyA medication for adequate symptom relief. All other 16 patients maintained symptom alleviation at the last follow-up. No patient presented elevated blood pressure or clinically significant elevation in creatinine levels. CONCLUSIONS: CyA appears to be an efficient treatment following HL fulguration or triamcinolone injection by allowing sustained pain alleviation, great subjective improvement and a decrease in UF and nocturia. The low dose of 1.5 mg/kg seems to limit AE while still preventing symptom recurrence. Source of Funding: None © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e97-e97 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Frederique Bouchard* More articles by this author Raphaëlle Brière More articles by this author Annie-Kim Gareau Labelle More articles by this author Le Mai Tu More articles by this author Expand All Advertisement PDF downloadLoading ...

Therapeutic options and prognosis of chronic idiopathic erythroderma in older adults.

The present authors have previously reported that chronic idiopathic erythroderma (CIE) that lasts for more than 3 months without specific causes occurs almost exclusively in older men. No standardized therapeutic treatments for the condition have been established to date. To assess the efficacies and safeties of current treatments for CIE, the present authors reviewed cases of CIE. Twenty cases were identified, of which CIE was treated with oral corticosteroids, oral cyclosporine A (CsA), ultraviolet therapy, or a combination of these therapies. CIE was cured in 8/20 (40%) of these cases, and the average time to cure was 19.3 months. Oral CsA was the most effective treatment at relatively low doses (50-100 mg/day), which resulted in cures in four cases. Ultraviolet therapy also effectively cured two subjects, and oral corticosteroids cured one patient. In patients that were treated with oral CsA or corticosteroids, the terminations of the treatments within 2 to 3 months resulted in relapses in multiple patients. The maintaining of the treatments for a certain period may be necessary in cases that involve treatments with these orally administered drugs. Although CIE is a chronic and potentially refractory disease, it can evidently be cured or well controlled via appropriate long-term therapies.

A Single Dose of Baicalin Has No Clinically Significant Effect on the Pharmacokinetics of Cyclosporine A in Healthy Chinese Volunteers.

Despite its narrow therapeutic window and large interindividual variability, cyclosporine A (CsA) is the first-line therapy following organ transplantation. Metabolized mainly by CYP3A and being a substrate of P-glycoprotein (P-gp), CsA is susceptible to drug–drug interactions. Baicalin (BG) is a drug used for adjuvant therapy of hepatitis in traditional Chinese medicine. Since its aglycone baicalein (B) inhibits CYP3A and P-gP, co-administration might affect CsA pharmacokinetics. This study investigated the effect of BG on CsA pharmacokinetics. In a two-period study, 16 healthy volunteers received a single 200 mg oral CsA dose alone (reference period) or in combination with 500 mg BG (test period). Pharmacokinetic evaluation of CsA was carried out using non-compartmental analysis (NCA) and population pharmacokinetics (popPK). Treatments were compared using the standard bioequivalence method. Based on NCA, 90% CIs of AUC and Cmax test-to-reference ratios were within bioequivalence boundaries. In the popPK analysis, a two-compartment model (clearance/F 62.8 L/h, central and peripheral volume of distribution/F 254 L and 388 L) with transit compartments for absorption appropriately described CsA concentrations. No clinically relevant effect of 500 mg BG co-administration on CsA pharmacokinetics was identified and both treatments were well tolerated.

Interaction of Cyclosporine A with Pomegranate Juice and Its Potential Nephroprotective Effect in Rats

Objectives: To study the effect of concomitant administering of pomegranate juice orally (PJ) on bioavailability of cyclosporine A (CsA) and independently its potential nephroprotective effect against CsA induced nephrotoxicity.&#x0D; Methods: A- Pharmacokinetic study (PK), Wister rats were divided into groups (each 6 rats) I-: CsA PO + Vehicle; II- CsA IP + Vehicle, III- CsA PO + PJ, IV- CsA IP + PJ. CsA dose was 20 mg/kg for 5 days the vehicle or PJ (2 ml) was given 1 h before drug administration. Blood samples were taken at the 1st and 5th day at specified times and CsA level was determined by immune assays. Relative bioavailability of CsA was determined.&#x0D; B- Nephroprotection study (separate study to administer bioequivalent CsA PO doses, in view of PK study), I- ( CsA 13 mg PO + 2 ml PJ .II- CsA 20 mg P0 + 2 ml vehicle (for 28 day). The design also includes two control groups (vehicle alone or PJ alone). Blood samples for drug analysis, biochemical investigations and kidney samples for histopathology were taken at the 28th day.&#x0D; Results: PJ juice enhanced the bioavailability of oral CsA by about 50% (P &gt; 0.05). But CsA (IP) was not affected after repeated administration for 5 days. Independently, the marked kidney damage induced by CsA was reversed by concomitant administration of PJ as well as it attenuated the increase in serum creatinine.&#x0D; Conclusions: Repeated administration of pomegranate juice enhance CsA oral bioavailability which likely due to inhibition of intestinal enzymes and transport pump. Independently it caused significant attenuation of CsA induced renal toxicity.

Cyclosporin-A Treatment in Steroid Nonresponsive Nephrotic Syndrome

Fifteen patients with steroid nonresponsive nephrotic syndrome (NS) aged 4-16 years received oral cyclosporin-A (CyA) for 12 weeks. Nine of the patients were boys. Out of the 15 patients, 7 were frequent relapsers, 3 were steroid dependents, 4 were steroid resistants and one with toxic steroid. After 12 weeks of CyA treatment;, 6 patients showed complete remission, 7 showed partial remission, and 2 patients did not respond at all. Side effects observed were slight renal function impairment, gingival hyperplasia, and a hump on the breast; all disappeared gradually after stopping CyA. Patients with total remission experienced relapse 2 to 12 months after discontinuation of CyA, while patients with partial remission experienced relapse 2 weeks to 3 months after CyA was discontinued A tentative conclusion can be drawn that CyA is a good alternative in the treatment of idiopathic NS, especially in steroid dependent patients who are at risk of developing steroid toxicity. CyA represent a major advance in the treatment selected SN patients who have failed with the conventional modes of therapy.

Optimal sampling time‑point for cyclosporin A concentration monitoring in heart transplant recipients

The present study was performed to determine an optimal time-point for monitoring the concentration of the immunosuppressive drug cyclosporin A (CsA) in heart transplant patients and its efficacy in the prevention of transplant rejection. A total of 32 transplant recipients were randomly assigned for three treatment approaches. Recipients in groups A (n=11), B (n=13) and C (n=8) received oral administration of CsA at doses of 3.2, 3.5 and 4.4 mg/kg, respectively. The plasma CsA concentrations were examined at 2 h intervals over 12 h. Furthermore, their correlation with the 4 h pharmacokinetic profiles as the area under the plasma CsA concentration vs. time curve (AUC0-4 h) were calculated The efficacy of CsA in inhibiting cardiac allograft rejection was assessed at 2 h after oral CsA intake (C2) and adverse events of the drug were examined in the C2-monitored recipients. The plasma CsA concentration rapidly increased in most recipients with a peak level detected at ~2 h after dosing. Regression analysis revealed that among all time-points assessed, the CsA had the highest correlation with the AUC0-4 h at C2. At C2, increasing CsA doses exhibited a positive association with the measure of AUC0-4 h. The efficacy of increasing CsA target levels at C2 in preventing heart transplant rejection was comparable, as the survival rate was 100% in all of the treatment groups. However, the proportion of recipients with side effects in group A was obviously lower than that in the other two groups. In conclusion, C2 is an ideal time-point for monitoring plasma CsA levels with a utility for individualising the next scheduled dose for each patient to ensure that target levels are maintained and achieve a high efficacy and safety of CsA therapy in heart transplant recipients (clinical trial no. 12002610).

Quercetin‑3‑O‑β‑D‑glucoside decreases the bioavailability of cyclosporin A through regulation of drug metabolizing enzymes, transporters and nuclear receptors in rats.

Quercetin is a flavonoid compound that is widely present in food and drink. Quercetin-3-O-β-D-glucoside (Q3GA) is a major metabolite of quercetin. The aim of the present study was to investigate the effect of Q3GA on the pharmacokinetics of orally and intravenously administered cyclosporin A (CsA) in rats, and to assess the effect of Q3GA on drug-metabolizing enzymes (DMEs), drug transporters (DTs) and nuclear receptors (NRs). The pharmacokinetic parameters of CsA were measured following oral (10 mg/kg) and intravenous (2.5 mg/kg) administration of CsA in the presence or absence of Q3GA. The mRNA and protein expression levels of DMEs, DTs and NRs in the liver and small intestine were detected by quantitative polymerase chain reaction and western blot analysis. The results indicated that the intravenous administration of Q3GA (2.5, 5 or 10 mg/kg) for 7 consecutive days reduced the bioavailability of oral CsA. By contrast, the pharmacokinetics of the intravenous administration of CsA were not affected by Q3GA. However, the mRNA and protein expression levels of DMEs and DTs were inhibited by Q3GA. The activation of DMEs and DTs by NRs, and the interplay between DMEs and DTs, may explain these results. The present study identified a novel flavonoid-drug interaction, which may have implications for patients taking CsA and quercetin supplements or on a quercetin-containing diet.

Efficacy, Side Effects, and Monitoring of Oral Cyclosporine in Interstitial Cystitis-Bladder Pain Syndrome

To evaluate the efficacy of oral cyclosporine A (CyA) in the treatment of refractory interstitial cystitis-bladder pain syndrome (IC-BPS) and to assess safety using drug level and renal function monitoring. Patients with IC-BPS who failed at least 2 prior treatments were enrolled in an open-label study of oral CyA. Medication was started at 3 mg/kg divided twice daily for 3 months. Dose was adjusted based on side effects and the drug level was measured 2 hours after the morning dose (C2). The primary end point was moderate or marked improvement of global response assessment or >50% improvement on the Interstitial Cystitis Symptom Index (ICSI) or Interstitial Cystitis Problem Index at 3 months. Twenty-two of 26 patients completed the 3-month follow-up; 18 completed the poststudy evaluation. The median symptom duration was 66 months (12-336). At 3 months, 31% (8/26) improved by global response assessment, 15% (4/26) had >50% improvement in the ICSI score, and 19% (5/26) had an improvement in the Interstitial Cystitis Problem Index score. Hunner lesions (HLs) predicted an improvement in the ICSI score (odds ratio = 15.4, 95% confidence interval: 1.7-224.6, P = .01), with 75% (3/4) of the responders having HL. Two patients withdrew because of hypertension or elevated serum glucose. The mean nuclear glomerular filtration rate declined at 3 months (98.9 ± 31.6 vs 84.2 ± 25.5 mL/min/1.73 m2, P = .01) and reversed to baseline after discontinuation of treatment. C2 levels did not correlate with symptoms but allowed dose reduction in 11 patients. Per American Urological Association guidelines, CyA can be effective in a proportion of patients with refractory IC-BPS. Patients with HL are more likely to benefit. Monitoring of C2 rather than trough levels can lead to dose reduction, thereby minimizing toxicity.

Low dose Cyclosporin A treatment increases live birth rate of unexplained recurrent abortion - initial cohort study

Pregnancy is similar to allogeneic transplantation. Eighty percent of unexplained recurrent spontaneous abortions (URSA) relate to disturbances of immune regulation. Cyclosporin A (CsA) is a immunosuppressant widely used after organ transplantation and to treat autoimmune disease. Animal studies show that low dose of CsA could induce maternal-fetal immunity tolerance while enhance trophoblast invasion. So far no clinical trial reported on the effect and safety of cyclosporin A treatment for URSA has been published. The objective of this study was to explore the effect, safety, and mechanism of low-dose CsA treatment in human patients in order to find a novel therapy to treat URSA. Eighty-six patients with eligible URSA treated at the clinic of the present hospital were included in this study from December 2009 to December 2012. The research was approved by the Ethics committee. Through a clinical study with prospective non-randomized controlled trials, the patients were divided into CsA treatment group (n = 66 cases) and in control group (n = 20 cases) based on the patients' choice. Both groups started treatment as soon as the pregnancy test was positive. Patients in the treatment group were treated with oral CsA 100 mg/day for 30 days. Patients in the control group were treated with progesterone 20 mg im per day until 12 weeks of gestation. Cytoimmunology test of CD3, CD4, CD8, CD4/8, CD4/25, CD19/21, and Th/Ts were examined before and after the treatment in both groups. Clinical consequences of mothers and fetuses were followed up and recorded. Live birth rate and cytoimmunology markers and their change before and after the treatment were analyzed and compared between the two groups. The live birth rate was significantly higher in study group (41/66, 62.1%) than in the control group (6/20, 30.0%) (p < 0.001). There was no obvious side effect and adverse consequence in the pregnancy women. No IUGR or birth defect was observed in fetus in this study. After CsA treatment, CD3 level in maternal blood was higher in successful group than abortion group but CD8 level was decreased after CsA treatment. Low-dose CsA treatment increases live birth rate of unexplained recurrent abortion. No maternal-fetal adverse consequence was observed in this study and it is safe in clinic use. The mechanism of CsA therapy may be related to immune regulation which may favor the success of pregnancy.

Biopharmaceutical Evaluation of Novel Cyclosporine A Nano-matrix Particles for Inhalation.

This study was undertaken to evaluate the biopharmaceutical properties of cyclosporine A (CsA)-loaded nano-matrix particles for inhalation. Nano-matrix particles of CsA with mannitol (nCsAm) were prepared by a flash nano-precipitation technique employing a multi-inlet vortex mixer and evaluated in terms of physicochemical properties, anti-inflammatory effect in the rat model of airway inflammation, pharmacokinetic behavior, and distributions of CsA to side-effect-related organs after intratracheal administration. In nCsAm, spherical nano-particles of CsA were covered with mannitol and the mean particle size was 1.3μm. The in vitro Next Generation Impactor analysis demonstrated fine inhalation performance with a fine particle fraction value of 65.8%. Intratracheal nCsAm (100μg-CsA/rat) significantly attenuated the recruitment of inflammatory cells into the airway in the rat model of airway inflammation, followed by suppression of the inflammatory biomarkers. After intratracheal nCsAm at a pharmacologically effective dose (100μg-CsA/rat), there was a 42-47-fold decrease in the distribution of CsA to side-effect-related organs such as the kidney and liver compared with oral CsA at a toxic dose (10mg-CsA/kg), potentially leading to avoidance of systemic side-effects of CsA. Upon these findings, nCsAm prepared with the flash nano-precipitation technique could be a novel dosage form of CsA for inhalation therapy of airway inflammation with a better safety margin.

Topical Cyclosporine A 1% for the Treatment of Chronic Follicular Conjunctivitis.

To evaluate the use of topical cyclosporine A (CSA) 1% in the treatment of chronic follicular conjunctivitis (CFC). Retrospective chart review from 2001 to 2012 identified 12 patients (22 eyes) with CFC (mean ± standard deviation [SD] age, 50.2 ± 15.4 years; 75% female; 92% white) treated with CSA. Main outcome measures included inflammation grade, visual acuity, concurrent corticosteroid (CS) therapy, effect on CS taper, and adverse effects. Mean ± SD follow-up time was 11.7 ± 9.7 months. Mean ± SD time from diagnosis to CSA treatment initiation was 2.4 ± 3.2 months. Mean ± SD duration of CSA treatment was 5.8 ± 2.8 months. Four patients (33%) complained of irritation (n = 2), redness (n = 1), itching (n = 1), and burning (n = 1) but none discontinued treatment. Concurrent CSs were tapered off in all patients after a mean ± SD of 5.0 ± 2.5 weeks. Mean ± SD initial vision was 0.078 ± 0.093 logMAR, whereas vision at final examination was 0.056 ± 0.081 logMAR (P = 0.02). Mean ± SD initial inflammation grade of 1.9 ± 1.0 was significantly reduced to final grade of 0.7 ± 0.9 (P = 0.0002). Mean ± SD time to initial inflammation control in 9 patients (75%) was 33.2 ± 24.5 days. Two patients (17%) switched to oral CSA because of lack of inflammation control. Topical CSA 1% is an effective and well-tolerated therapy that decreased chronic inflammation and tapered topical CS in patients with CFC. The use of CSA in such patients warrants further investigation.