Apomorphine in treatment of Parkinson''s disease: comparison between subcutaneous and sublingual routes.

The efficacy of two routes of apomorphine, subcutaneous (SC) and sublingual (SL), successively administered in 7 Parkinsonian patients with motor fluctuations, was compared in reducing the daily duration of "off" phases. The mean duration of SC and SL treatment was 7.7 and 6.8 months respectively. The mean time spent in "off" phase was 55% after SC and 68% after SL treatment. The mean time before turning "on" after an "off" period was 14 minutes after SC and 28 minutes after SL treatment. Two patients developed stomatitis after SL route. SL apomorphine may be helpful in the treatment of motor fluctuations in PD.     

Absorption of apomorphine by various routes in parkinsonism

We wanted to determine the absorption and clinical effect of sublingual (SL) and transdermal apomorphine in parkinsonism. Patients received single SL apomorphine doses (N = 7) and the absorption was compared with parenteral (N = 5) and oral (N = 4) doses. One patient received a transdermal dose of apomorphine. The relative bioavailability of SL apomorphine ranged from 10 to 22% of a parenteral apomorphine dose. Oral apomorphine was less than 4% bioavailable, and the transdermal dose did not produce detectable plasma levels. Three patients with motor fluctuations responded to SL apomorphine, with a latency to effect of 20-40 min and a duration of effect of 15-100 min. One patient used SL apomorphine as an adjunct with levodopa, and during 1 month reported a large decrease in "off" periods. We conclude that apomorphine is effectively absorbed by the sublingual route.     

Sublingual administration of apomorphine in the treatment of motor fluctuations in Parkinson disease]

Apomorphine, a mixed dopaminergic agonist was given sublingually to 12 patients with Parkinson's disease disabled by severe on-off fluctuations. The patient's mean age was 57 years and the duration of Parkinson's disease was 12 years. All patients were also given domperidone (60 mg/day). Apomorphine was administered as soon as the off periods appeared. On periods were observed in 11 patients, with a mean apomorphine dose of 40 mg for each administration (extremes values: 20-60 mg). One patient had no motor benefit after an apomorphine dose of 120 mg. The mean duration of daily off periods was reduced by 64 per cent in 11 patients, for a mean duration of 8 months (extremes values: 2-12 months). Four patients developed stomatitis or gingival edema and stopped treatment. This pilot study shows that sublingual apomorphine, during a mean period of 8 months, significantly decreases off periods in parkinsonian patients. Others studies are necessary to confirm these results.     

Sublingual apomorphine in the treatment of Parkinson's disease complicated by motor fluctuations.

Subcutaneous apomorphine is a useful treatment for refractory motor fluctuations in Parkinson's disease. We have now clinically evaluated a formulation of sublingual apomorphine (57 mg) and performed preliminary pharmacokinetic studies. In acute studies, all 10 patients switched "on" after a mean latency of 25 min with a mean duration of motor benefit of 118 min. In three patients followed for a mean of 4.7 months, we have shown that chronic sublingual use can be effective, safe, and convenient in controlling motor fluctuations. The pattern of clinical response followed closely the plasma profile of apomorphine with a mean Cmax of 76 pmol/ml (50-106 pmol/ml) and a mean Tmax of 60 min (45-80 min), with moderate interpatient variability in bioavailability. Sublingual apomorphine is a practical alternative to subcutaneous use in selected patients with severe motor fluctuations.     

Dopaminergic sensitivity and cocaine abuse: response to apomorphine

Ten male patients with chronic cocaine abuse received a single dose of the dopamine agonist apomorphine. Self-ratings of cocaine craving, depression, and anxiety decreased in response to apomorphine. Neuroendocrine response was consistent with central dopaminergic stimulation. Patients in the "craving" phase of the cocaine abuse cycle differed in behavioral but not neuroendocrine response to apomorphine from patients in the "crash" phase. Decrease in cocaine craving correlated with decrease in plasma homovanillic acid (pHVA). Total cocaine consumption correlated negatively with baseline prolactin and pHVA levels and inversely with peak change in prolactin following apomorphine. Patients had blunted neuroendocrine response to apomorphine in comparison to historical normal controls. Implications for the "dopamine" hypothesis of cocaine abuse are discussed.     

Apomorphine test: a predictor for motor responsiveness to deep brain stimulation of the subthalamic nucleus

The value of the apomorphine test as a predictor of the clinical outcome of deep brain stimulation of the subthalamic nucleus (STN) was evaluated in patients with advanced idiopathic Parkinson’s disease (IPD) or multiple system atrophy (MSA). Thirteen IPD patients with severe diurnal fluctuations and one MSA patient not responding to dopaminergic drugs were assessed with the Unified Parkinson’s Disease Rating Scale (UPDRS) and the timed finger tapping test (FTT), measured preoperatively on and off apomorphine and postoperatively on and off STN stimulation. UPDRS motor items 20–25 were assessed intraoperatively on and off STN stimulation when the clinically effective target was approached. The motor response to immediate intraoperative and long-term STN stimulation was correlated with results of the apomorphine test. The response to immediate intraoperative STN stimulation was accurately predicted by apomorphine challenge in all 13 IPD patients. Clinical outcome following long-term STN stimulation was correlated significantly with preoperative changes due to apomorphine measured with the UPDRS motor scores (r = 0.7125, P < 0.01) and FTT (r = 0.9276, P < 0.001). Moreover, comparison of long-term STN stimulation to preoperative drug treatment displayed a significant reduction in the duration of off-phases and a significant increase in the duration of on-phases. However, in the single patient with MSA no beneficial response was obtained either to apomorphine or to STN stimulation intraoperatively and during the postoperative externalized test period. Our results indicate that the apomorphine test can predict the outcome of immediate and long-term STN stimulation and may help in the selection of candidates for surgery. Received: 3 April 1998 Received in revised form: 19 January 1999 Accepted: 16 February 1999     

Effect of apomorphine on growth hormone and prolactin secretion in schizophrenic patients, with or without oral dyskinesia, withdrawn from chronic neuroleptic therapy.

Serum growth hormone (GH) and prolactin (PRL) concentrations were measured after administration of the dopamine receptor agonist, apomorphine HC1 (0.75 mg subcutaneously), to 17 chronic schizophrenic patients, four of whom had an oral dyskinesia, who were withdrawn from chronic neuroleptic therapy for periods of two to 15 weeks, and in 21 control subjects (normal volunteers or physically healthy alcoholics not exposed to neuroleptics). Six of the schizophrenic patients, but none of the controls, had raised baseline levels of GH (greater than 6 ng/ml). After apomorphine all controls showed an increase in serum GH with a peak concentration of 9 ng/ml or more, whereas eight subjects withdrawn from neuroleptics showed an inadequate response (peak less than 6 ng/ml) and in two others an inadequate response was obtained on one of two trials. The peak GH concentration was significantly less after apomorphine in patients withdrawn from neuroleptics (11.90 +/- 3.19 ng/ml) compared with controls (20.80 +/- 2.11 ng/ml) (P less than 0.05). Among patients withdrawn from neuroleptics, those with an oral dyskinesia had significantly lower peak GH concentration 2.46 +/- 0.93 ng/ml) after apomorphine compared with those without (14.85 +/- 3.83 ng/ml) (P less than 0.05). There were no differences in serum PRL concentrations, before or after apomorphine administration, between patients withdrawn from neuroleptics and controls. In uncontrolled observations none of the four patients with an oral dyskinesia showed any worsening of the movement disorder after apomorphine. These data provide no evidence for supersensitivity of dopamine receptors in chronic schizophrenic patients withdrawn from chronic neuroleptic therapy.     

Intranasal apomorphine in parkinsonian on-off fluctuations.

The efficacy of intranasal apomorphine was assessed in seven patients with Parkinson's disease and severe levodopa (L-dopa)-related "off-period" disabilities. All patients responded favorably to treatment with intranasal apomorphine. The speed and the quality of motor response and the pharmacokinetic profile showed results similar to those seen after subcutaneous injection of apomorphine administered by insulin pen syringe. The simplicity in the technique of intranasal apomorphine administration was found to be superior by all patients.     

The apomorphine test in parkinsonian syndromes.

The dopamine receptor agonist apomorphine has been used successfully to treat on-off swings in Parkinson's disease. Its value as a predictor of dopa responsiveness in idiopathic Parkinson's disease (IPD) was assessed and its potential role in differentiating IPD from the Parkinsonian plus syndromes (PPS) of multisystem atrophy, progressive supranuclear palsy and olivopontocerebellar atrophy was investigated. The response to an injection of apomorphine was observed in 20 patients with IPD and eight with PPS after being off levodopa for 12 hours. Patients were reassessed after taking levodopa for one month. Nineteen of the 20 patients (95%) with IPD showed a positive response to apomorphine and 18 (90%) to oral levodopa. In the PPS group, two patients (25%) responded to the apomorphine injection but not to oral levodopa. Apomorphine produced severe drowsiness in the PPS patients. It is suggested that the test can predict dopa responsiveness in IPD and may be of help in confirming a doubtful diagnosis. It has potential value in differentiating IPD from PPS.     

Apomorphine monotherapy in the treatment of refractory motor complications of Parkinson's disease: long-term follow-up study of 64 patients.

Continuous subcutaneous infusion of apomorphine is now increasingly recognized as an effective treatment for refractory off periods and peak-dose dyskinesias in Parkinson's disease. We have reviewed our experience with apomorphine infusions, after a strategy decision in 1995 based on emerging preclinical data, to treat all patients with steady-state plasma levels of apomorphine throughout the waking day, minimizing additional pulsatile stimulation either by oral dopaminergic medication or bolus parenteral injections of apomorphine. Sixty-four patients have been treated with apomorphine pumps and 45 of these successfully converted to monotherapy, managing to discontinue all other forms of dopaminergic stimulation during the daytime treatment period with apomorphine. Patients were followed up for a mean of 33.8 months (range, 4-108 months) and clinical data analyzed retrospectively. The mean maintenance dose of apomorphine was 98 mg per 24 hours (monotherapy group: 103 mg/24 hours; polytherapy group: 93 mg/24 hours), which did not significantly increase at final follow-up. There was a mean maximum dyskinesia reduction of 64% (S.D. = 20) in the monotherapy group, compared to 30% (S.D. = 33) in those continuing on polytherapy (P < 0.001), despite a maintained increase in on time (monotherapy group: 55%, P < 0.005; polytherapy group: 50%, P = 0.05). Fifteen patients failed to successfully convert to monotherapy but benefited nonetheless, and only 3 failed apomorphine infusional therapy altogether. Reasons for failure were mixed, including difficulty with compliance and adverse effects such as daytime somnolence, skin complications, and painful dystonias. There was a significantly higher success rate in patients able to manage the treatment either independently or with the help of their caregiver. These results confirm that subcutaneous apomorphine monotherapy can reset peak-dose dyskinesia threshold in levodopa-treated patients and further reduce off-period disability after all available forms of oral medication, including long-acting dopamine agonists, have been tried.     

Dopaminergic function in two patients with catalepsy

Apomorphine HCI (2 mg subcutaneously), a dopamine receptor agonist, was administered to two schizophrenic patients with catalepsy. In one of these patients the clinical response to apomorphine was compared with that of sodium amytal and the growth hormone response to apomorphine (0.75 mg subcutaneously) was compared with that of 25 control subjects. Apomorphine had no effect whereas sodium amytal caused rapid disappearance of catatonic symptoms including catalepsy. The peak growth hormone response to apomorphine was similar to that of controls. These data suggest that unlike experimental catalepsy in animals, catalepsy associated with schizophrenia may not be dependent on impaired dopaminergic function. Further case studies as well as the use of other dopamine receptor agonists are required before definite conclusions can be drawn.     

Subcutaneous apomorphine in the treatment of Parkinson''s disease.

Apomorphine a dopamine receptor agonist was given subcutaneously to 57 levodopa treated parkinsonian patients with refractory off-period disabilities for a median period of 16 months. In 30 given intermittent suprathreshold injections the mean number of hours spent in a disabling off state fell from 6.9 to 2.9. Similar benefit was observed in 21 patients receiving continuous infusions with additional boluses on demand by mini-pump (mean reduction of hours off from 9.9 to 4.5). Twelve patients have been treated for over two years without tachyphylaxis or loss of response. The incidence of neuropsychiatric side-effects has been low (7%). Six patients failed to show a sustained worthwhile response; severe disabilities during "on" periods being the major problem. Subcutaneous apomorphine is proposed as an effective treatment for patients with incapacitating "off" period disabilities refractory to oral medication and should be considered before experimental implantation procedures.     

Effects of central dopaminergic stimulation by apomorphine on speech in Parkinson's disease

OBJECTIVE: To determine the effect of central dopaminergic stimulation with apomorphine on speech in PD. BACKGROUND: Most patients with PD have a speech disorder. Of those, 89% have involvement of laryngeal function, and 45% have additional articulatory dysfunction. The effect of dopaminergic medications on these two dimensions of speech impairment in PD has not been selectively studied. METHODS: In a randomized, double-blind, placebo-controlled crossover design, patients with PD and speech impairment, Hoehn and Yahr stages 2 to 4 "off," and without severe dyskinesias were given placebo or apomorphine injections 0.05 mg/kg subcutaneously during two consecutive outpatient visits. They were pretreated with domperidone for 48 hours and were tested off their parkinsonian medications for 12 hours. Laryngeal function was assessed by maximum sustained vowel phonations and comfortable vowel phonations. Articulatory function was evaluated by speech intelligibility score, speaking rate, and efficiency ratio. RESULTS: Ten patients, mean age 73.4 years (SD = 6.6), disease duration 8.7 years (SD = 6.3), were tested. The baseline motor score on the Unified Parkinson's Disease Rating Scale (UPDRSm) and all experimental speech variables were equivalent on both placebo and apomorphine days. At a dose of apomorphine that provoked improvement in UPDRSm (p = 0.0078), no index of either laryngeal or articulatory function improved significantly after apomorphine administration. CONCLUSION: Laryngeal and articulatory speech components are not under prominent dopaminergic control in PD. Treatment regimens should focus on nondopaminergic pharmacology and other therapies.     

Apomorphine for the acute treatment of "off" episodes in Parkinson's disease

Many patients with advanced Parkinson's disease (PD) experience motor complications, which negatively impact quality of life, despite optimized oral therapy. It is important for patients to have a treatment option that may provide rapid relief from "off" episodes. In three pivotal, randomized, placebo-controlled trials, subcutaneous apomorphine was effective in acutely treating "off" episodes, significantly improving Unified Parkinson Disease Rating Scale motor scores and reducing the number of "off" hours per day, with a significantly shorter time to patient-declared onset of relief than placebo. Thus, clinical trial data support the efficacy of intermittent subcutaneous apomorphine as a rapid acute treatment for "off" episodes in advanced PD.     

Motor response following repeated apomorphine administration is reduced in Parkinson's disease

Ten patients with Parkinson's disease (PD) with motor fluctuations under levodopa treatment were given repeated equal subcutaneous injections of apomorphine [minimal effective dose (MED)] in 1 day. The MED was defined as the dose of apomorphine necessary to induce at least 60% reduction of motor disability for a minimum period of 10 min. MED was found for each patient in previous study days. In eight a subcutaneous infusion of apomorphine was performed on a different day. Four patients with simple fluctuations ("wearing off") showed a progressive reduction of the motor response to apomorphine injections, but three of the four had a stable response (continuous "on") to apomorphine infusion. Six patients with complicated fluctuations also exhibited a decreasing response to successive apomorphine injections and often completely failed to respond to some of the boluses. The response to a subcutaneous infusion of apomorphine was unstable in three of four cases. These findings indicate that a reduction of striatal dopaminergic receptor sensitivity is associated with repeated "pulsatile" apomorphine administration in parkinsonian patients with oscillations of motor performance. It is suggested that altered regulation of dopaminergic receptor sensitivity following pulsatile stimulation with levodopa may be a relevant phenomenon in the pathogenesis of motor fluctuations in PD.     

Apomorfina w zaawansowanej chorobie Parkinsona

Apomorphine is the most potent dopamine receptor agonist and its symptomatic effectiveness is comparable to levodopa. Subcutaneous apomorphine is rapidly and completely absorbed. Plasma peak concentrations are achieved after 5–15 minutes and onset of clinical effect is within 20 minutes. Apomorphine intermittent subcutaneous injections are effective as rescue therapy for unpredictable off periods in advanced Parkinson disease (PD). More often apomorphine is administered as a subcutaneous infusion which secures the continuous dopaminergic stimulation. The benefit on ‘off’ periods is consistent across all studies, but dyskinesia improvement is not so obvious. Two infusion therapies (apomorphine and intraduodenal levodopa) and deep brain stimulation (DBS) are effective in advanced PD patients with untreatable motor complications. Apomorphine infusions should be considered in patients unable to undergo DBS because of cognitive impairment and neurosurgical contraindications.     

Apomorphine infusion and the long-duration response to levodopa in advanced Parkinson's disease

The authors investigated the long-duration response to levodopa in advanced Parkinson's disease. Eight patients with advanced Parkinson's disease disabled by severe ON/OFF fluctuations treated by chronic daytime subcutaneous apomorphine infusion with supplemental oral levodopa were studied. On day 1, oral levodopa was withdrawn at 4:00 pm and on the following morning subcutaneous apomorphine infusion was continued at the same rate without levodopa therapy. While receiving apomorphine alone, seven of the eight patients turned ON, and their usual dyskinesias returned. The ON phase persisted for 60 to 100 minutes (mean, 185.7 minutes) but then, despite continued, constant-rate apomorphine infusion to stabilize plasma levels, switched to an OFF phase. The authors conclude that the clinical effect of apomorphine is sustained by levodopa long-duration response. This effect is probably the result of postsynaptic mechanisms. In patients with advanced Parkinson's disease, the long-duration response to levodopa is present although slightly diminished.     

Continuous apomorphine infusion and neuropsychiatric disorders: a controlled study in patients with advanced Parkinson’s disease

Abstract. The aim of this study was to asses whether patients with Parkinsons disease (PD) develop cognitive and psychiatric complications more frequently during prolonged therapy with continuous apomorphine infusion compared with standard oral treatment. Thirty consecutive PD patients with severe motor fluctuations were included in the study. Twelve patients accepted the treatment with subcutaneous continuous apomorphine infusion, while the remaining 18 preferred to continue with oral dopaminergic therapy. The two groups were evaluated with neuropsychological, psychiatric, and motor tests at baseline and after 1 year. The off daily duration and the levodopa dosage were significantly reduced in infused patients. The neuropsychiatric assessment did not change in both groups compared with baseline, except for a significant improvement of mood in the apomorphine group.     

Motor response to levodopa in patients with parkinsonian motor fluctuations: a follow-up study over three years.

To clarify the way in which the clinical response to levodopa changes with the progression of Parkinson's disease, a longitudinal study was performed to quantify motor response characteristics to single doses of levodopa by mouth over three years in 23 patients with fluctuating motor function. A significant increase in motor disability in "on" (time of peak motor improvement) and "off" (before levodopa dose) phases occurred and "on" phase dyskinesia increased by 24%, though the amplitude of motor response was conserved. There was no evidence of progressive loss of response of certain motor deficits affecting axial muscles and gait. The mean duration of motor response decreased by 17%. Both shortening of response duration and increase in "off" phase disability contribute to the development of motor fluctuations. A short response time to the levodopa test dose was not an invariable finding in patients with severe fluctuations, whereas all had large response amplitudes and high "off" phase disability scores. Patients who have developed motor fluctuations may continue to respond to dopaminergic treatment until late in the disease course, despite the unstable nature of their responses.     

Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson's disease: a prospective study using single-dose challenges.

Continuous subcutaneous (SC) infusion of the dopamine agonist apomorphine was shown in retrospective studies to improve drug-induced dyskinesias in Parkinson's disease (PD). We prospectively assessed the antidyskinetic effect of continuous SC apomorphine therapy using subjective and objective measures, and sought to determine whether any observed dyskinesia reduction could be corroborated using single-dose dopaminergic challenges. Twelve PD patients with on-off fluctuations and disabling dyskinesias who were scheduled to start apomorphine pump treatment underwent acute levodopa and apomorphine challenges at baseline and 6 months later. Video recordings involving motor tasks were rated blindly by two independent raters using modified AIMS and Goetz dyskinesia scales. At 6 months, mean apomorphine dose was 75.2 mg per day and the mean L-dopa dose had been reduced by 55%. Daily off time in patients' diaries was reduced by 38% (2.4 hours). The L-dopa challenges showed a reduction of 44% in AIMS and 40% in Goetz scores (both P < 0.01). Apomorphine challenges showed a reduction of 39% in AIMS and 36% in Goetz scores (both P < 0.01). Patients' self-assessment scores reflected these significant changes. Dyskinesia improvement correlated with reduction in oral medication and with the final apomorphine dose (P < 0.05). This prospective study confirms marked dyskinesia reduction on continuous subcutaneous apomorphine therapy, paralleled by reduced dyskinesias during dopaminergic challenge tests. Our findings support the concept that replacement of short-acting oral antiparkinsonian medication with continuous dopamine receptor stimulation may reverse, at least partially, the sensitization process believed to mediate the development of drug-induced dyskinesias in PD.