Dag Nyholm

Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease

Objectives: To compare daytime intraduodenal levodopa/carbidopa infusion as monotherapy with individually optimized conventional combination therapies in patients with advanced Parkinson disease (PD) for motor fluctuations and quality of life (QoL). Methods: Twenty-four patients with motor fluctuations and dyskinesia were studied in a randomized crossover design to compare individualized conventional treatment and intraduodenal infusion of a levodopa/carbidopa gel for 3 + 3 weeks. Video scoring of motor function was assessed by blinded assessors on a global Treatment Response Scale from −3 to 0 to +3 (from severe “off” to “on” to “on” with severe dyskinesia). Patient self-assessment of motor performance and QoL was done using an electronic diary. Results: Median percentage of ratings in a functional “on” interval (−1 to +1) was increased from 81 to 100% by infusion therapy (p < 0.01). This improvement was accompanied by a decrease in “off” state (p < 0.01) and no increase in dyskinesia. Median Unified Parkinsons Disease Rating Scale score decreased from 53 to 35 in favor of infusion (p < 0.05). QoL was improved, using the two instruments: Parkinsons Disease Questionnaire-39 and 15D Quality of Life Instrument (p < 0.01). Adverse events were similar for both treatment strategies. Conclusions: Continuous intraduodenal infusion of the levodopa/carbidopa enteral gel as monotherapy is safe and clinically superior to a number of individually optimized combinations of conventional oral and subcutaneous medications in patients with motor fluctuations. Intraduodenal infusion of levodopa offers an important alternative in treating patients with advanced Parkinson disease.

Optimizing levodopa pharmacokinetics: intestinal infusion versus oral sustained-release tablets.

Continuous duodenal infusion of carbidopa/levodopa has been shown to control motor fluctuations in advanced Parkinsons disease (PD). The authors compared the pharmacokinetics of levodopa and 3-O-methyldopa in patients with advanced PD after administration of an oral sustained-release levodopa preparation and after continuous intestinal levodopa infusion with a new formulation as a gel suspension. A randomized crossover trial was carried out in 12 patients. Carbidopa/levodopa was administered as an oral sustained-release tablet and by nasoduodenal continuous infusion for 3-week periods for each treatment. Plasma levodopa concentrations and motor performance were evaluated every 30 minutes during 3 test days of each treatment period. The average intraindividual coefficient of variation for the plasma levodopa concentrations after oral therapy was 34% and was significantly lower (14%, p < 0.01) during continuous infusion. Hourly video evaluations showed a significant increase in ON time during infusion and a significant decrease in OFF time and dyskinesia. Continuous intraduodenal delivery of a new carbidopa/levodopa formulation offers a means for markedly improved control of motor fluctuations in late stages of PD.

Duodenal levodopa infusion in Parkinson's disease--long-term experience.

Motor fluctuations in parkinsonian patients can be reduced by intraduodenal infusion of levodopa. Between 1991 and 1998 continuous daytime administration of levodopa through a transabdominal port has been used in 28 very advanced patients over a total period of 1045 months. A stable suspension of levodopa and carbidopa (Duodopa®) has been developed. Patients were characterized by early onset, long history of disease and levodopa therapy. The reason for infusion was in all cases related to on–off fluctuations. All patients experienced a general improvement after the introduction of continuous treatment. There have been no severe complications. Six patients have taken the decision to curtail their treatment. The mean daily levodopa consumption has been slightly reduced on infusion as compared to oral therapy. Nine of the first group of patients participating in the new therapy have been regularly evaluated by means of rating scales and movement analyses. Short‐term results have already been published and a follow‐up showing continued positive effect after 4–7 years of continuous duodenal infusion is presented.

Pharmacokinetic optimisation in the treatment of parkinson's disease : An update

Pharmacotherapy for Parkinson’s disease is focused on dopaminergic drugs, mainly the dopamine precursor levodopa and dopamine receptor agonists. The elimination half-life (t½) of levodopa from plasma (in combination with a decarboxylase inhibitor) of about 1.5 hours becomes more influential as the disease progresses. The long-duration of response to levodopa, which is evident in early Parkinson’s disease, diminishes and after a few years of treatment motor performance is closely correlated to the fluctuating plasma concentrations of levodopa. Absorption of levodopa in the proximal small intestine depends on gastric emptying, which is erratic and may be slowed in Parkinson’s disease. The effects of levodopa on motor function are dependent on gastric emptying in patients in the advanced stages of disease.The current treatment concept is continuous dopaminergic stimulation (CDS). Sustained-release formulations of levodopa may provide more stable plasma concentrations. Oral liquid formulations shorten the time to reach peak concentration and onset of effect but do not affect plasma levodopa variability. The t½ of levodopa can be prolonged by adding a catechol-O-methyltransferase inhibitor (entacapone or tolcapone), which may reduce fluctuations in plasma concentrations, although both peak and trough concentrations are increased with frequent administration. Intravenous and enterai (duodenal/jejunal) infusions of levodopa yield stable plasma levodopa concentrations and motor performance. Enteral infusion is feasible on a long-term basis in patients with severe fluctuations.Among the dopamine receptor agonists the ergot derivatives bromocriptine, cabergoline, dihydroergocryptine and pergolide, and the non-ergot derivatives piribedil, pramipexole and ropinirole, have longer t½ compared with levodopa. Thus, they stimulate dopamine receptors in a less pulsatile manner, yet pharmacokinetic studies of repeated doses of dopamine receptor agonists are few. Optimisation of these drugs is often performed with standardised titration schedules. Apomorphine and lisuride have short t½ and are suitable for subcutaneous infusion, with results similar to those of levodopa infusion. Transdermal administration of dopamine receptor agonists such as rotigotine might be an alternative in the future. In general, initial dopamine receptor agonist monotherapy is associated with poorer motor performance and lower incidence of motor complications compared with levodopa.Buccal administration of the monoamine oxidase-B inhibitor Selegiline (deprenyl) provides better absorption and less formation of metabolites compared with standard tablets.To conclude, several new drugs, formulations and routes of administration have been introduced in the treatment of Parkinson’s disease during the last decade, mainly with CDS as the aim. CDS can be approached by optimising the use of dopaminergic drugs based on pharmacokinetic data.

Enteral Levodopa/Carbidopa infusion in advanced Parkinson disease : Long-term exposure

Objectives: In patients with advanced Parkinson disease, levodopa/carbidopa formulated as a gel suspension (Duodopa) permits continuous delivery into the small intestine using a portable pump, resulting in less variability in levodopa concentrations and fewer motor fluctuations and dyskinesias than with oral levodopa administration. This is a retrospective analysis of the long-term clinical experience with this agent. Methods: All but 1 of the patients who had received enteral levodopa infusion treatment between January 1, 1991, and June 30, 2002, consented to a review of their hospital charts. Results Of the 65 patients with initial testing of the treatment, 86% opted for continued treatment via percutaneous endoscopic gastrostomy or gastrojejunostomy. Total exposure to levodopa infusion was 216 patient-years (mean, 3.7 years). Maximum treatment duration was 10.7 years. Fifty-two patients were treated for 1 year or longer. The adverse effect profile of levodopa/carbidopa infusion was similar to that observed with oral administration of levodopa. Seven deaths occurred, all considered unrelated to the treatment. Intestinal tube problems, including dislocation of the intestinal tube to the stomach, were the most common technical problem, occurring in 69% of the patients during the first year. The optimal daily dose of levodopa decreased by an average of 5% during follow-up. Conclusions: The safety of enteral infusion of levodopa/carbidopa formulated as a gel suspension was found acceptable. For most patients, the technical challenges posed by the enteral infusion system were offset by the improvement in motor fluctuations and dyskinesias offered by this technique.

Enteral levodopa/carbidopa gel infusion for the treatment of motor fluctuations and dyskinesias in advanced Parkinson’s disease

Pharmacotherapy designed to alleviate the symptoms of Parkinson’s disease is focused on the stimulation of striatal dopamine receptors. The ideal pharmacological treatment would involve continuous dopaminergic stimulation. Currently, the most effective pharmacotherapy available is levodopa delivered orally; however, its short plasma half-life in combination with erratic gastric emptying and intestinal absorption makes dopaminergic stimulation pulsatile. Motor fluctuations and dyskinesias develop with time as a consequence and can become disabling. A gel formulation of levodopa/carbidopa has been developed for enteral (duodenal or jejunal) infusion via a portable pump. The infusion provides smooth plasma levodopa levels, more continuous dopaminergic stimulation and effective treatment of motor complications.

Selecting deep brain stimulation or infusion therapies in advanced Parkinson's disease: an evidence-based review

Motor complications in Parkinson’s disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine.

Levodopa Pharmacokinetics and motor performance during activities of daily living in patients with Parkinson's disease on individual drug combinations

Pharmacokinetics and pharmacodynamics of levodopa were evaluated at a high-resolution level in a heterogeneous group of 10 patients with idiopathic Parkinsons disease during their normal daily activity. A physician and a nurse spent 10 hours with each patient from the first morning dose of levodopa during daily activities at home and at work. Plasma samples were obtained every 20 minutes for analysis of levodopa and 3-O-methyldopa by high-performance liquid chromatography. To assess clinical response, mobility was rated on every test occasion by patients and by investigators. Food and fluid intake and physical activity were also monitored. There was a large intra- and interindividual variability in the pharmacokinetics of levodopa regardless of the different drug combinations used. Mean plasma levodopa concentration ranged between 0.45 to 7.07 &mgr;g/mL and peak concentrations between 0.95 to 13.75 &mgr;g/mL. In 44 of 58 dosing events, an oral dose of levodopa was related to a peak in plasma concentration. Assessment of the clinical effects was more sensitive when given by patients than when given by the investigators. The fluctuations of the levodopa concentration in plasma had a clear effect on the clinical parameters assessed, even during early disease stages. Variation in levodopa concentration is the determining factor for motor fluctuations also in patients on clinically optimized combinations with dopamine agonists and enzyme inhibitors.

Irregular gastrointestinal drug absorption in Parkinson's disease.

Background: Symptomatic treatment of Parkinsons disease (PD) is based on the dopamine precursor levodopa. Levodopa is only absorbed in the small intestine, where transit time is ∼ 3 h and the plasma elimination half-life is short. Therefore, gastric emptying is a major determining factor for onset of symptom relief. Objective: Gastric emptying is delayed in PD, thereby causing motor fluctuations such as ‘delayed on’. Factors that further slow gastric emptying should be recognised and eliminated if possible. Methods: A literature search was performed with the aim to cover the area of irregular gastrointestinal drug absorption in PD. Results/conclusion: Methods for facilitation of pyloric passage or increase of bioavailability are discussed. Development of new drug formulations and alternative routes of administration is ongoing. Transdermal patches and pumps for subcutaneous or intraduodenal infusions are available for patients with severe fluctuations due to erratic gastric emptying.

Wireless real-time electronic data capture for self-assessment of motor function and quality of life in Parkinson's disease

Frequent assessment of the symptoms in Parkinsons disease (PD) is important in both clinical and experimental settings, especially when motor fluctuations are present. Patient diaries are increasingly used in studies, allowing patients to stay in their home environments. However, traditional paper diaries may not reflect reality because of a lack in compliance or retrospective data entries. This study presents a comparison between paper diaries and a new method, real‐time data capture with a hand‐held computer (electronic diary). Twenty patients with PD diagnosed at least 5 years previously were randomly assigned to use either a paper diary or an electronic diary on 8 days during 1 month. Questions were answered every 2 hours over a 12‐hour period on each day. Median compliance was 88% with the electronic diary and 98% with the paper diary, although strict compliance to the scheduled times by patients using the paper diary was 78%. Neither age nor earlier experience with computers affected the patients ability to use the electronic diary. Electronic diaries can be used for self‐assessment of PD symptoms. The real‐time feature provides fast access to clean data with knowledge of true compliance.