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.     

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.     

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 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.     

Motor fluctuations

The therapeutic approach of motor fluctuations is based on the need for recognizing various types of motor fluctuations for each patient by a meticulous interrogation and also to have a good knowledge of the pharmacology of the various anti-parkinsonian drugs. The treatment of the morning akinesia is linked to the use of anti-parkinsonian drugs with fast action like levodopa in dispersible formulation or apomorphine. The levodopa formulations with prolonged release can be proposed in the treatment of the noctural akinesia. "End of dose" and "on-off" fluctuations require a stable dopaminergic stimulation. It requires the use of drug associations which, for the majority, were never validated by rigorous therapeutic studies. Severe motor fluctuations require the use of apomorphine or chronic stimulation of the subthalamic nucleus.     

A 10 year retrospective audit of long-term apomorphine use in Parkinson’s disease

Abstract Objectives Apomorphine is a potent dopamine agonist useful in the treatment of Parkinsons disease patients with disabling motor fluctuations and off periods, not responding to oral medication. It can also be of benefit in reducing dyskinesia by providing more constant dopaminergic stimulation and permitting lower levodopa dosage. However, there is a paucity of information on long-term benefits of apomorphine, including no large-scale phase III trial. We have examined our experience of apomorphine over the last 10 years, to assess indications, pattern of use, efficacy, and side effect profile. Methods All patients requiring apomorphine were identified through the Parkinsons disease Nurse Specialists records. An audit form was produced so that the same information was gathered from all case-notes. Results There were 107 patients (61 males and 46 females). Mean age of disease onset was 50.9 years, SD±9.3 (range 29–78). The mean duration of disease at start of apomorphine treatment was 10 years (SD±4.8, range2–29). The most common indications for apomorphine were severe unpredictable off periods (75.7 %), motor fluctuations (18.7 %) and dyskinesia (5.6 %). Most patients (63.6 %) used both intermittent subcutaneous injections and infusion via pump; 25.2% were on intermittent injection, and 11.2 % infusion alone. Mean dose per injection was 3.7mg. Mean infusion dose 69.8mg, running over a mean of 13.5 hours. The mean duration of intermittent apomorphine use was 48.2 months. The mean duration of infusion was 25.1 months. Complications included skin problems in 16 patients, 2 had symptomatic hypotension, 2 worsening confusion, 1 new confusion and 5 new hallucinations (after sometime on apomorphine). Sixteen patients have stopped using apomorphine completely. Thirteen have stopped the pump, but continue on intermittent injections. Conclusion Subcutaneous apomorphine is easy for patients to use, is well tolerated and has a low incidence of side effects, especially confusion.     

Sublingual apomorphine in Parkinson's disease: a clinical and pharmacokinetic study.

The clinical response and the pharmacokinetic parameters of 3 mg subcutaneous (SC) and 30 mg sublingual (SL) apomorphine were compared in nine patients with Parkinson's disease. The magnitude of the motor responses (evaluated by tapping and walking tests and the Webster scale) was similar for SC and SL apomorphine. However, the onset to action was delayed after SL when compared with SC apomorphine. No significant difference was found in bioavailability (area under the curve: AUC) or peak plasma concentration (Cmax) between SC and SL apomorphine, whereas time to peak plasma concentration (Tmax) was shorter after SC apomorphine. Eight other patients were treated for a mean time of 4 months with SL apomorphine with a significant reduction in daily "off" hours. However, four of these eight patients developed stomatitis after some weeks of treatment. These results indicated that (a) pharmacokinetics parallel the clinical response to SL apomorphine, (b) SL apomorphine can reduce severe off periods in parkinsonian patients when used chronically, and (c) its long-term use is limited by a severe side effect (stomatitis).     

Le traitement par apomorphine en perfusion continue sous-cutanée dans la maladie de Parkinson : analyse rétrospective d’une série de 81 patients

Background

Continuous subcutaneous infusion of apomorphine (CAI) has shown efficacy in the treatment of motor fluctuations but its place in the therapeutic arsenal remains poorly defined in terms of indication, acceptability and long-term tolerance. Indeed, few studies have been carried out with a follow-up greater than 12 months. The main objective was to assess the quality of life of Parkinson's disease (PD) patients treated with CAI. We also evaluate the effectiveness on the motor fluctuations, the long-term tolerance of this treatment with its causes of discontinuation and the treatment regimens used.

Methods

We conducted a retrospective study of 81 PD patients treated with CAI between April 2003 and June 2012. Data were collected from medical records. A repeated measures analysis of variance by the linear mixed model was used (significance level: 5%).

Results

In August 2012, 27/81 patients were still treated with CAI with a mean duration of 28 months, 46/81 discontinued CAI (9 precociously), and 8 were lost to view. We didn’t show improvement in the quality of life nor efficacy of CAI on the UPDRS IV score (P = 0.54) and dyskinesia score (P = 0.95). The CGI score patient also reflects this result with a majority response suggesting no significant change with CAI. We observed relative good cognitive and psychiatric tolerance. Adverse events were frequent but often benign. The average (± SD) rate of apomorphine was 3.15 ± 1.71 mg/h and the oral dopaminergic treatment was decreased by 37.8%.

Discussion

The results are consistent with the literature except for the lack of efficiency on motor fluctuations which may be due to the use of too small doses of apomorphine. This seems to be a leading cause of discontinuation of CAI, especially when it is associated with side effects or important constraints. For better efficiency on motor fluctuations, we recommend the use of apomorphine at higher doses to obtain an optimal continuous dopaminergic stimulation.     

Deep brain stimulation of the subthalamic nucleus: effectiveness in advanced Parkinson's disease patients previously reliant on apomorphine

OBJECTIVES: To assess the efficacy of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with advanced Parkinson's disease previously reliant on apomorphine as their main antiparkinsonian medication. METHODS: Seven patients with motor fluctuations despite optimal medical treatment given as predominantly apomorphine infusion (n=6), or intermittent apomorphine injections (n=1) underwent bilateral STN DBS using frameless stereotactic surgery. Standard assessments of parkinsonism and motor fluctuations, using Unified Parkinson's Disease Rating Scale (UPDRS) were performed before and six months after surgery. Assessments were performed both on and off medication, and postoperative with the stimulators switched on and off. RESULTS: Bilateral STN DBS improved motor scores (UPDRS III) by 61% when off medication (p<0.05). Clinical fluctuations (UPDRS IV items 36-39) were reduced by 46.2% (p<0.05). Total daily apomorphine dose was reduced by 68.9% (p<0.05) and apomorphine infusion via a pump was no longer required in four patients. There were no operative complications. Two patients required treatment for hallucinations postoperatively but there was no significant change in mini-mental state examination. CONCLUSIONS: In patients with advanced Parkinson's disease, previously reliant on apomorphine, bilateral STN DBS is an effective treatment to reduce motor fluctuations and enable a reduction in apomorphine use.     

Apomorphine: a rapid rescue agent for the management of motor fluctuations in advanced Parkinson disease

Parkinson disease is one of the most common neurodegenerative diseases in the United States, and the number of late stage patients is rising. In advance-stage disease, fluctuations in motor function, variability in response to dopaminergic therapy, and dyskinesias related to increasing doses of dopamine agonists and levodopa, present a variety of challenges to a managing physician. Traditional methods of treatment have concentrated on therapies to anticipate or prevent states of poor motor function. With the approval of apomorphine as a rapid-acting, subcutaneous injectable anti-Parkinson disease therapy, these off periods may now be treated with apomorphine as a "rescue" medication when they occur. This article reviews the pharmacology of apomorphine, the clinical data that support its use and suggest dosing and methods for initiating therapy in this challenging population of patients with Parkinson disease.     

Fluctuations and dyskinesias as early L-dopa-induced motor complications in severe Parkinsonian's patients

Daily fluctuations of motor performance and dyskinesias in patients with Parkinson's disease (PD) treated with levodopa represent a difficult challenge to our understanding. We report 10 patients diagnosed of severe PD (Hoehn and Yahr: III-IV/V) treated with levodopa (range of dose: 750-900 mg/day) in single drug therapy since their diagnosis (mean time of levodopatherapy: 4.8 2.4 months, range: 3-6 months). All patients developed motor complications within weeks to months after initiating L-dopatherapy. Two patients received an intravenous apomorphine infusion (mean dose: 8.5 mg/day) during a mean time of 7.5 hours, but motor complications persisted during the infusion in spite of continuous dopaminergic stimulus. The degree of nigrostriatal damage (disease severity) seems to be a very important risk factor for the development of treatment-related motor complications.     

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.     

A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events

OBJECTIVE: To assess the safety and efficacy of subcutaneous apomorphine hydrochloride administration for off-state (poor motor function) periods in patients with Parkinson disease with motor fluctuations under both inpatient titration and outpatient therapeutic conditions. PATIENTS AND METHODS: Twenty-nine patients had advanced Parkinson disease with 2 hours or more off time despite aggressive oral therapy. Patients randomly received titrated doses of subcutaneous apomorphine hydrochloride (2-10 mg, n = 20) or pH-matched vehicle placebo (n = 9) during an inpatient and 1-month outpatient phase. A change in the United Parkinson Disease Rating Scale motor score 20 minutes after inpatient dosing during a practically defined off-state event and the percentage of injections successfully aborting off-state events were the primary inpatient and outpatient efficacy factors. RESULTS: The average (SEM) levodopa equivalent dose of apomorphine hydrochloride was 5.4 +/- 0.5 mg and the mean placebo dose was 1.0 mL. Mean inpatient United Parkinson Disease Rating Scale motor scores were reduced by 23.9 and 0.1 points (62% and 1%) by apomorphine treatment and placebo, respectively (P<.001). The mean percentage of outpatient injections resulting in successful abortion of off-state events was 95% for apomorphine and 23% for placebo (P<.001). Inpatient response was significantly correlated with and predictive of outpatient efficacy (P<.001). The levodopa dose was not predictive of the apomorphine dose requirement. Frequent adverse events included dyskinesia, yawning, and injection site reactions. CONCLUSION: Apomorphine by intermittent subcutaneous injection is effective and safe for outpatient use to reverse off-state events that occur despite optimized oral therapy.     

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.     

Safety of entacapone and apomorphine coadministration in levodopa-treated Parkinson's disease patients: pharmacokinetic and pharmacodynamic results of a multicenter, double-blind, placebo-controlled, cross-over study.

We investigated whether administration of the catechol-O-methyl transferase (COMT) inhibitor entacapone, at doses of 200 mg and 400 mg, alters the pharmacokinetics of apomorphine in Parkinson's disease patients experiencing severe motor fluctuations. In addition, the pharmacodynamics and safety of entacapone and apomorphine coadministration in these patients were examined. The study followed a three-sequence, three-period, crossover design. Patients were randomly assigned to one of three sequences that included single oral doses of entacapone 200 mg, entacapone 400 mg, and placebo in a predefined order. On 3 separate test days, study treatment was administered before apomorphine. The study evaluations (pharmacokinetics, tapping test, and dyskinesia evaluation [Abnormal Involuntary Movements Scale - AIMS]) were performed on these days. Furthermore, Unified Parkinson Disease Rating Scale (UPDRS) scores were evaluated at baseline and study end. Pharmacokinetic parameters for apomorphine (C(max), AUC, t(max), t(1/2)) were unchanged by the administration of entacapone, and changes in both the tapping test and AIMS score were similar with all treatments (entacapone 200 mg, entacapone 400 mg, and placebo). There was no significant difference in mean total UPDRS scores between baseline and study end. The administration of entacapone did not change the pharmacokinetic or pharmacodynamic effects of apomorphine in these patients or prolong the clinical effect of apomorphine. Thus, apomorphine may be safely administered to patients receiving therapy with levodopa and entacapone, providing a useful addition to treatment for patients with advanced Parkinson's disease.     

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.     

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.     

Pulsatile or continuous dopaminomimetic strategies in Parkinson's disease

Levodopa is the most effective treatment for Parkinson's disease (PD) for both motor and non-motor control. Pulsatile levodopa administration likely contributes to the development of motor fluctuations and dyskinesia after a few years. All studies comparing levodopa versus dopamine agonist early therapy indicate that initiation with agonists is associated with a reduced risk of motor complications - in particular, dyskinesias - possibly because agonists' longer half-lives provide continuous dopaminergic delivery. Indeed, this therapeutic strategy may delay the emergence of motor fluctuations and dyskinesia which is essential to maintaining satisfactory quality of life. In advanced disease various levodopa-based strategies may be tried to control motor complications, such as dose fragmentation (smaller, more frequent dosing) or the use of orally administered, liquid levodopa formulations that may reduce off-time intervals or facilitate absorption. More recently introduced, continuous levodopa delivery by duodenal infusion (but also apomorphine infusion) may represent a more effective approach to treat motor complications in advanced PD, and its effect can be perceived by improvement both in clinical scales as well as in health-related items. Infusion therapies may reverse motor complications in complicated patients with significant benefit on quality of life.     

Levodopa: A new look at an old friend

Levodopa is the most effective antiparkinsonian agent, but chronic treatment is associated with the development of motor complications in the majority of patients with PD. Recent scientific and clinical advances are improving this situation. Long‐term, double‐blind studies demonstrate that dose is an important risk factor for the development of both motor fluctuations and dyskinesia, and suggest that it is best to use low doses of l ‐dopa when possible. Inhaled l ‐dopa and sublingual apomorphine are now being developed as rescue therapies that permit rapid and predictable reversal of off periods. Finally, substantial evidence suggests that motor complications are related to the nonphysiological restoration of brain dopamine with intermittent oral doses of standard l ‐dopa. Double‐blind studies demonstrate significant clinical benefits with continuous intraintestinal infusion of l ‐dopa. New approaches that provide continuous plasma l ‐dopa levels without the need for a surgical procedure are currently being investigated. Finally, the development of an oral long‐acting form of l ‐dopa that provides continuous plasma l ‐dopa levels is actively being pursued. Collectively, these approaches offer the potential to considerably reduce and even prevent the disability associated with l ‐dopa‐induced motor complications. © 2017 International Parkinson and Movement Disorder Society     

Enfermedad de Parkinson avanzada. Características clínicas y tratamiento. Parte II

Introduction

Many patients who have had Parkinson's disease (PD) for several years will present severe motor fluctuations and dyskinesias which require more aggressive therapies. The different approaches which are now available include deep brain stimulation of the subthalamic nucleus or medial globus pallidus, subcutaneous infusion of apomorphine, and intestinal infusion of levodopa-carbidopa.

Objective

To define the indications and results for the 3 available therapies for advanced PD.

Development

Exhaustive review of the literature concerning the indications and results of deep brain stimulation, subcutaneous apomorphine infusion and duodenal infusion of levodopa/carbidopa gel to treat patients with advanced Parkinson disease.

Conclusions

Although numerous studies have confirmed the efficacy of the 3 different therapies in advanced PD, there are no comparative studies that would allow us to define the best candidate for each technique.