Worsened motor test performance following acute apomorphine injection in previously untreated patients with Parkinson's disease

Instrumental tests and clinical rating assess motor disability in Parkinson's disease (PD) patients. Previous long-term dopaminergic substitution influences the behaviour following acute dopaminergic stimulation. Objective of this study was to investigate the motor response following an apomorphine application in previously untreated-, treated- and before treated PD patients, who received placebo. Outcomes of instrumental tests worsened in previously untreated-, but not in before treated PD patients after apomorphine injection and in the PD subjects under the placebo condition. Generally, rating scores of motor symptoms significantly improved after apomorphine administration, whereas placebo application showed no effects. Tolerance to sedative effects of apomorphine in treated PD patients or sensitivity of employed motor tests to presynaptic dopaminergic autoreceptor mediated inhibition of endogenous dopamine release or postsynaptic dopaminergic overstimulation with resulting decreased cognitive function in previously untreated PD patients hypothetically caused this discrepancy between outcomes of subjective clinical rating and objective motor test performance.     

A novel sublingual apomorphine treatment for patients with fluctuating Parkinson's disease.

We tested a novel preparation of a sublingual apomorphine hydrochloride tablet (APO) in 10 patients with advanced Parkinson's disease complicated by motor fluctuations. After a dose titration, patients took either 40 mg APO three times per day alternating with levodopa doses (eight patients) or six doses of 20 mg APO taken concurrently with levodopa doses (two patients) for 3 months. Assessments included timed tapping and ambulation tests, Unified Parkinson's Disease Rating Scale (UPDRS), and patient diaries. Tapping speed while taking only APO (12 hours after stopping levodopa) was faster than while taking only levodopa (p <0.05). The daily levodopa dose decreased by 32.1% (p <0.01), yet the total "on" time increased from 73.5% +/- 10.2% to 81.5% +/- 7.5% of the day (p <0.01) after starting APO. "On" UPDRS part II scores (p <0.05) and "on" UPDRS part III (motor examination) scores (p <0.05) also improved. Adverse events such as nausea, orthostatic hypotension, and disagreeable taste did not limit the dose of APO in any case. The short-term benefit and tolerability demonstrated in this study warrant further study of this new APO preparation.     

The motor response to repeated apomorphine administration in Parkinson's disease

Seven patients with Parkinson's disease and levodopa-induced motor fluctuations were studied with repeated injections of apomorphine over a 10-h period to explore possible changes in the latency, duration, and quality of motor response with recurrent dopaminergic stimulation. Doses were given when the motor effects induced by the previous dose had just worn off. No significant change in the motor response to repeated boluses of subcutaneous apomorphine was found. Our results do not support the suggestion that rapid changes in receptor sensitivity during repeated intermittent dopaminergic stimulation are a major factor in the pathogenesis of parkinsonian motor fluctuations.     

Motor response to apomorphine in patients with Parkinson's disease with long-duration response to levodopa

The authors studied the motor response to apomorphine before and 1 year after levodopa therapy in 12 patients with Parkinson's disease. At the 1-year evaluation, the basal tapping score, recorded after a 12-hour levodopa withdrawal, was higher compared with the test performed while patients were de novo, indicating the presence of a long-duration response to levodopa. The amplitude (net increase) of the motor response to apomorphine was similar before and during levodopa therapy. However, because of the better baseline, the maximal tapping score was higher during levodopa therapy. The duration and the latency of the motor response to apomorphine did not change. The presence of a short-duration response to apomorphine, in the presence of a long-duration response to levodopa, may imply that either different compartment (i.e., postsynaptic versus presynaptic) or transduction pathways are involved in such responses.     

Subcutaneous continuous apomorphine infusion in fluctuating patients with Parkinson's disease: long-term results

Fluctuations in motor disability and dyskinesias are the major problem in the long-term treatment of Parkinson's disease (PD). Many authors and ourselves have shown that by giving patients a continuous infusion of levodopa it is possible to control motor fluctuations. Levodopa can be administered continuously only be intravenous, intragastric or intrajejunal delivery. Continuous dopaminergic stimulation an be achieved more easily by infusing dopamine agonists subcutaneously. Apomorphine is a potent water-soluble dopamine receptor agonist that has been shown to successfully control motor fluctuation when subcutaneously infused in complicated parkinsonian patients. We report the clinical data of 30 PD patients having at least five years of treatment with subcutaneous continuous apomorphine infusion.     

Efficacy and tolerability of a novel sublingual apomorphine preparation in patients with fluctuating Parkinson's disease

We tested a novel preparation of sublingual apomorphine hydrochloride (APO) in 10 patients with advanced Parkinson's disease complicated by motor fluctuations and dyskinesias. After dose titration, patients underwent a blinded comparison of APO versus placebo, and an unblinded comparison of APO versus optimally dosed carbidopa/levodopa using timed tapping and walking paradigms. APO was significantly better than placebo in both measures: Tapping speed was 30.8% faster than with placebo (p < .0005), and ambulation speed was 45.2% faster than with placebo (p < .05). Ambulation speed with APO was also 15.9% faster than that with optimal doses of carbidopa/levodopa (p < .05). The latency to onset of clinical improvement with each APO dose was 10 to 40 minutes, and the duration of effect was 60 to 130 minutes. Adverse events included nausea, orthostatic hypotension, and disagreeable taste in the patient's mouth. Aside from the bitter taste, all other side effects resolved with continued use and did not limit dosing in any case. We feel that the good short-term efficacy and tolerability demonstrated in this study warrant further study of this new preparation, as there are several potential advantages of sublingual administration compared with traditional APO preparations.     

Time interval between repeated injections conditions the duration of motor improvement to apomorphine in Parkinson's disease.

Behavioral hyposensitivity to repeated apomorphine administration occurs in fluctuating parkinsonian patients. To determine to what extent the interval between doses influences the response, we administered equal paired apomorphine injections to 10 fluctuating parkinsonian patients. Subjects received two apomorphine injections at 2-hour and at 4-hour intervals on different days after a 10- to 12-hour overnight period without levodopa. Following apomorphine doses at 2-hour intervals, the duration of response was reduced by 40% (61 versus 42 minutes, p less than 0.001) but was of equal duration when the doses were given at 4-hour intervals. These findings indicate that the interval between doses is a critical determinant of motor response. We postulate a time-dependent period of partial hyposensitivity to pulsatile DA stimulation.     

Comparison of motor response to apomorphine and levodopa in Parkinson''s disease.

The magnitude and pattern of motor responses to single doses of subcutaneous apomorphine and oral levodopa were compared in 14 patients with Parkinson's disease. Although apomorphine produced much shorter motor responses than levodopa, the quality of response to the two drugs was virtually indistinguishable. These clinical observations support the notion that integrity of striatal post-synaptic dopamine receptors is a key determinant of responsiveness to dopaminergic treatment in Parkinson's disease.     

Predicting beneficial response to a protein-redistribution diet in fluctuating Parkinson's disease.

To identify factors that might help in predicting the benefit to be gained from a protein-redistribution diet (PRD) we subjected 26 parkinsonian patients with motor fluctuations refractory to optimal timing and dosage of levodopa plus bromocriptine to a 2,000-2,500 Kcal., 65-80 g/d protein containing diet maintained for 8-12 weeks. Fifteen patients were eligible for evaluation, 10 of whom being benefited by the PRD (79 percent reduction in the mean "off" time in "on-off" charts). When the duration and pattern of the fluctuations were compared in the 10 diet-benefit patients with those in 5 diet-failure patients only dose-failures consistently occurring postprandially were resolved by the PRD. Wearing-off failures responded unpredictably while random "on-off" fluctuations were present only in the diet-failure group. Nocturnal akinesia and peak-dose dyskinesias often worsened. In no patient "on"-time quality was modified by the diet. In addition, the diet-failure group was characterized by a younger mean age at onset (p less than 0.05) and by longer duration in their fluctuations (p less than 0.001). Though requiring confirmation in a larger series, our results suggest that parkinsonian patients showing fluctuations over prolonged periods, particularly those having a pattern of random "on-off" oscillations in motor performance and dose-failures unrelated to meals are unlikely to benefit from a PRD.     

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.     

Subcutaneous administration of apomorphine in motor fluctuations in Parkinson's disease

Apomorphine, a dopaminergic agonist was given over a period of 12 months to 14 parkinsonian patients suffering from severe L-dopa induced on-off effects. Nine patients (mean age: 52 years; mean age at onset of the disease: 37 years), were treated by continuous infusion with a portable minipump, and 5 others by multiple injections with a penject. The mean duration of daily off periods was reduced by two thirds in all patients. The motor fluctuation intensity was only diminished in the 9 patients treated by continuous infusion. These patients received a mean apomorphine daily dose of 93 mg and L-dopa dosage was reduced by 53 p. 100. Red fibrous subcutaneous nodules occurred at the injection sites in all patients treated by infusion. This study confirms the effectiveness of subcutaneous apomorphine administration in the treatment of severe motor fluctuations.     

Controlled-release transdermal apomorphine treatment for motor fluctuations in Parkinson's disease

Neurological Sciences - This study evaluated the efficacy in Parkinson's disease (PD) of a new pharmacologic preparation of apomorphine included in microemulsions and administered by...     

Differences in sleep in patients with Parkinson's disease.

Twenty-three Parkinson patients were recorded during 2 or 3 consecutive nights. Their treatment, if any, was withdrawn for at least 15 days before the first recording session. Some qualitative abnormalities were noticed during each night in 13 of these patients. They consisted in: 1. Repetitive blinking at the beginning of the night when the lights were turned off, persistence of the electromyographic activity of the chin muscles during paradoxical sleep, occurrence of rapid eye movements and blepharospasms during slow wave sleep before the onset of paradoxical sleep episodes, and alpha rhythm during paradoxical sleep. 2. The study of these signs showed that association between blinking and persistence of the activity of the chin muscles during paradoxical sleep is never encountered. 3. The patients with chin muscle activity during paradoxical sleep had a 50% decrease in paradoxical sleep as compared with the group of patients with repetitive blinking. 4. The possibility that lesions of the locus coeruleus are responsible for this decrease in paradoxical sleep is discussed.     

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.     

Sustained bromocriptine therapy in previously untreated patients with Parkinson's disease.

The progress of 50 previously untreated patients with idiopathic Parkinson's disease taking maximum tolerated doses of bromocriptine is compared with patients who had taken levodopa. Twenty-eight of the bromocriptine treated patients showed sustained benefit for at least one year and in five this persisted longer than five years. Fewer of the late complications of levodopa therapy occurred in those taking bromocriptine; drug-induced dyskinesia was seen in only one patient and oscillations in performance were not observed. There was a tendency for deterioration to develop after two years treatment when patients then failed to respond well to levodopa. It was not possible to extend the period of effective control of disabilities by first giving bromocriptine.     

Longitudinal study of the motor response to levodopa in Parkinson's disease.

In this prospective study of 34 patients with Parkinson's disease, measurements of the short duration levodopa motor response have been performed in defined off states at 3 yearly intervals over a mean period of 11.4 years from the point of commencement of levodopa treatment. Twenty-two patients were still available for study; 10 had died and 2 were lost to follow-up. The levodopa motor response amplitude increases over the first 5 years of treatment, and thereafter, on and off scores worsen in parallel with conservation of the response. Patients who developed motor fluctuations within the first 5 years of treatment had, on average, a stronger response to levodopa with significantly better on phase motor function (P = 0.003). Although the proportion of "midline" motor disability (affecting gait, balance, and cranial motor function) increases with time, these deficits do not actually become unresponsive to levodopa. Patients who developed dementia had a significantly more rapid decline in motor function. The latest graph of serial scores for the whole cohort shows an upward curving or exponential increase in motor disability after the first decade of treatment. Applying a notional untreated disability line to this graph--an estimate of the disability that would have accrued if drugs had never been given--we suggest that the long-duration response to levodopa eventually runs down with disease progression.     

Heart rate variability in patients with untreated Parkinson's disease

The aim of this study was to evaluate cardiovascular responses as a marker of autonomic nervous system (ANS) disturbances in patients with untreated Parkinson's disease (PD) and to assess the relationship between them and the clinical characteristics of PD. The ANS functions were investigated in 50 patients with PD and 55 healthy subjects by measuring standard cardiovascular autonomic reflexes and heart rate variability (HRV) at rest using spectral analysis (the autoregressive model and the fast Fourier transformation), the percentage of the counts of beat-to-beat variation greater than 50 ms and the fractal dimension. Significantly attenuated HRV and deficient blood pressure reaction to tilting were found in the PD patient group. The patients with hypokinesia/rigidity as the initial symptom of PD had a more pronounced HRV deficit than those with tremor onset. Untreated PD patients suffer significant failure in cardiovascular nervous system regulation, and in patients with hypokinesia/rigidity as their initial disease manifestation the risk of this ANS dysfunction is high. However, in the early stages of PD these changes did not reach significance at individual level.     

Acoustic voice analysis in untreated patients with Parkinson's disease

To quantify several acoustic features of the voice in patients with Parkinson's disease (PD) not treated with dopaminergic drugs, 22 PD patients and 28 age and sex-matched controls were studied. The Computerized Speech Lab 4300 program (Kay Elemetrics) was used. Two seconds of a sustained /a/ and a sentence were captured with a microphone and laryngograph equipment. Measures included fundamental frequency (F(0)), frequency perturbation (jitter), intensity perturbation (shimmer), and harmonic/noise ratio (HIN) of the vowel /a/, and frequency and intensity variability of a sentence, phonational range, dynamic range at the natural frequency, maximum phonational time and s z ratio. All subjects underwent indirect laryngoscopy and/or laryngeal fibroscopy. When compared to controls, PD patients showed higher jitter and shimmer, lower H N ratio, and lower frequency variability of the sentence in the microphonic signal and reported a higher frequency of presence of low voice intensity, monopitch, harshness, voice arrests, and tremor.     

Differences in motor and cognitive function in patients with Parkinson's disease with and without orthostatic hypotension

Patients with Parkinson's disease (PD) often present with orthostatic hypotension (OH) as a result of the dysautonomia associated with the disease or as a side effect of the dopaminergic medications used to treat the disease. The purpose of this study was to investigate differences in motor and cognitive function in patients with PD with and without OH. Forty-four patients with a diagnosis of PD were evaluated and stratified by the presence of OH based on orthostatic blood pressure recordings. Both groups underwent assessments of motor and cognitive function. OH was present in 17 of 44 patients (39%) with PD. These patients with OH had significantly lower scores in gross motor, balance, and cognitive function (p < .05). No significant difference between groups was found in the finger tapping scores. These results suggest that patients with PD should be routinely screened for OH as it commonly occurs and may negatively impact gross motor, balance, and cognitive function.     

Thermal and mechanical pain thresholds in patients with fluctuating Parkinson's disease

Study results evaluating pain thresholds in patients with Parkinson's disease (PD) vary widely. Thus, we designed our study to determine the effects of levodopa on the thresholds of pressure (PPT), heat (HPT) and cold pain (CPT) in PD patients with motor fluctuations (18 patients: 10 men, 8 women; age: 65 ± 10 years; mean disease duration: 11.6 ± 6 years), six of whom (33%) reported pain related to their disease. We compared these thresholds in patients in the ON and OFF states with those in 18 age- and sex-matched controls. Pain thresholds were assessed over: the frontal bones, C5-C6 zygapophyseal joints and second metacarpals (PPT); the dorsal aspect of the hand (HPT and CPT); and the tibialis anterior (TA) muscles. PD patients in the OFF state had lower PPT thresholds at all sites (P < 0.001) than healthy controls. Moreover, HPT and CPT thresholds were lower at all sites except over the TA muscle (P < 0.01). In the ON state, the PPT and CPT thresholds in PD patients were lower than in controls at all points, except over the TA (CPT) and the second metacarpals (PPT) P < 0.01. Pain thresholds were no different in PD patients in the ON or OFF state (P > 0.10), and the existence of pain did not influence the results. We detected mechanical and thermal pain hypersensitivity in PD patients in the OFF state, and levodopa administration did not increase these thresholds. Thus, while dopamine may modulate pain responses, other mechanisms are likely to be implicated in the modulation of these pain responses in PD patients.