• YAKHAK HOEJI
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• v.59 no.4
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• pp.177-183
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• 2015

The mechanism of melanogenesis induced by cyclosporin A (CsA) was investigated in B16 melanoma cells. CsA stimulated the production of melanin in a dose-dependent manner in the cells. In addition, CsA increased intracellular $Ca^{2+}$ concentration in a dose-related fashion. Treatment with BAPTA/AM, an intracellular $Ca^{2+}$ chelator significantly inhibited the CsA-induced intracellular melanin synthesis. CsA profoundly induced $Cl^-$ efflux, which was significantly blocked by niflumic acid (NFA) and flufenamic acid (FFA), specific and nonspecific inhibitors of $Ca^{2+}$-activated $Cl^-$ channels (CaCCs), respectively. Furthermore, these inhibitors of CaCCs significantly inhibited the CsA-induced stimulation of melanin synthesis. Taken together, these results suggest that the activation of CaCCs may play an important role in the CsA-induced stimulation of melanin synthesis in B16 cells. These results further suggest that CaCCs may be a good target for the management of hyperpigmentation of the skin reported in the patients treated with CsA.

• Journal of Microbiology and Biotechnology
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• v.20 no.7
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• pp.1086-1091
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• 2010

This study explored the use of gellan gum as an immobilization matrix for the production of cyclosporin A (CyA) by immobilized spores and mycelia of Tolypocladium inflatum MTCC 557. Different carriers, such as gellan gum, sodium alginate, celite beads, and silica, were tested as immobilization carriers, along with the role of the carrier concentration, biomass weight, number of spore-inoculated beads, and repeated utilization of the immobilized fungus. The maximum CyA production was 274 mg/l when using gellan gum [1% (w/v)], and a mycelial weight of 7.5% (w/v) supported the maximum production of CyA. Additionally, the addition of a combination of $_L$-valine (6 g/l) and $_L$-leucine (5 g/l) after 48 h of fermentation produced 1,338 mg/l of CyA when using gellan gum. The immobilized mycelia beads were found to remain stable for four repetitive cycles, indicating their potential for semicontinuous CyA production.

• Journal of Microbiology and Biotechnology
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• v.19 no.11
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• pp.1385-1392
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• 2009

This work evaluates the effect of different amino acids on production of Cyclosporin (CyA) production in solid-state fermentation that was previously optimized for different fermentation parameters by one factor at-a-time for the maximum production of CyA by Tolypocladium inflatum MTCC557. Based on the Plackett-Burman design, glycerol, ammonium sulfate, $FeCl_3$, and inoculum size were selected for further optimization by response surface methodology (RSM). After identifying effective nutrients, RSM was used to develop mathematical model equations, study responses, and establish the optimum concentrations of the key nutrients for higher CyA production. It was observed that supplementation of medium containing (% w/w) glycerol, 1.53; ammonium sulfate, 0.95; $FeCl_3$, 0.18; and inoculum size 6.4 ml/5g yielded a maximum of 7,106 mg/kg as compared with 6,480 mg CyA/kg substrate using one factor at-a-time. In the second step, the effect of amino acids on the production of CyA was studied. Addition of $_L$-valine and $_L$-leucine in combination after 20 h of fermentation resulted in maximum production of 8,166 mg/kg.

• Biotechnology and Bioprocess Engineering:BBE
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• v.11 no.6
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• pp.526-529
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• 2006

The aim of this study was to prepare cyclosporin A-loaded liposome (CyA-Lip) as an oral delivery carrier, with their encapsulation into microspheres based on alginate or extracellular polysaccharide (EPS) p-m10356. The main advantage of liposomes in the microspheres (LIMs) is to improve the restricted drug release property from liposomes and their stability in the stomach environment. Alginate microspheres containing CyA-Lip were prepared with a spray nozzle; CyA-Liploaded EPS microspheres were also prepared using a w/o emulsion method. The shape of the LIMs was spherical and uniform, and the particle size of the alginate-LIMs ranged from 5 to $10\;{\mu}m$, and that of the EPS-LIMs was about $100\;{\mu}m$. In a release test, release rate of CyA in simulated intestinal fluid (SIF) from the LIMs was significantly enhanced compared to that in simulated gastric fluid (SGF). In addition, the CyA release rates were slower from formulations containing the liposomes compared to the microspheres without the liposome. Therefore, alginate-and EPS-LIMs have the potential for the controlled release of CyA and as an oral delivery system.

• Journal of Microbiology and Biotechnology
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• v.11 no.6
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• pp.1055-1060
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• 2001

Experimental data for the on-line estimation of cell concentration and growth rate are presented. For this purpose, we utilized the on-line calculation of the oxygen uptake rate (OUR), which was derived from a liquid phase dynamic mass balance for the oxygen during the active growth phase in cyclosporin A (CyA) fermentation. The cell yield coefficient, based on the oxygen $(Y_{x/o})$for both suspended and immobilized cells of Tolypocladium inflatum, was estimated as $1.9 gDCW/gO_2$ from a very good linear correlation between the cell mass produced and the total oxygen consumed. The calculated yield showed a good agreement with the value of $(Y_{x/o})$ generated from the correlation between the cell growth rate and the oxygen uptake rate. In addition, further experimental data are given, which were also applied to determine the specific oxygen uptake rate of T. inflatum cells during the exponential phase of CyA fermentation. A theoretical basis for the analysis of these fermentation parameters is also provided.

• Journal of Pharmaceutical Investigation
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• v.39 no.2
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• pp.111-115
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• 2009

The pharmacokinetics of cyclosporin A (CsA) after single and multiple oral dosing of new CsA self-micro-emulsifying drug delivery system (SMEDDS) in dogs were estimated. A single dose study was performed following a two-way crossover design against six dogs with reference SMEDDS. For a multiple dose study, three dogs were allocated for each drug, and 100 mg of drug was administered daily for 6 days. Whole blood concentration of CsA was analyzed by radio-immunoassay. Both drug showed identical blood concentration profiles in both studies, and no statistical difference was detected in pharmacokinetic parameters. The relative bioavailabilities of test SMEDDS were 91.4% and 89.1%, respectively, in the single dose study and the last day of multiple dose study. Especially, multiple dose study proved the good relationship between C-0/C-2 and AUC for reference SMEDDS, which is an indispensable part of therapeutic drug monitoring. These results suggest newly formulated CsA SMEDDS possibly shows identical pharmacokinetics and pharmacodynamic behaviors in clinical trials.

• The Journal of Internal Korean Medicine
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• v.19 no.2
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• pp.317-332
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• 1998

The purpose of this study is to find out the effects of Poria extract on rat's nephrotoxicity induced by CsA. The experimental animals were divided into 3 groups and treated as follows; Nothing was given to Sample A, Sample B was given normal saline after IV injection of CsA and Sample C was given Poria extract after CsA injection. After precription of medicine, serum BUN, creatinine, total protein, sodium, potassium, chloride ions were measured. 1. Changes in serum level. ALT, BUN, chloride ion were significantly reduced in experimental group as compaired to control group, and total protein showed significant elevation in experimental group. AST was reduced, but not significant and creatine level was below the normal range. K level showed mild elevation initially and later showed mild decrease, but no significance is noted. There were no significant differance in the sodium level. 2. Changes in Urine level. Urinary specific gravity showed significant increase in experimental group compaired to control group. Urinary creatinine level initially increased, and later decreased but showed no significance. To conclude, it can be inferred that Poria may improve nephrotoxicity and hepatotoxicity in rat induced by Cyclosporin A.

• Microbiology and Biotechnology Letters
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• v.24 no.6
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• pp.717-725
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• 1996

We have developed an efficient immobilized cell separator for continuous operation of immobilized fungal cell cultures, and applied this separator to actual fermentation process for the production of cyclosporin A (CyA), a powerful immunosuppressant. In the experiments employing highly viscous polymer (carboxymethyl cellulose) solution, the decantor showed good separating performances at high solution viscosites and fast dilution rates. Air duct and cylindrical separator installed inside the decantor turned out to play key roles for the efficient separation of the immobilized cells. By installing the decantor in an immobilized perfusion reactor system (IPRS), continuous immobilized culture was stably carried out even at high dilution rate for a long period, leading to high productivities of free cells and CyA. Almost no immobilized biomass existed in effuluent stream of the IPRS, demonstrating the effectiveness of the decan- tor system for a long-term continuous fermentation. It was noteworthy that we could obtain these results despite of the unfavorable fermentation conditions, i.e., reduced density of the biosupports caused by overgrowth of cells inside the bead particles and existence of high density of suspended fungal cells (10g/l) in the fermentation broth.

• Journal of Chest Surgery
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• v.27 no.1
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• pp.15-23
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• 1994

This study examined the effects of cyclosporin A [CsA] and methylprednisolone[MP] on the viability of the devascularized trachea after heterotopic transplantation. Fourty-two tracheal segments were harvested from 21 donor Wistar rats. Those tracheal segments were heterotopically implanted into the abdomen of recipient rats after wrapping in omentum. Heterotopical implantation was performed in six groups of rats:Group I was Wistar syngeneic controls, and five groups of Sprague Dawley recipients, receiving no immunosuppression[Group II], CsA alone[Group III, V], and CsA in combination with MP[Group IV, VI]. After 14 days, the tracheal segments were histologically evaluated.Epithelial thickness and the degree of epithelial regeneration were significantly different between group I and group II, III, VI, VI [p< 0.05]. There were significant differences in the epithelial thickness between group II, III, IV and group V, VI. In the degree of epithelial regeneration, there were significant differences in group II, group III-IV, and group V-VI. Without immunosuppression there was virtually no epithelium, whereas low-dose immunosuppression yielded intermediated viability, and with high dose CsA and MP we observed improved tracheal viability. Our results suggest that optimal combination of CsA and MP may improve the viability in heterotopic tracheal allografts.

• The Journal of Dong Guk Oriental Medicine
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• v.2 no.2
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• pp.1-15
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• 1993

The purpose of this study is to observe the effect of Woogyuyem on serum reaction and hepatic tissue in Cyclosporin A treated rats. In this study, the experimental rats divided two group(Control group and Sample group). Under the same condition, both control group and sample group were injected to abdomen with Cyclosporin A for 7days. And then, control group were administered water, sample group were administered Woogy-uyeum for 300days. The change of transaminase and bile acid and SOD activity in blood serum, hepatic tissue were measured at 3rd, 7th, 15th, 30th day. The obtained results are summarised as follows : 1. In the change of SGOT contents, as compared with control group, sample group was significantly decreased at 7th and 15th day. 2. In the. change of SGPT contents, as compared with control group, sample group was significantly decreased at 15th day. 3. In the change of serum bile acid contents, as compared with control group, sample group was significantly decreased at 7th and 15th day. 4. In the change of serum SOD activity, as compared with control group, sample group was significantly increased at 15th and 30th day. 5. In the change of hepatic tissue, as compared with control group, the vacuolation of hepatocytes in the sample group was reduced, the liver plates were reconstructed, and the epitheriai cell wasn't destructed.