Diurnal responsiveness to apomorphine

Many parkinsonian patients respond to L-dopa better in the morning than at other times. To explore the possibility that this phenomenon represents diurnal fluctuations in dopaminergic receptor responsiveness, we compared the effects of subcutaneously administered apomorphine during "off" periods in the mornings and afternoons in nine fluctuating patients. The duration of response and area under the time-response curve, but not the magnitude of improvement, were dose responsive. Response durations to the same dose administered in the morning and afternoon were similar, although at threshold doses three subjects responded only to the afternoon dose. These observations suggest there is no large diurnal change in striatal dopaminergic responsiveness.     

Levodopa consumption reduces dopaminergic receptor responsiveness in Parkinson's disease

In seven patients with Parkinson's disease with daily motor fluctuations, we found that the same subcutaneous apomorphine dose that improved motor function when given in the morning after a normal night without taking levodopa failed to turn patients "on" during afternoon and evening "off" periods, and on a different morning after receiving levodopa during the night. No significant changes in levodopa or 3-O-methyldopa plasma levels that could explain these variations were detected. These findings suggest that increased daily levodopa consumption may reduce striatal responsiveness to dopaminergic stimulation.     

Levodopa and 3-O-methyldopa plasma levels in parkinsonian patients with stable and fluctuating motor response

Many parkinsonian patients with motor fluctuations in response to levodopa show a good response to initial morning doses but fail to respond in the afternoon and evening. We have studied levodopa and 3-O-methyldopa (3-OM-dopa) plasma profiles in 21 patients with fluctuations and eight patients with stable motor function throughout the day. Levodopa plasma peaks and valleys were similar for both group of patients. No significant difference for levodopa absorption index [defined as levodopa plasma levels after each dose divided by the quantity (mg) of ingested levodopa] was found between the first and the second levodopa-carbidopa dose in either group of patients. Even in patients who failed to improve after the second levodopa-carbidopa tablet (p.o.) on the day of the study, no significant variation in levodopa absorption index was observed. 3-OM-dopa values depended mainly upon levodopa consumption and were not different for patients with fluctuating or stable motor response. These findings provide further evidence of the prime role of central pharmacokinetic and pharmacodynamic factors in the pathogenesis of motor fluctuations in Parkinson's disease.     

Motor response to acute dopaminergic challenge with apomorphine and levodopa in Parkinson''s disease: implications for the pathogenesis of the on-off phenomenon.

OBJECTIVES--To evaluate the contribution of postsynaptic changes to motor fluctuations, three groups of parkinsonian patients with differing responses to treatment were acutely challenged with two dopaminergic drugs-apomorphine and levodopa-having different mechanisms of action. METHODS--Forty two patients with Parkinson's disease (14 untreated, eight with a stable response to levodopa, and 20 with levodopa induced motor fluctuations) were challenged on two consecutive days with apomorphine and levodopa. The latency, duration, and magnitude of motor response was measured. RESULTS--A progressive shortening of mean latency after levodopa challenge was found passing from the untreated to the stable and fluctuating groups; the difference between untreated and fluctuating patients was statistically significant (P < 0.01). Response duration after levodopa challenge was similar in untreated and stable patients, whereas it showed a significant shortening in patients with motor fluctuations (P < 0.05 v both untreated and stable patients). When subcutaneous apomorphine was given, untreated patients had a longer response duration than those who had developed motor fluctuations (P < 0.05). Although baseline disability was significantly greater in the fluctuating patients than in the untreated and stable patients, the severity of residual parkinsonian signs after both apomorphine and levodopa challenge was similar for all three groups; as a result, the degree of improvement in parkinsonian signs after dopaminergic stimulation was substantially greater in more advanced than in early cases. Linear regression analysis also indicated that latency and duration after apomorphine challenge did not significantly correlate with those after levodopa challenge, whereas magnitude of response to apomorphine showed a strong positive correlation with that after levodopa challenge (r = 0.9, P < 0.001). CONCLUSION--The progressive shortening of motor response after both apomorphine and levodopa suggests that pharmacodynamic factors play an important part in determining the duration of motor response and argue against altered central pharmacokinetics of levodopa being principally responsible for the on-off effect. The widening response amplitude and increasing off phase disability occurring during disease progression are also critical factors in determining the appearance of motor fluctuations.     

Challenge tests to predict the dopaminergic response in untreated Parkinson's disease

To clarify the predictive role of dopaminergic challenge tests, we compared the responses to subcutaneous apomorphine and oral levodopa with the therapeutic effect of ongoing levodopa treatment in 45 previously untreated patients with idiopathic Parkinson's disease. The response to long-term levodopa was accurately predicted by apomorphine in 67% (30) of patients and by levodopa in 80% (35) of patients. There were nine cases without a definite response to sustained levodopa, four in patients who developed atypical clinical features during the period of follow-up. These tests have a predictive value for subsequent dopaminergic responsiveness and may help in the early differential diagnosis of parkinsonian syndromes.     

Treatment of Parkinson's disease in Japan

In this paper, the course of therapy for Parkinson's disease is outlined. The rationale for the use of DA-receptor-agonist (DA agonist) monotherapy or early combination therapy using levodopa and a DA agonist is that these therapies are asociated with a lower incidence of motor complications. However, the disease progresses, the use of levodopa in combination with a DA agonist results in motor complications and development of levodopa dependency in parkinsonian patients, because the effect of levodopa on parkinsonism is very strong. In this study, a positive correlation between the Hoehn-Yahr severity score at off-periods and duration of illness was observed in parkinsonian patients with long duration of illness. This indicates that responsiveness to dopaminergic therapy still exists even in patients in advanced stages of Parkinson's disease, indicating that continuous stimulation of DA receptors and reducing the excessive fluctuation in the plasma levodopa level possibly improve motor complications. If the dose of the DA agonist is simply increased without reduction of levodopa doses, dyskinesia worsens. Although levodopa therapy is essential in the case of patients in advanced stages of Parkinson's disease, the therapeutic principle, which depends on levodopa efficacy, must be changed. Reduction of the levodopa dose and administration of a sufficient dose of a DA agonist, which is equivalent to levodopa dose reduction, is one of the possible means of effective therapy of the disease.     

The duration of the motor response to apomorphine boluses is conditioned by the length of a prior infusion in Parkinson's disease

“Pulsatile” administration of levodopa has been invocated a relevant factor for motor fluctuations in Parkinson's disease (PD). We studied dopaminergic sensitivity to apomorphine in 10 parkinsonian patients with motor fluctuations. Patients were tested as follows: the minimal effective dose of apomorphine (MED‐1) was administered in the morning to induce an on response. Fifteen minutes after this motor response had disappeared, an apomorphine infusion was initiated and maintained to ensure on periods of three different durations on different days. Infusion lasted for ～30, 60 and 90 minutes. Subsequently, the infusion was stopped, and after 15 minutes in the off state, a second bolus of apomorphine (MED‐2) was given. The mean infusion doses were 49.2 ± 5.4, 108.4 ± 10.3, and 150 ± 8.2 mg. These elicited on periods of 48.2 ± 4.1, 110 ± 4.5, and 195 ± 3.8 minutes. The MED‐2 elicited on responses with a duration of 30 ± 4.5, 18.4 ± 3.2, and 11.2 ± 4.1 minutes. The duration of the on response induced by the apomorphine infusions correlated inversely (P < 0.01) with the on induced by the MED‐2 of apomorphine. Our findings indicate that a continuous dopaminergic stimulus may induce pharmacodynamic changes associated with tolerance in PD patients. © 2009 Movement Disorder Society     

Differences in the motor response to apomorphine between untreated and fluctuating patients with Parkinson's disease.

Behavioral hyposensitivity to repeated apomorphine administration has been observed in fluctuating parkinsonian patients. To investigate whether a similar phenomenon occurs in patients never treated with levodopa, we studied the response to apomorphine in 20 de novo patients with Parkinson's disease. Six patients showed no or minimal improvement after apomorphine injections (maximal dose 3.5 mg). Fourteen patients responded and were then given up to four repeated subcutaneous injections of apomorphine [minimal effective dose (MED)]. The responses of de novo patients were compared with responses in 10 patients with motor fluctuations previously studied by the same protocol. There was no significant difference in latency and duration of motor responses after repeated apomorphine injections in de novo patients. MED was similar in de novo and fluctuating patients, but duration of improvement induced by each apomorphine bolus was longer in the de novo group. These results indicate that response duration to apomorphine is longer in previously untreated patients and that behavioral tolerance associated with pulsatile dopaminergic stimulation by apomorphine occurs mainly in patients with more advanced disease under chronic levodopa therapy.     

Wearing-off fluctuations in Parkinson's disease: Contribution of postsynaptic mechanisms

Wearing-off phenomenon that complicates levodopa therapy of Parkinson's disease has been attributed to a reduction in striatal dopamine storage due to the progressive degeneration of presynaptic dopaminergic terminals. To determine whether postsynaptic mechanisms also contribute to these response fluctuations, the duration of the antiparkinsonian response in parkinsonian patients grouped by disease severity was compared following discontinuation of a steady-state optimal-dose infusion of apomorphine. Although the plasma half-life of this dopamine receptor agonist remained constant, its mean efficacy half-time declined from 66 minutes in early, levodopa-naive patients to 33 minutes in advanced, complicated parkinsonians (p < 0.005). Since the motor effects of apomorphine do not depend on the presence of dopaminergic terminals, changes at the postsynaptic level undoubtedly contribute to the diminished response duration. The only slightly greater attenuation of levodopa's motor effects observed previously under similar conditions suggests these postjunctional alterations, possibly involving relatively plastic striatal dopaminoceptive systems, account for most of the shortening in the duration of levodopa action that underlie wearing-off fluctuations.     

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.     

Kinetic-dynamic relationship of oral levodopa: possible biphasic response after sequential doses in Parkinson's disease.

The potential difference in the concentration-effect relationship of oral sequential doses of levodopa was explored in six Parkinsonian patients with complex fluctuating response. These patients showed "wearing-off phenomena" characterized by a transient worsening of motor function at the end of the first morning dose response to below baseline values and complained of a progressive reduction of levodopa effect during the day. A first standard levodopa dose was given in the morning, after an overnight fast and levodopa withdrawal. A second equal levodopa dose was administered immediately at the end of the first dose deterioration phase. Postimprovement worsening of motor response was also observed after the second levodopa dose in all patients. No significant difference in the pharmacokinetics of levodopa or in duration or magnitude of motor response could be appreciated between the two doses. These results further support the suggestion that, under controlled dietary conditions, plasma levodopa levels and effects relationship is reproducible between doses. Moreover, even when transient deterioration of motor function occurs between levodopa doses, the central dopaminergic system appears to remain responsive to the drug.     

The L-dopa test in Parkinson's disease

Seventy parkinsonian patients (mean age: 59.6 +/- 1.2 years; duration of disease: 9 +/- 0.6 years) with severe fluctuations of disability under L-Dopa treatment received a single dose of L-Dopa (200 mg + benserazide, a peripheral decarboxylase inhibitor) after 24-72 h interruption of treatment. The delay and duration of action of a single dose of L-Dopa, and the percentage of improvement of the parkinsonian symptoms were 39 +/- 2 and 162 +/- 6 minutes, and 57 +/- 2 p. 100 respectively. Estimation of the difference between the basal parkinsonian score and the score during maximum clinical improvement under levodopa treatment, and the score under levodopa treatment may reflect the severity of dopaminergic and of non dopaminergic lesions in the brain respectively. Modification of the treatment to obtain continuous clinical improvement can be performed according to the delay and duration of action of a single dose of L-Dopa.     

Apomorphine test in de novo Parkinson's disease.

We administered apomorphine, a powerful dopaminergic agonist, subcutaneously to 25 untreated patients with parkinsonian features and evaluated motor response with the aim of discriminating idiopathic Parkinson's disease (IPD) from multiple system atrophy and progressive supranuclear palsy. The response to apomorphine was strongly predictive of responsiveness to subsequent levodopa follow-up and of the final diagnosis, made on the basis of both clinical and instrumental evaluation. Our data confirm that the apomorphine test is helpful in the differential diagnosis of IPD.     

Levodopa peripheral pharmacokinetics and duration of motor response in Parkinson''s disease.

To assess the relative influence of central pharmacodynamic and peripheral pharmacokinetic factors on the duration of motor response to levodopa, the relationship between motor function and plasma levodopa levels was studied in 31 Parkinsonian patients. Duration of benefit from single levodopa doses while fasting depended on the degree to which the plasma levodopa level had declined over four hours; wearing off occurred when the plasma levodopa level had fallen to approximately 50% of peak concentration, irrespective of the duration of the motor response. Whilst the amplitude of motor response to levodopa is likely to be modified by alternations in dopamine receptor stimulation and sensitivity as the disease progresses, it is proposed that the duration of response is primarily determined by levodopa peripheral pharmacokinetics rather than by central pharmacodynamic factors associated with dopamine storage capacity.     

Levodopa treatment does not affect low-dose apomorphine test in patients with Parkinson's disease.

Challenge with low-dose apomorphine causes a significant rise in growth hormone (GH) in patients with Parkinson's disease (PD) compared to controls and patients with multiple system atrophy (MSA) who have not previously received dopaminergic treatment. To date, it has not been demonstrated whether an apomorphine-induced rise in GH can still be detected in PD patients who are currently treated with levodopa. We investigated whether an ongoing treatment with levodopa influences the GH response to subcutaneously applied low-dose apomorphine in PD patients. We studied 44 patients with idiopathic PD using the low-dose apomorphine test. Twenty-three patients were under treatment with levodopa and 21 patients were without any dopaminergic therapy. GH and cortisol levels were analyzed at time of injection and 45 minutes and 60 minutes after subcutaneous apomorphine injection. Forty-five minutes after apomorphine injection, there was no significant difference between the mean rise in plasma GH in untreated PD patients compared with levodopa-treated patients (P = 0.235). There was no increase of cortisol levels in each treatment group. Age, sex, duration, and severity of the disease did not show a covariate effect with GH levels. A small group of PD patients (n = 8) treated with dopamine agonists and a small group of patients with MSA (n = 5) as well as patients with vascular parkinsonism (n = 5) did not show any increase of GH. Our data suggest that the apomorphine-induced rise in GH does not depend on previous levodopa treatment in PD patients but, as expected, is blocked by dopamine agonists and is not present in patients with other than idiopathic parkinsonian syndrome. Thus, the low-dose apomorphine test may also be a useful biological marker in the early differential diagnosis of PD patients who have already received levodopa treatment.     

Diurnal differences in response to oral levodopa.

Diurnal differences in duration and quality of motor response to levodopa are frequently described by patients. The quality and duration of motor responses were objectively assessed to morning and afternoon oral levodopa doses in five patients with Parkinsonian motor fluctuations who complained of diurnal variation in response to their normal levodopa medication. Results suggest that under controlled conditions which eliminated the effects of diet and overlapping levodopa effects the response to levodopa remained unchanged throughout the day, and that the duration of response could be predicted by plasma levodopa levels.     

Increased growth hormone response to apomorphine in Parkinson disease compared with multiple system atrophy

BACKGROUND: Parkinson disease (PD) is often difficult to distinguish from parkinsonian syndromes of other causes in early stages of the disease. In search of a suitable endocrinologic challenge test, we investigated dopaminergic sensitivity in patients with de novo parkinsonian syndromes. OBJECTIVE: We measured the growth hormone (GH) response to a subthreshold dose of the dopamine 1-dopamine 2 receptor agonist apomorphine hydrochloride to differentiate parkinsonian syndromes from PD. PATIENTS AND METHODS: Seventeen patients with a clinical diagnosis of PD, 16 patients with a clinical diagnosis of multiple system atrophy, and 11 healthy controls. The GH response to a subthreshold dosage of apomorphine and to somatorelin (GH-releasing factor) was tested in a randomized order; on the third day the protocol was repeated with a clinically effective dose of apomorphine. RESULTS: The GH response to the low dose of apomorphine was significantly increased in patients with PD when compared with patients with multiple system atrophy or the control subjects (multivariate analyses of covariance; univariate F test, all P<.05). In contrast, there were no significant group differences with use of the higher dose of apomorphine or in the somatorelin-induced GH release. CONCLUSIONS: The GH response to a subthreshold dose of apomorphine appears to be a useful tool to identify patients with PD vs multiple system atrophy. The enhanced GH response to a subthreshold dopaminergic stimulus may reflect a hypersensitivity of the extrastriatal dopamine receptors in PD.     

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.     

Motor features and response to oral levodopa in patients with Parkinson’s disease under continuous dopaminergic infusion or deep brain stimulation

Background: Subthalamic nucleus deep brain stimulation (STN DBS) and continuous dopaminergic infusions (jejunal levodopa or subcutaneous apomorphine) are indicated in complicated Parkinson’s disease (PD), although it remains unsettled how they compare to each other. Methods: We investigated the daytime motor condition in patients with advanced PD under monotherapy with jejunal levodopa, subcutaneous apomorphine, or STN DBS and also measured the motor changes produced by an additional standard morning dose of levodopa. Motor performance was assessed with the UPDRS‐III, hand taps, the AIMS dyskinesia score and patients’ diaries. Outcome measures were time to best motor ‘on’ after start of morning treatment, daytime variability of motor condition, motor scores. Results: The time to ‘on’ was longest in the jejunal levodopa group. DBS and jejunal levodopa treatments produced stable motor conditions without appreciable ‘off’ episodes. Continuous apomorphine infusion was associated with the worst motor scores (UPDRS‐III and taps) and the most frequent off‐states. Jejunal levodopa infusion was associated with the highest AIMS scores. Addition of a levodopa dose produced shortening of time to ‘on’ and a transient motor improvement in the jejunal levodopa group without increase in dyskinesias; in the DBS and apomorphine groups, there was an increase in dyskinesias without changes in UPDRS‐III or taps. Conclusions: STN DBS provided adequate trade‐off between motor improvement and dyskinesia control, although dyskinesias could be elicited by adding oral levodopa. Jejunal levodopa infusion produced adequate motor improvement with slow time to ‘on’ and moderate dyskinesias. Apomorphine infusion produced insufficient motor control and negligible dyskinesias.     

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.