title: Early effect of tacrolimus in improving excitation-contraction coupling in myasthenia gravis.
abstract: OBJECTIVE
  Tacrolimus (FK506) is a macrolide T-cell immunomodulator used to treat myasthenia gravis (MG). Besides immunosuppression, tacrolimus has been reported to have the potential to increase muscle strength by enhancing ryanodine receptor (RyR) function. However, few attempts have been made to demonstrate the early effect of tacrolimus as an RyR enhancer in clinical investigation.
  
  
  METHODS
  In 20 MG patients, masseteric compound muscle action potential (CMAP) and mandibular movement-related potentials (MRPs) were recorded simultaneously after stimulating the trigeminal motor nerve with a needle electrode. The excitation-contraction (E-C) coupling time (ECCT) was calculated by the latency difference between CMAP and MRP. Bite force was measured using a pressure-sensitive sheet. Serial assessments of % decrement in masseteric repetitive nerve stimulation (RNS), ECCT and bite force were performed before and within 4 weeks of tacrolimus (3 mg day(-1)) treatment. The median (mean, range) interval of assessment was 2 (2.4, 1-4) weeks. We also measured serum antibodies against RyR, acetylcholine receptor and muscle-specific receptor tyrosine kinase.
  
  
  RESULTS
  Bite force increased after tacrolimus treatment accompanying clinical improvement assessed by Myasthenia Gravis Foundation of America classification, but the bite force difference did not reach statistical significance. Wilcoxon matched-pairs signed-ranks test detected a significant ECCT shortening in 12 patients assessed after 1-2 weeks of tacrolimus treatment as well as in eight patients assessed after 3-4 weeks. In contrast, masseteric CMAP and % decrement showed no significant changes after short-term tacrolimus treatment.
  
  
  CONCLUSIONS
  Tacrolimus induces ECCT shortening accompanying clinical improvement despite no improvement in % decrement within 2 weeks.
  
  
  CONCLUSIONS
  This early effect of tacrolimus may imply a pharmacological enhancement of RyR function to improve E-C coupling in MG.
authors.affiliation: Department of Neurology, Sapporo Medical University School of Medicine, Sapporo, Japan. toimai@sapmed.ac.jp
authors.forename: Tomihiro
authors.initials: T
authors.lastname: Imai
authors.forename: Emiko
authors.initials: E
authors.lastname: Tsuda
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Hozuki
authors.forename: Rika
authors.initials: R
authors.lastname: Yamauchi
authors.forename: Masaki
authors.initials: M
authors.lastname: Saitoh
authors.forename: Shin
authors.initials: S
authors.lastname: Hisahara
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yoshikawa
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Motomura
authors.forename: Jun
authors.initials: J
authors.lastname: Kawamata
authors.forename: Shun
authors.initials: S
authors.lastname: Shimohama
mesh_terms: D000328:Adult; D000368:Aged; D001732:Bite Force; D016022:Case-Control Studies; D004558:Electric Stimulation / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay; D019054:Evoked Potentials, Motor / Q000187:drug effects; D056966:Excitation Contraction Coupling / Q000187:drug effects*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008406:Masseter Muscle / Q000187:drug effects / Q000503:physiopathology; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology; D009157:Myasthenia Gravis / Q000188:drug therapy / Q000503:physiopathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism; D012189:Retrospective Studies; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012720:Severity of Illness Index; D016559:Tacrolimus / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D011950:Receptors, Cholinergic; D019837:Ryanodine Receptor Calcium Release Channel; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D016559:Tacrolimus