4.3 Previous Experience with Constant Infusion of Levodopa

The dosage of oral levodopa is difficult to establish when the therapeutic window is narrow and patients experience “on-off” fluctuations in motor performance. The strategy to optimize the dose is to decrease the doses and increase the number of dosage occasions. This improves the pharmacokinetic profile and the dopamine production is thereby smoother with several moderately high peaks during the day. This mimics the physiological tonic dopaminergic stimulation better than when levodopa is given only 3 to 4 times a day. Most patients in the severely fluctuating stage of Parkinson’s disease take levodopa tablets once per hour or once per 2 hours.

However, levodopa uptake into the circulation is from the upper part of the small intestine, not from the stomach. Gastric emptying is, therefore, a determining factor for the access to orally administered levodopa. Erratic gastric emptying gives a fluctuating levodopa concentration-time curve (Kurlan et al., 1988b). The longer levodopa remains in the stomach or small intestine, the more extensively it is metabolised and made unavailable for absorption (Rivera-Calimlim et al., 1971). Furthermore, levodopa absorption from the intestine and transport over the blood-brain barrier occurs via the large neutral amino acid (LNAA) transport system (Lennernas et al., 1993, Mearrick et al., 1974, Wade, Mearrick & Morris, 1973). These food amino acids compete with levodopa and inhibit levodopa absorption (Lennernas et al., 1993).

As previously described, the principle behind constant levodopa infusion is to achieve continuous dopaminergic stimulation with an optimised dose that can be kept stable in the therapeutic window. To make this possible, the gastric emptying must be bypassed. The first human experiments with intravenous infusion in 1975 showed favourable effects in 5 severely “on-off” fluctuating patients, as compared to oral administration of levodopa (Shoulson et al., 1975): “A constant intravenous infusion of levodopa resulted in stable plasma dopa concentrations and virtual disappearance of motor fluctuations”. Since then, a series of clinical studies have been reported in the literature showing that intravenous infusion of levodopa or levodopa/carbidopa ameliorates the fluctuations (see Table 1). However, continuous intravenous infusions are impractical for long-term use, and, therefore, attempts were made to deliver the drugs by intraduodenal infusion, thus bypassing the problems with gastric emptying.

In 1986, the first intraduodenal infusions were presented (Kurlan, et al, 1986). The motor response was dramatically improved and comparable to the effects of intravenous infusions: “In 3 patients with resistant on-off fluctuations, direct duodenal continuous infusion of levodopa via a nasoduodenal tube resulted in a heightened therapeutic effect, including a reduction in motor fluctuations.” The authors concluded that “This mode of delivery ameliorates motor fluctuations and is suitable for chronic therapy, particularly with the advent of improved ambulatory infusion-pump technology.” The group later presented results from 10 patients who got nasoduodenal, nasogastric, and oral levodopa (Kurlan et al., 1988a). The same reduction in motor fluctuations as in the previous study was found with duodenal infusion, but also gastric infusion “produced improved mobility compared to standard oral therapy.”

Since then, a large number of successful clinical studies with intraduodenal infusion of levodopa or levodopa/carbidopa from different academic research groups have been published (see Table 1) with successful outcomes. The first reports (Sage et al., 1988a and 1989a) were on patients with severe on-off phenomena who used infusion of levodopa for at least 4 months, indicating that “continuous long-term levodopa infusions are a practical but complex form of therapy for patients failing more conventional treatment.” Long-term experience from 22 patients chosen for infusion therapy because of severe motor fluctuations and unresponsive to conventional medical treatment has been published by Syed et al. (1998). They had intractable and frequent off periods, intolerable dyskinesias, or both. “Nearly all patients continued to have dramatically increased “on” time for the duration of follow-up” with daytime continuous levodopa infusion. A double-blind, placebo-controlled, crossover study of continuous duodenal administration for 2 separate days versus intermittent oral levodopa/carbidopa administration for 2 separate days showed that “all 10 patients had significantly decreased variability in levodopa levels permitting better titration of levodopa dosage to individual requirements” (Kurth et al., 1993). Regarding motor function, it was stated that: “Seven patients experienced increased functional “on” hours and decreased number of “off” episodes.” Because of the perceived benefit noted during the open-label phase of the trial, all patients elected to continue nasoduodenal infusion therapy after completion of the study. The authors concluded that: “duodenal infusion may be a useful and beneficial treatment modality for younger, motivated patients who continue to experience severe motor fluctuations on optimal tablet therapy.”

Continuous subcutaneous infusions of dopamine agonists such as apomorphine (Colzi et al., 1998) and lisuride have shown similar stable effects, but the pattern of side effects is different and long-term subcutaneous infusion often produces skin reactions. Such infusions are intended as add-on therapy to oral levodopa, which means that motor fluctuations caused by fluctuating pharmacokinetics of levodopa still remain. Levodopa is still considered to be the most effective drug for treatment of Parkinson’s disease (Olanow et al., 2001).

It has thus been known for a long time that advanced Parkinson’s disease can benefit from continuous levodopa infusion. However, the experimental infusion systems were impractical. Intravenous long-term therapy is not desirable and the low solubility of levodopa demanded large volumes of infusion fluid (1000/2000 ml depending upon the dose), making pumps and solutions laborious to handle. In one of the studies of intravenous levodopa infusion described above (Stocchi et al., 1986), it is stated that “its low solubility, requiring large quantities of solvent and large infusion pumps, rules out an application in standard chronic therapy.” It is suggested in several studies that continuous infusion not only improves motor fluctuations but also widens the therapeutic window (Stocchi et al., 1996).

In summary, several independent research groups have repeatedly demonstrated the advantages of continuous dopamine-receptor stimulation achieved by intravenous or intraduodenal infusion of levodopa in advanced cases of Parkinson’s disease with motor fluctuations not responding adequately to available options for oral treatment. However, practical problems with handling large volumes of dilute levodopa solutions needed for a daily dose of the drug have limited its usefulness. The development of Duodopa, an innovative formulation permitting 10 times higher levodopa concentrations than ordinary solutions, has made treatment with daily intraduodenal infusion feasible. The problems with oral levodopa and earlier levodopa infusions systems that have been solved by Duodopa can be summarized as follows:

In studies preceding the development of Duodopa by a Swedish academic group, both intravenous and intraduodenal infusions were used (Bredberg et al., 1990) for pharmacokinetic calculations. It was observed that: “The patients remained clinically stable during the period of the intraduodenal infusion.” The first study according to the Duodopa concept was published (Bredberg et al., 1993) and short-term as well as long-term follow-up studies have since been reported (Nilsson et al., 1998; Nilsson et al., 2001) showing that the clinical outcome with Duodopa is in agreement with previous studies.

A listing of published studies regarding intravenous and intraduodenal infusion of levodopa is provided in Table 1 below.

Table 1
Published Studies on Intravenous (iv) and Intraduodenal (id) Infusion of Levodopa in Chronological Order (the number of patients treated may be smaller than the sum total, since some patients may have contributed data to several publications by the same group of investigators)

Outcome
In 3 patients, replacement of oral treatment by continuous intravenous infusion of levodopa with oral administration of decarboxylase inhibitor produced a prolonged and stable clinical response, even when ambulant. This response was maintained not only in 1 subject showing predictable fluctuations but also in 2 subjects with unpredictable response to oral treatment. The addition of intravenous levodopa infusion to the ongoing oral regimen of the first patient when she was experiencing prolonged “off” periods despite generous doses of oral levodopa with decarboxylase inhibitor also produced stable clinical benefit

Outcome
Bypassing absorption by constant infusion of the drug produced a stable clinical state lasting for 12 h in all of 6 patients and for up to 36 h in some.

Outcome
All patients remained continuously mobile and ambulant during the infusions.

Outcome
Intravenous infusion at a constant rate brought about a dramatic extension of the duration of mobility and reduced the frequency of fluctuations compared with oral therapy.

Outcome
(A study on the effect of carbidopa on the pharmacokinetics of iv levodopa) A representative patient had an equivalent clinical response to both infusions, becoming mobile and mildly dyskinetic within 1–2 h of starting the infusion and continuing to have a sustained response throughout the day.

Outcome
All of our fluctuating patients had a clinical response related to elevated plasma levodopa levels, a response that disappeared within 15–90 minutes of discontinuing the infusions

Outcome
14 patients were constantly “on” during levodopa infusion as soon as the optimal rate was reached. Therapeutic effect and drug dosage kept stable during the 3-day trial.

Outcome
Smoother clinical response and maintained plasma levodopa concentrations within narrower limits compared with conventional oral therapy.

Outcome
Heightened therapeutic effect, including a reduction in motor fluctuations.

Outcome
Immediate and sustained stabilization of plasma levodopa levels in both the wearing-off and on-off groups. Motor variability also diminished within the first 24 h of infusion, although to a much greater extent in patients with the wearing-off phenomenon. Over the next 5–11 days of intravenous treatment, further reductions in motor fluctuations occurred in both groups, at a substantially faster rate in the wearing-off group than in the on-off group.

Outcome
Better mean mobility and an increase in the percentage of on ratings when compared to the standard oral route. Motor fluctuations, as measured by variance of mobility, were reduced. Fluctuations of plasma levodopa were reduced. It is possible to produce very steady plasma concentrations of levodopa with a corresponding reduction in motor fluctuations by continuous intraduodenal infusion of the drug.

Outcome
All patients had marked decreases in motor fluctuations on the infusions compared with tablets.

Outcome
L-Dopa controlled fluctuations in almost all the subjects, whereas only 7 patients were continuously mobile while taking lisuride. Dyskinesias were present in all patients during “on” phases, with both levodopa and lisuride treatment.

Outcome
Motor fluctuations virtually disappeared in both patients during the time of the day when the pump was in use.

Outcome
In all 4 patients, it was possible to produce a sustained “on” state with continuous intraduodenal infusion of levodopa (range 50–70 mg/h) in the fasting state.

Outcome
Dystonia was unrelieved by multiple medication regimens but responded well to continuous, duodenal levodopa infusions. Patients were able to remain mobile without severe dystonia despite a very narrow window of benefit between the levodopa concentration necessary to achieve the “on” state and that which caused the onset of dystonic spasms.

Outcome
In each of the 9 patients, the short-term response to continuous levodopa infusions consisted of immediate amelioration of clinical fluctuations. Eight (8) of the 9 patients remained “on,” with minimal to moderate dyskinesia and few “off” periods. One (1) patient had diminished fluctuations, although he still experienced a moderate number of “off” periods per day as he attempted to control dyskinesia by decreasing the infusion rate.

Outcome
Virtually all patients who have already developed motor complications will respond to steady-state infusions of levodopa of sufficient duration. Hence, of critical importance is the development of practical means for providing stable level dopaminergic replacement chronically for ambulatory parkinsonian patients.

Outcome
Increased the proportion of “on” time to 100%. The patient could progressively reduce levodopa intake while remaining continuously ‘on.’

Outcome
Every patient’s short-term response to continuous infusions consisted of immediate amelioration of clinical fluctuations. Three (3) patients have remained on continuous infusions for up to 20 months. All 3 patients have attempted to return to tablets several times during the past year but were unable to achieve as smooth a response and, therefore, went back to use of the continuous infusion system.

Outcome
The patients remained clinically stable during the period of the intraduodenal infusion.

Outcome
Sleep disturbances improved immediately. There was a gradual reduction in “off” time and severity of dyskinesias during the waking day.

Outcome
All 10 patients had significantly decreased variability in levodopa levels permitting better titration of levodopa dosage to individual requirements. Five (5) patients continued to use infusion 12–20 months after completion of this study.

Outcome
Duodenal infusion improved motor function in all 5 patients and the fluctuations were reduced when compared to the oral therapy. Variation in plasma levodopa concentrations was 3–10 fold during oral therapy, while during infusion, a stable concentration was obtained, at most 2-fold.

Outcome
Continuous intravenous levodopa shifted the dyskinesia dose-response curve to the right, reduced maximum dyskinesia activity, but did not significantly alter dose response for relief of parkinsonism. Improvement in dyskinesia was apparent by the second day of continuous levodopa; during which, ratios of plasma dopa/3-O-methyldopa remained constant.

Outcome
Ten (10) subjects had motor fluctuations during the infusions. Zero to 68% of the variability of tapping speed could be explained by variation in plasma LNAA concentrations in individual subjects. Fluctuations occurred more commonly later in the day, which may be related to the tendency for LNAAs to increase during the day.

Outcome
Nearly all patients continued to have dramatically increased “on” time for the duration of follow-up.

Outcome
(Duodopa) Improvement and decreased variance of motor function. In the 2 patients followed over a period of 2.5 years, levodopa plasma concentration showed reduced fluctuations on infusion and the levodopa consumption as well as mean levodopa plasma concentration decreased.

Outcome
(Duodopa) The total infusion time in the 28 cases was 1045 months (i.e., 87 years). All patients experienced a general improvement after the introduction of continuous levodopa administration. There have been no severe or serious complications. Only 6 of the patients have returned to oral therapy over the years. No or very little progress of the disease is seen in 5 out of the 7 closely monitored patients after 4–7 years of continuous treatment with Duodopa.

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