Objective: To clarify the potential to preserve glycolytic energy homeostasis (GEH) with the Istradefylline combined to L-DOPA (IST-LD), and to prevent LD-induced weight loss and dyskinesia.

Background: Parkinson’s disease (PD) appears with the non-motor symptoms and some metabolic disfunctions such as the type 2 diabetes mellitus (T2DM) and weight loss, preceding the motor disabilities. A_2AR antagonist/IST/KW6002 is the PD pharmaceutics as adjunctive therapy to LD, which have been shown to exert off time reduction and increased good on time, with the pharmacodynamics of abrogate the excitability of indirect pathway. Clinical study of IST combined to LD with pharmacokinetics of metabolic homeostasis have not been evaluated.

Method: The single-center-prospective open cohort-study were conducted at the department of neurology in Okinawa islands, Japan.
The combined incident and prevalent cohort with PD were recruited, non-randomly assigned to the IST-LD combination group (n=94) and LD group (n=157), then followed with open-label treatment in clinical practice from October 2013 to September 2020 for 7 years.
PD patients were seen in an outpatient clinical setting for neuropsychological evaluation by a clinical neurologist. The all cohorts were evaluated with blood biomarker of glycolytic energy homeostasis (b-GEH); fasting glucose (mg/dl), HbA1c and insulin (μIU/ml, CLEIA), insulin like growth factor I (IGF-I, ng/ml, IRMA), hexokinase II (colorimetric quantitative assay).

Results: Primary clinical outcome with the 7 years ⊿changes of MDS-UPDRS showed less worsening in IST-LD compared with LD (0.29±5.2, 3.8±5.0, p=0.01). Secondary clinical outcome with LD-induced weight loss  (⊿weight loss) were evident in IST-LD compared to LD (46.5%, and 30.0%, p=0.01) and also with LD-induced dyskinesia (40%, and 28%, p=0.01), those conditions were associated with higher dose of LD/LEDD (p=0.01). Both groups showed lower frequency of ICD (0.01%, 0.06%, p=0.97). The b-GEHs were dysregulated at the PD onset naïve to LD, at the phase with drastic weight loss or dyskinesia break out.

Conclusion: We showed the LD-induced catabolic dysregulation with clinical manifestation of weight loss and dyskinesia, accompanied with dynamic alternations of blood biomarkers. The IST-LD was cooperative for long-term to preserve global motor functions and attenuate an objective global disability, in a part via preserving GEH.

References: Acknowledgement; We thank Tomoyuki Kanda, PhD and Akihisa Mori, PhD (Research fellow of Kyowa Kirin Co., Ltd.) for the helpful discussion. ORCID; Naomi Kanzato https://orcid.org/0000-0001-9661-6456

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MDS Abstracts - https://www.mdsabstracts.org/abstract/istradefylline-l-dopa-combination-therapy-for-parkinsons-disease-and-blood-markers-of-glycolytic-energy-homeostasis/