Twenty-two participants were screened; 14 met inclusion criteria and were admitted to the OCTRI (). Baseline characteristics of the 13 participants who completed at least 2 study days and were included in the statistical analysis are listed in . Mean age was 61 years. The average patient had PD for 16 years, 11 years of levodopa treatment with 9 years of motor fluctuations, and 7 years of dyskinesia. Four of the 13 participants reported a history of beginning-of-dose inhibitory effects when asked whether they sometimes experienced increased parkinsonism after taking levodopa, before its beneficial effects were noticeable. Beginning-of-dose inhibitory effects, by patient report, occurred 15 to 30 minutes after taking levodopa and lasted 10 to 45 minutes.
Baseline Characteristics of Patients With PD
Mean apomorphine concentration curves for the first 3 participants are shown in . Apomorphine concentrations responded quickly to changes in infusion rate and appeared to plateau within 2 hours. Maximum plasma concentration was linearly related to infusion rate (3.68, 8.31, 19.42, and 39.16 ng/mL for the 12.5–, 25–, 50–, and 100–μg/kg/h infusions, respectively [R2=0.99]). Time to maximum plasma concentration was 80 minutes for the 12.5– and 50–μg/kg/h infusions and 120 minutes or longer for the 25– and 100–μg/kg/h infusions, suggesting that time to maximum plasma concentration may have been influenced by order of infusions.
Figure 2 Mean apomorphine hydrochloride concentration curves for the first 3 participants during the placebo, low-dose apomorphine hydrochloride, and high-dose apomorphine hydrochloride infusions. The infusions were initiated at 9 AM, the infusion rates were doubled (more ...)
Levodopa concentrations, drawn each morning, ranged from undetectable to 0.33 μg/mL (mean, 0.09 μg/mL). These levodopa concentrations are subthreshold in patients with motor fluctuations.15
RESPONSES TO INFUSIONS
Response of finger and foot tapping to subthreshold apomorphine hydrochloride infusions (12.5 and 25 μg/ kg/h) did not differ from the response to placebo infusions ( and ). With data divided into 4 time intervals for statistical analysis (baseline, first 2 hours of infusion, last 2 hours of infusion, and wash-out), threshold and suprathreshold apomorphine hydrochloride infusions increased foot tapping during the first 2 hours (P=.007) and the last 2 hours (P<.001) of infusion relative to placebo (). Threshold and suprathreshold apomorphine hydrochloride levels showed a trend toward increased finger tapping compared with placebo (P=.15).
Mean foot tapping rate vs time (n=13) on the placebo, low-dose apomorphine hydrochloride, and high-dose apomorphine hydrochloride infusion days.
Finger and Foot Tapping Rates in Participants Receiving Apomorphine Hydrochloride vs Placebo Infusion
The subgroup of 4 participants who reported beginning-of-dose inhibitory effects had increased finger tapping (P=.03, first 2 hours of infusion; P=.009, last 2 hours) and foot tapping (P=.03, first 2 hours; P=.02, last 2 hours) during high-dose apomorphine hydrochloride infusion relative to placebo. The remaining 9 participants only showed a difference in foot tapping during the last 2 hours of high-dose apomorphine hydrochloride infusion (P=.002).
Dyskinesia, as measured by the research nurses, was low and sporadic, with a mean score below 0.20 (on a 0–24 scale) throughout the low-dose and placebo days. During the high-dose apomorphine hydrochloride infusion, mean dyskinesia score increased to higher than 1.00. Mean (SD) maximum dyskinesia scores were 0.54 (0.95) for the placebo day, 0.23 (0.60) for the low-dose day, and 4.54 (4.42) for the high-dose day. Analog scales of mood, anxiety, and fatigue were not affected by any of the treatments.
Adverse effects were mild (). One participant left the study after 2 days (low-dose apomorphine hydrochloride and placebo) because of a persistent off state. Another participant completed only the high-dose infusion because of anxiety while in the off state during the washout period. Infusions were briefly stopped twice because of orthostatic hypotension, though mean blood pressure and pulse did not differ between treatment types.
Adverse Effects in PD Patients Given Apomorphine Hydrochloride and Placebo Infusions