Continuous Subcutaneous Foslevodopa/Foscarbidopa in Parkinson's Disease: Safety and Efficacy Results From a 12-Month, Single-Arm, Open-Label, Phase 3 Study.

INTRODUCTION: Foslevodopa/foscarbidopa, a soluble formulation of levodopa/carbidopa (LD/CD) prodrugs for the treatment of Parkinson's disease (PD), is administered as a 24-hour/day continuous subcutaneous infusion (CSCI) with a single infusion site. The efficacy and safety of foslevodopa/foscarbidopa versus oral immediate-release LD/CD was previously demonstrated in patients with PD in a 12-week, randomized, double-blind, phase 3 trial (NCT04380142). We report the results of a separate 52-week, open-label, phase 3 registrational trial (NCT03781167) that evaluated the safety/tolerability and efficacy of 24-hour/day foslevodopa/foscarbidopa CSCI in patients with advanced PD. METHODS: Male and female patients with levodopa-responsive PD and ≥ 2.5 hours of "Off" time/day received 24-hour/day foslevodopa/foscarbidopa CSCI at individually optimized therapeutic doses (approximately 700-4250 mg of LD per 24 hours) for 52 weeks. The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in normalized "Off" and "On" time, percentage of patients reporting morning akinesia, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Parkinson's Disease Sleep Scale-2 (PDSS-2), 39-item Parkinson's Disease Questionnaire (PDQ-39), and EuroQol 5-dimension questionnaire (EQ-5D-5L). RESULTS: Of 244 enrolled patients, 107 discontinued, and 137 completed treatment. Infusion site events were the most common adverse events (AEs). AEs were mostly nonserious (25.8% of patients reported serious AEs) and mild/moderate in severity. At week 52, "On" time without troublesome dyskinesia and "Off" time were improved from baseline (mean [standard deviation (SD)] change in normalized "On" time without troublesome dyskinesia, 3.8 [3.3] hours; normalized "Off" time, -3.5 [3.1] hours). The percentage of patients experiencing morning akinesia dropped from 77.7% at baseline to 27.8% at week 52. Sleep quality (PDSS-2) and quality of life (PDQ-39 and EQ-5D-5L) also improved. CONCLUSION: Foslevodopa/foscarbidopa has the potential to provide a safe and efficacious, individualized, 24-hour/day, nonsurgical alternative for patients with PD. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT03781167.

Novel capsaicin-induced parameters of microcirculation in migraine patients revealed by imaging photoplethysmography.

BACKGROUND: The non-invasive biomarkers of migraine can help to develop the personalized medication of this disorder. In testing of the antimigraine drugs the capsaicin-induced skin redness with activated TRPV1 receptors in sensory neurons associated with the release of the migraine mediator CGRP has already been widely used. METHODS: Fourteen migraine patients (mean age 34.6 ± 10.2 years) and 14 healthy volunteers (mean age 29.9 ± 9.7 years) participated in the experiment. A new arrangement of imaging photoplethysmography recently developed by us was used here to discover novel sensitive parameters of dermal blood flow during capsaicin applications in migraine patients. RESULTS: Blood pulsation amplitude (BPA) observed as optical-intensity waveform varying synchronously with heartbeat was used for detailed exploration of microcirculatory perfusion induced by capsicum patch application. The BPA signals, once having appeared after certain latent period, were progressively rising until being saturated. Capsaicin-induced high BPA areas were distributed unevenly under the patch, forming "hot spots." Interestingly the hot spots were much more variable in migraine patients than in the control group. In contrast to BPA, a slow component of waveforms related to the skin redness changed significantly less than BPA highlighting the latter parameter as the potential sensitive biomarker of capsaicin-induced activation of the blood flow. Thus, in migraine patients, there is a non-uniform (both in space and in time) reaction to capsaicin, resulting in highly variable openings of skin capillaries. CONCLUSION: BPA dynamics measured by imaging photoplethysmography could serve as a novel sensitive non-invasive biomarker of migraine-associated changes in microcirculation.

Arterial hypertension in migraine: Role of familial history and cardiovascular phenotype.

Recent studies indicate that migraine is associated with increased risk of cardiovascular diseases. However, links between autonomic cardiovascular regulation, arterial hypertension (AH) and migraine are still little explored. In this study, we evaluated autonomic regulation in migraine patients with and without hypertension. We studied 104 patients with migraine, aged 34±10 y, including 28 with and 76 without hypertension (M+AH and M-AH groups, respectively). The control group consisted of 88 healthy volunteers matched by age and sex. The autonomic regulation of circulation was examined with the tilt-table test, deep-breathing and Valsalva Maneuver, handgrip test, cold-stress induced vasoconstriction, arterial baroreflex, and blood pressure variability measurements. We found that migraine patients with concomitant hypertension demonstrated reduced arterial baroreflex, whereas other parameters of cardiac autonomic regulation were unchanged. In contrast, most indicators of vasomotor reactivity (blood pressure response to the hand-grip, Valsalva maneuver and cold vasoconstriction) were enhanced in migraine patients with no significant differences between migraine patients with and without hypertension. Patients from both M+AH and M-AH groups more commonly had a family history of cardiovascular disorders. Our data revealed increased vasomotor reactivity in migraine patients, with or without concomitant hypertension. This was associated with the family history of cardiovascular diseases.

Autonomous control of cardiovascular reactivity in patients with episodic and chronic forms of migraine.

BACKGROUND: The autonomous cardiovascular control can contribute to progression of migraine. However, current data on cardiovascular reactivity in migraine, especially severe forms, are essentially contradictory. The main aim of this study was to compare the autonomous regulation of circulation in patients with episodic and chronic migraine and healthy subjects. METHODS: Seventy three migraine patients (mean age 35 ± 10) including episodic migraine (51 patients, 4-14 headache days/months) and chronic migraine (22 patients, ≥15 headache days/month) along with age-match control (71 healthy voluntaries) were examined. The autonomic regulation of circulation was examined with the tilt-table test, a deep breathing and Valsalva Maneuver, handgrip test, cold-stress vasoconstriction, arterial baroreflex and blood pressure variability. RESULTS: The changes in heart rate induced by deep breathing, Valsalva Maneuver, and blood pressure in tilt-table test in patients with migraine did not differ from the control group. In contrast, the values of cold-stress-vasoconstriction forearm blood-flow reactivity (p <0.001), the increase in diastolic blood pressure in handgrip test (p <0.001), mean blood pressure in the late stage of the second phase of Valsalva Maneuver (p <0.001) and blood pressure variability (p <0.005) were all higher in patients with migraine than in the control group. CONCLUSION: Thus, both episodic and chronic migraine are associated with significant disturbances in autonomous control resulting in enhanced vascular reactivity whereas the cardiac regulation remains largely unchanged.