Individual pharmacodynamics assessed by antilymphocyte action predicts clinical cyclosporine efficacy in psoriasis*

Hirano, Toshihiko; Oka, Kitaro; Umezawa, Yoshinori; Hirata, Michiko; T, Ohi; Koga, Michiyuki

doi:10.1016/s0009-9236(98)90042-x

Cited by 37 publications

(44 citation statements)

References 25 publications

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“…Lymphocyte Culture and Evaluation of Drug Effect These procedures were carried out according to the methods we described previously. 11) In brief, 200 ml of the cell suspension, as prepared above, was placed into each of the 96 flatbottom wells of a microtitre plate. ConA was added as a mitogen to a final concentration of 5.0 mg/ml.…”

Section: Methodsmentioning

confidence: 99%

P-Glycoprotein Function in Peripheral Blood Mononuclear Cells of Myasthenia Gravis Patients Treated with Tacrolimus

Tanaka

Hirano

Saito

et al. 2007

Biological & Pharmaceutical Bulletin

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Myasthenia gravis (MG) is an autoimmune disorder generally mediated by antibodies against the acetylcholine receptors (ACh-R) of skeletal muscles.1) Production of these antibodies in B cells depends upon ACh-R specific T cells.2) In general, four therapeutic strategies are available for MG: enhancement of neuromuscular transmission by means of anticholinesterase agents, thymectomy, immunosuppression with glucocorticoids (GCs) and plasma exchange. 1)In addition to GCs, tacrolimus (FK506) is currently used for the treatment of MG. The drug acts by inhibiting calcium-calcineurin pathways, which results in a reduction of T cell proliferation.3) We have previously reported on the individual variations in the suppressive potencies of FK506 on in vitro blastogenesis of PBMCs from MG patients. 4)The MDR-1 gene codes for a drug efflux pump P-gp, 5) which is expressed on the surface of lymphocytes 6) and actively transports these ligands, including FK506, out of target cells, thereby reducing their efficacy. 7) These substrates for P-gp may induce P-gp overexpression in either PBMCs or select drug-resistant cell subpopulations.MDR-1 gene expression and its corresponding protein membrane density in clinical samples have been studied by quantitation of P-gp mRNA with the reverse transcriptasepolymerase chain reaction (RT-PCR) and by immuno-histochemical techniques.8) However, the evaluation of MDR-1 or P-gp with these methods was not found to be parallel with the data for functional P-gp, 9) ignoring the possibility that regulation may occur at the transcriptional, translational, and/or post-translational levels. An alternative approach, consisting of the measurement of the extrusion of fluorescent dyes from individual cells, was found to allow for the evaluation of the functional activity of P-gp. 10)This study was undertaken to examine the influence of FK506 therapy on P-gp function in PBMCs and the relationship between P-gp function and PBMC-sensitivity to FK506 in vitro. In addition, we will also report on the clinical response to FK506 in MG patients. 11 Bq/mmol) was purchased from New England Nuclear Co., U.S.A. The other reagents were of the best available grade. MATERIALS AND METHODS ReagentsSubjects In this study, 10 MG patients and 18 healthy subjects, as a control, were included. The clinical characteristics of the patients are summarized in Table 1. Six patients received FK506 and four patients were administered prednisolone (PSL) as an immunosuppressant and/or anticholinesterase agents. FK506 was administered at a daily dose of 3 mg. PSL was administered before and during the present study. Most of the patients (8/10) had undergone a thymectomy before immunosuppressive drug administration. Eighteen healthy control subjects (8 male and 10 female; 25.3Ϯ6.2 years of age) were concurrently included in the study. Twenty milliliters of venous blood from each subject were obtained and heparinized. The study using human PBMCs was approved by the ethical committee of Tokyo University of Pharmacy and life Science, and co...

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Section: Methodsmentioning

confidence: 99%

P-Glycoprotein Function in Peripheral Blood Mononuclear Cells of Myasthenia Gravis Patients Treated with Tacrolimus

Tanaka

Hirano

Saito

et al. 2007

Biological & Pharmaceutical Bulletin

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“…8 Peripheral Blood Mononuclear Cell Culture PBMCs were separated from heparinized venous blood collected from healthy volunteers, as described previously. [9][10][11] The cells were suspended in RPMI-1640 medium containing 10% FBS, 100000 IU/l penicillin and 100 mg/l streptomycin at a density of 1ϫ10 6 cells/ml. Nine hundred eighty microliters of this cell suspension were placed into each well of 24-well flat-bottomed plates (Iwaki Co., Chiba, Japan), and twenty microliters of each test compound solution in ethanol were added at a final concentration of 10 mg/ml.…”

Section: Methodsmentioning

confidence: 99%

Induction of Apoptosis in Human Lung Fibroblasts and Peripheral Lymphocytes in Vitro by Shosaiko-to Derived Phenolic Metabolites.

Liu

Tanaka

Horigome

et al. 2002

Biological & Pharmaceutical Bulletin

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Shosaiko-to (TJ-9), a drug-extract preparation comprised of 7 kinds of herbal components, is one of the most commonly used Kampo medicines being mainly indicated for chronic liver injury in Japan. Recently, over 200 cases of interstitial pneumonia have been reported resulting from TJ-9 therapy.2,3) The cases of interstitial pneumonia have been noted to increase when treated with interferon (IFN)-a and TJ-9 at the same time.4) Accordingly, the combination has been contraindicated in Japan since 1994; however, the mechanisms of interstitial pneumonia induced by TJ-9 and IFN-a are not fully understood. It was observed that TJ-9 and IFN-a inhibited the proliferation of lung fibroblasts and increased the production of interleukin-6 (IL-6) by fibroblasts from healthy subjects and patients with idiopathic pulmonary fibrosis (IPF) in vitro.5) Although interstitial pneumonia induced by TJ-9 and/or IFN-a has been suggested to be caused by an allergic-immunological mechanism rather than toxicity, 4) other possible explanations remain to be investigated.Identification of the biologically active compounds might be a solution in clarifying the serious side effect of this crude drug. As possible candidates, 7 phenolic compounds have been found in human urine after administration of TJ-9 (Fig. 1). 6) They include medicarpin and liquiritigenin derived from Glycyrrhiza glabra; baicalin, baicalein, oroxylin A and wogonin from Scutellaria baicalensis; and davidigenin, a hydrogenated metabolite of liquiritigenin. Since these compounds are actually absorbed into the body and excreted in the urine as free and glucuronide conjugate forms, 7) we hypothesized that they would play an important role for the clinical effects of TJ-9. Therefore, in the current study, we investigated the effects of these 7 compounds and IFN-a on inducing apoptosis in human lung fibroblasts and peripheral Shosaiko-to is a Kampo medicine used for the treatment of chronic hepatitis in Japan. Lately, over 200 cases of interstitial pneumonia have been reported resulting from Shosaiko-to therapy, and the number of cases increased when patients were administrated interferon (IFN)-a a at the same time. However, the mechanisms of this Shosaiko-to implicated interstitial pneumonia are not fully understood. In this study, we examined by flow cytometry analysis the in vitro effects of 7 phenolic compounds (lignans and flavonoids), which were detected from human urine after administration of Shosaiko-to, and IFN-a a on inducing apoptosis in human lung fibroblasts and peripheral blood mononuclear cells (PBMCs). Among the 7 compounds, baicalein and medicarpin (10 m mg/ml) showed significant apoptosis-inducing effects on human PBMCs. In human lung fibroblasts, medicarpin exhibited a significantly higher activity to induce apoptosis compared to the control, and the percentage of cells undergoing apoptosis showed time-and dose-dependent increases. Baicalein (0.1 and 1 m mg/ml), liquiritigenin (10 m mg/ml) and davidigenin (10 m mg/ml) also showed significant effects after 96 h...

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“…This 20 ml sample size was the smallest possible to carry out the drug sensitivity tests for four immunosuppressive agents, but occasionally not all four of these agents could be tested for each subject. The heparinized blood was loaded on 3 ml of Ficoll-Hypaque (Nakarai Co., Japan), centrifuged at 1300 ×g for 20 min, and PBMCs were separated as described previously [4][5][6]21]. For the evaluation of PBMC-sensitivity to immunosuppressive drugs, cells were washed and suspended in RPMI 1640 medium containing 10% fetal bovine serum, 100,000 IU/l penicillin, and 100 mg/l streptomycin to a final density of 1× 10 6 cells/ml.…”

Section: Isolation Of Pbmcs and Evaluation Of Drug Effects In Vitromentioning

confidence: 99%

“…However, variations in the clinical efficacy of the drugs in individual patients have been observed, and patients with poor responses to the drugs have required long-term or relatively high doses and thus experience serious side effects with less improvement in their conditions [1]. One of the attractive ways to predict the clinical efficacy of immunosuppressive drugs in individual patients is the cellular pharmacodynamics of drugs using PBMCs of patient origin [4][5][6]. It has been reported that the in vitro response of PBMCs to the suppressive effects of immunosuppressive drugs correlate with clinical efficacy in asthma [7], renal transplantation [5,8], minimal change nephrotic syndrome [5,6], psoriasis [4], rheumatoid arthritis [9], and ulcerative colitis [10].…”

Section: Introductionmentioning

confidence: 99%

“…One of the attractive ways to predict the clinical efficacy of immunosuppressive drugs in individual patients is the cellular pharmacodynamics of drugs using PBMCs of patient origin [4][5][6]. It has been reported that the in vitro response of PBMCs to the suppressive effects of immunosuppressive drugs correlate with clinical efficacy in asthma [7], renal transplantation [5,8], minimal change nephrotic syndrome [5,6], psoriasis [4], rheumatoid arthritis [9], and ulcerative colitis [10]. We have also revealed a large individual differences in the PBMC-suppressive effects of glucocorticoids, cyclosporine and tacrolimus between patients, and that patients with PBMCs exhibiting poor response to the drugs in vitro also show low responses to the clinical efficacy of the drugs [4,8,11,12].…”

Section: Introductionmentioning

confidence: 99%

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Bacterial superantigen TSST-1 attenuates suppressive efficacy of glucocorticoids and calcineurin inhibitors against blastogenesis of peripheral blood mononuclear cells from patients with antineutrophil cytoplasmic antibody-associated vasculitis and nephrosis

Hirano

Fukushima

Sasaki

et al. 2006

International Immunopharmacology

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Individual pharmacodynamics assessed by antilymphocyte action predicts clinical cyclosporine efficacy in psoriasis*

Cited by 37 publications

References 25 publications

P-Glycoprotein Function in Peripheral Blood Mononuclear Cells of Myasthenia Gravis Patients Treated with Tacrolimus

P-Glycoprotein Function in Peripheral Blood Mononuclear Cells of Myasthenia Gravis Patients Treated with Tacrolimus

Induction of Apoptosis in Human Lung Fibroblasts and Peripheral Lymphocytes in Vitro by Shosaiko-to Derived Phenolic Metabolites.

Bacterial superantigen TSST-1 attenuates suppressive efficacy of glucocorticoids and calcineurin inhibitors against blastogenesis of peripheral blood mononuclear cells from patients with antineutrophil cytoplasmic antibody-associated vasculitis and nephrosis

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