Objective: Quantifying Istradefylline(IST) effects in L-Dopa(LD) resistant tremor in Parkinson’s disease(PD) patients.

Background: The adenosine A2A receptors control the indirect pathway. 

Adenosine A2A receptor activation decreases the affinity of D2 receptors for dopamine and reduces mobility.

IST is a selective adenosine A2A antagonist used to address “OFF” episodes in PD.

​In Clinical Practice, patients with tremor-dominant PD report subjective improvement of tremors after treatment with IST.​ A retrospective analysis showed tremor-dominant PD cases had benefit in tremor with IST. There are no prospective studies with IST about the tremor effect.

Method: This is a 6-month, open-label, single-arm, prospective, Investigator-Initiated Study.

27 patients with tremor-resistant PD, optimized on LD, were treated with 40 mg/day IST with a two-week start-up period with 20 mg.

Patient symptoms were evaluated with MDS-UPDRS part I-IV at baseline and 24 weeks. MDS-UPDRS Part III was measured at 4 and 8 weeks. Primary endpoint included MDS-UPDRS part III tremor score change and secondary endpoints included changes of non-motor symptoms, cognition, mood, behavior, and activities of daily living.

Tremor severities were evaluated using an iPhone’s accelerometry via Mindsquare Tremor app.

Results: 27 patients were enrolled in the study. Out of the 27 patients, 25 completed the study.

Primary endpoint, MDS-UPDRS part III tremor scores improved by the 8th week with an average of –4.24 (p < 10−6). The average tremor scores also improved at the 24th-week visit compared to the baseline by an average change of -4.70 (p < 10−6).

MDS-UPDRS part III total scores improved by –15.88 (p = 8.4×10−5) in the 8th week visit. In the week 24 visit, the improvement was –18.74 (p = 2×10−6) compared to baseline.

Conclusion: IST is an A2A antagonist approved for the reduction of off time and the improvement of on-time for PD patients on LD. IST’s reduction in the indirect pathway activity makes it an attractive add-on therapy for patients with LD resistant tremor, as our most effective treatment Deep Brain Stimulation(DBS) similarly exerts its therapeutic benefit by inhibiting the indirect pathway.

Based on our study, IST improved tremor scores in patients with LD resistant tremor predominant Parkinson’s disease. Therefore, we conclude a larger placebo-controlled trial should be considered.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/istradefylline-effects-on-l-dopa-resistant-tremor-in-parkinsons-disease/