Clinical study of fk506 in patients with myasthenia gravis

Konishi, Tetsuro; Yoshiyama, Yasumasa; Takamori, Masaharu; Yagi, Koichi; Mukai, E; Saida, Takahiko

doi:10.1002/mus.10472

Cited by 81 publications

(79 citation statements)

References 77 publications

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“…Various clinical situations have been studied, such as in patients refractory to, or intolerant of, corticosteroids or additional immunosuppression, presence of thymoma, and in patients with a relatively new diagnosis. The most common dosing strategies were: a fixed daily dose of 3 mg with or without assessment of trough drug concentrations; and a weight-based approach of 0.1 mg/kg/day in divided doses with dosage titrated to achieve a trough concentration of 7-8 ng/ml [Shimojima et al 2006;Nagaishi et al 2008;Tada et al 2006;Konishi et al 2003Konishi et al , 2005Zhao et al 2011;Yoshikawa et al 2011;Ponseti et al 2005aPonseti et al , 2005bPonseti et al , 2006Nagane et al 2005;Mitsui et al 2007]. While the weight-based regimen is within the manufacturer's dosing recommendations for prevention of transplant rejection, the 3 mg dose falls below the FDA-approved dosing range [Astellas Pharma, 2013].…”

Section: Discussionmentioning

confidence: 99%

“…Citations of retrieved articles were also examined for relevance and included if applicable. A total of 12 studies met inclusion criteria [Shimojima et al 2006;Nagaishi et al 2008;Tada et al 2006;Konishi et al 2003Konishi et al , 2005Zhao et al 2011;Yoshikawa et al 2011;Ponseti et al 2005aPonseti et al , 2005bPonseti et al , 2006Nagane et al 2005;Mitsui et al 2007]. Table 2 provides a summary of the pertinent findings from each trial.…”

Section: Data Sourcesmentioning

confidence: 99%

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The emerging role of tacrolimus in myasthenia gravis

Cruz

Wolff

Vanderman

et al. 2015

Ther Adv Neurol Disord

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Objective: To describe and evaluate the available evidence assessing the role of tacrolimus in the management of patients with myasthenia gravis (MG). Data sources: A literature search of MEDLINE (1946 to September 2014 and EMBASE (1947 to September 2014) was performed using the terms 'tacrolimus' and 'myasthenia gravis'. Citations of retrieved articles were examined for relevance. Study selection and data extraction: The search was limited to prospective clinical trials focused on clinical outcomes in patients with generalized MG. Case reports, retrospective evaluations and non-English articles were excluded. Data synthesis: A total of 12 studies met inclusion criteria, of which seven articles evaluated tacrolimus in steroid-dependent patients and two examined the utility of tacrolimus in patients failing corticosteroids and cyclosporine. Other studies evaluated early initiation of tacrolimus after thymectomy, effectiveness of tacrolimus in de novo MG and the effectiveness of tacrolimus post-thymectomy in thymoma patients versus nonthymoma. A total of eight trials showed statistically significant improvements in quantitative MG score (QMGS) and postintervention status criteria -Myasthenia Gravis Foundation of America (PSC-MGFA). Of the trials examining steroid reduction with tacrolimus, two reported high rates of complete withdrawal; however, the most robust trial was unable to detect a difference in mean steroid dose. Long-term effects of tacrolimus (up to 5 years) were assessed in eight trials, which consistently showed positive effects on QMGS or reduction in adjunct therapies. Conclusions: There is limited yet promising information to suggest a beneficial role for tacrolimus in reducing QMGS and corticosteroid burden in patients with refractory symptoms or new-onset MG. Long-term use appears to be safe in this population.

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Section: Discussionmentioning

confidence: 99%

Section: Data Sourcesmentioning

confidence: 99%

The emerging role of tacrolimus in myasthenia gravis

Cruz

Wolff

Vanderman

et al. 2015

Ther Adv Neurol Disord

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“…Therefore, the development of new means to treat MG and to prevent recurrence is necessary. Although tacrolimus hydrate (FK506) has recently been approved for this purpose, 24) it causes severe adverse effects, such as renal toxicity and opportunistic infection.…”

Section: Discussionmentioning

confidence: 99%

A Novel Immunomodulator, FTY720, Prevents Development of Experimental Autoimmune Myasthenia Gravis in C57BL/6 Mice

Kohno

Tsuji

Hirayama

et al. 2005

Biological & Pharmaceutical Bulletin

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It has been well established that myasthenia gravis (MG) is caused by autoimmune responses against nicotinic acetylcholine receptor (AChR) on postsynaptic membrane in neuromuscular junctions.1) Experimental autoimmune myasthenia gravis (EAMG) has been used as an animal model for human MG. This model is prepared by immunizing mice or rats with AChR from Torpedo californica; the animals develop MG-like symptoms, including muscle weakness, with production of autoantibody against AChR.2)The novel immunomodulator (immunosuppressant) FTY720, which was discovered by Fujita et al. 3,4) of our group, is a synthetic structural analogue of myriocin (ISP-I), a metabolite of Isaria cinclairii.5) The efficacy of FTY720 has been well established in preclinical transplantation models, 6) and also recently in renal transplantation in humans. [7][8][9][10] Although the mechanisms of pharmacological action of FTY720 remain to be fully clarified, 11,12) it has been proposed that FTY720 is phosphorylated by sphingosine kinase, and the product, FTY720 monophosphate, suppresses immune response by sequestering lymphocytes from blood and peripheral tissues to the secondary lymphoid tissues.13-16) FTY720 has no inhibitory effect on cytokine production in vitro, in contrast to established immunosuppressants (cyclosporin and tacrolimus hydrate).16) Its mechanism of action is unique and differs from that of the established immunosuppressants. The development of FTY720 was described in our previous report. 17)In this study, we examined the efficacy of FTY720 for preventing the development of EAMG, an animal model of human MG. MATERIALS AND METHODSAnimals Specific pathogen-free (SPF) C57BL/6 mice (7 weeks of age, females) were purchased from Japan SLC Inc., Shizuoka, Japan. The mice were given g-ray-irradiated food (CRF-1, Oriental Bio Co., Kyoto, Japan) and distilled water for injection (Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan).FTY720 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (FTY720) was kindly provided by Yoshitomi Pharmaceutical Industries, Ltd., Japan.Acetylcholine Receptor from Torpedo californica Electric organ of Torpedo californica was purchased from Aquatic Research Consultants (San Pedro, CA, U.S.A.), and acetylcholine receptor (tAChR) was purified by the method of Froehner and Rafto using cobrotoxin-coupled Sepharose.18) AChR concentration was quantified by the Lowry method.Evaluation of Clinical Symptoms of EAMG Muscle strength was evaluated by the inverted hanging technique as described by Karachunski et al. 19,20) Mice with a holding time of 10 min or more were considered normal, and those with a holding time of less than 10 min were considered as having EAMG.Study Protocol Twelve C57BL/6 mice were immunized intracutaneously on the back with tAChR (5 mg) in the presence of Freund's complete adjuvant at 8, 10 and 11 weeks of age. Six mice (treated group, Nos. 1-6) out of the twelve were orally given FTY720 in water (1.0 mg/kg) three times a week from the day before the first immunization. The other...

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“…FK506 has been proven safe and effective in preventing organ rejection in clinical organ transplantation [8]. Furthermore, in noncontrolled studies, it has been observed that even a low dose of FK506 can be used as an effective supplementary treatment for MG and produces no significant side effects [9,10,11]. In the present study, we examined the efficacy of low-dose FK506 for treatment of de novo MG patients in a randomized prospective clinical trial.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Low-Dose FK506 in the Treatment of Myasthenia gravis – A Randomized Pilot Study

et al. 2005

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To determine the efficacy of low-dose FK506 in the treatment of myasthenia gravis (MG), untreated de novo patients were randomly selected to receive treatment with (n = 18) or without (n = 16) FK506, and were evaluated for 1 year after treatment with limitation of daily dose of prednisolone. Low-dose FK506 reduced the duration of early-phase therapy in hospital (p < 0.05) and the need for combined therapy with plasmapheresis and high-dose intravenous methylprednisolone or high-dose intravenous methylprednisolone alone (p < 0.05). It also reduced the daily dose of prednisolone (p < 0.05) required to maintain minimal manifestations of MGFA postintervention status. None of the patients exhibited significant side effects up to 1 year after treatment. These findings suggest that low-dose FK506 is safe and efficacious for the treatment of de novo MG patients.

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Clinical study of fk506 in patients with myasthenia gravis

Cited by 81 publications

References 77 publications

The emerging role of tacrolimus in myasthenia gravis

The emerging role of tacrolimus in myasthenia gravis

A Novel Immunomodulator, FTY720, Prevents Development of Experimental Autoimmune Myasthenia Gravis in C57BL/6 Mice

Efficacy of Low-Dose FK506 in the Treatment of Myasthenia gravis – A Randomized Pilot Study

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