Madopar HBS in Parkinson patients with nocturnal akinesia

Madopar Hydrodynamically Balanced System (HBS), a new sustained-release levodopa preparation, was used to control severe nightly disabilities in 15 outpatients suffering from Parkinson's disease in an advanced state and with long-term levodopa therapy. This medication was given ante noctem in addition to an otherwise unchanged daily regimen of levodopa administration. In 13 patients a considerable diminution in nocturnal akinesia and in the frequency of waking up was reached with a mean dosage of 308 mg of Madopar HBS. Early morning akinesia was only slightly alleviated in four patients. The nocturnal off-period pain disappeared in one patient. Adverse effects consisted of nocturnal dyskinesia in two patients and early morning dystonia in another two patients. The regular use of sleeping pills was clearly reduced after Madopar HBS therapy.     

A controlled release form of Madopar in Parkinsonian patients with advanced disease and marked fluctuations in motor performance

Flucuations in motor performance is a major problem in long-term levodopa treatment of Parkinsonian patients. A slow release preparation of levodopa with benserazide, Madopar HBS, has been developed in an attempt to decrease this problem. Eleven of 22 Parkinsonian patients with advanced disease and marked fluctuations experienced long-lasting benefit with reduction of their fluctuations in motor performance on treatment with Madopar HBS; 11 dropped out within the first 5 months of the trial. This was probably due to lack of experience with the effect of this new slow-release formulation. Nine patients (82%) required an additional dose of standard Madopar, especially in the morning. Significant improvements were found for akinetic phenomenon and dystonic cramps, and with the global evaluation of motor fluctuations. The occurrence of peak dose dyskinesia remained unchanged. No abnormalities in laboratory values were found.     

Effectiveness of Madopar HBS plus Madopar standard in patients with fluctuating Parkinson's disease: two years of follow-up

Clinical response to a new galenic formulation of levodopa plus benserazide, Madopar HBS, was studied in 25 fluctuating parkinsonians. This open study was planned in two phases. In the first phase, the administering of HBS alone resulted in a surprisingly high number of dropouts. In the second phase, Madopar standard in association with Madopar HBS, the follow-up period was 24 months. A stable long-lasting improvement in predictable fluctuations and their severity was maintained for the whole period without any change in drug dose. Nocturnal and early morning akinesia improved too. The study shows that Madopar HBS plus Madopar standard is effective in producing a prolonged and stable response in parkinsonian fluctuating patients.     

A double-blind, cross-over trial with madopar HBS in patients with Parkinson's disease

Fourteen patients with Parkinson's disease and motor fluctuations were given 125 mg of Madopar HBS or placebo twice a day in addition to their optimal standard Madopar treatment in a double-blind, cross-over study. Clinical response was evaluated by the King's College Hospital Parkinson's Disease Rating Scale, the Mobility in Bed Scale and self-scoring diaries. A significant improvement with the drug was found according to the rating scales, whereas evaluation by self-scoring diaries showed no significant changes. In three patients we observed worsening of abnormal involuntary movements. The present trial suggests that a low dose of Madopar HBS can be useful in addition to levodopa therapy in some patients on long-term treatment.     

Open study of sustained-release formulation of levodopa and benserazide in parkinsonian patients

The efficacy of a novel oral sustained-release preparation of levodopa/benserazide (Madopar HBS) was compared to that of previous conventional levodopa/benserazide treatment in 15 patients with idiopathic Parkinson's disease and with severe fluctuations in motor response to long-term levodopa therapy. In ten patients who suffered from clear-cut "end-of-dose" deterioration, significant benefit was obtained on HBS form, while 5 patients did not respond well to the new levodopa preparation. Plasma levels of levodopa were more stable with HBS compared to conventional levodopa preparation in our patients, although doses of HBS form required for an optimal response averaged 1.48 times that of previous conventional levodopa.     

Comparative single- and multiple-dose pharmacokinetics of levodopa and 3-O-methyldopa following a new dual-release and a conventional slow-release formulation of levodopa and benserazide in healthy volunteers

The objective was to assess the single- and multiple-dose pharmacokinetics of levodopa and 3-O-methyldopa following administration of a new dual-release and conventional slow-release formulation of levodopa/benserazide in the dose ratio of 4:1. In an open-label, two-way cross-over study, 20 healthy volunteers were randomized to receive first either Madopar DR or Madopar HBS for 8 days. Then they crossed over to the other formulation. A first dose of 200 mg levodopa and 50 mg benserazide ('250' mg) was given on day 1, '125' mg t.i.d. on the subsequent 6 days (days 2-7), followed by '250' mg on day 8. The two treatment periods of 8 days were separated by a wash-out period of at least 7 days. Blood samples were taken at specific times over a 12-hour period (day 1) or a 36-hour period (day 8). Plasma concentrations of levodopa and 3-O-methyldopa were measured by high-performance liquid chromatography for pharmacokinetic evaluation. The pharmacokinetics of levodopa after a single-dose administration (day 1) of Madopar DR and Madopar HBS were significantly different as reflected by the respective mean values of maximum plasma concentration (C(max) 1.99 vs. 0.82 mg x l-1), time to reach maximum concentration (t(max) 0.7 vs. 2.6 h) and area under the plasma concentration-time curve (AUC(0- infinity ) 4.52 vs. 3.18 mg x h x l-1). The respective values after multiple doses (day 8) were: C(max) 1.98 vs. 0.93 mg x l-1, t(max) 0.7 vs. 2.3 h and AUC(0-infinity ) 4.84 vs. 3.96 mg x h x l-1. The relative bioavailability (Madopar DR vs. Madopar HBS) was 1.73 on day 1 and 1.32 on day 8. Bioequivalence could not be demonstrated for log-transformed data of AUC and C(max) within a predefined range of 80-125 and 70-143%, respectively. In conclusion, the observed differences in C(max), t(max) and AUC are consistent with a faster rate and higher extent of levodopa absorption after administration of Madopar DR. Statistical evaluation of these kinetic data showed that Madopar DR is not bioequivalent to Madopar HBS.     

An acute and long-term study with a dispersible formulation of levodopa/benserazide (Madopar®) in Parkinson's disease

The clinical efficacy, tolerability and administration regimens of a dispersible formulation of levodopa/benserazide (DM) were investigated in 30 patients with idiopathic Parkinson's disease, complicated by motor fluctuations. All 30 patients showed delayed- “on” phenomenon after administration of the first morning dose of standard levodopa (SM), and 20 showed delayed- “on” phenomenon after the first afternoon dose. Patients were receiving standard formulations of levodopa as monotherapy or in combination. A double-dose study of the dispersible vs the standard formulation was performed in 30 patients, 24 of whom participated in a 36-month, follow-up clinical study. In the long-term study, SM was replaced with DM by substituting the first morning dose or the first morning and first afternoon doses. In the double-dose study, mean latency to “on” after the first morning dose was significantly shorter with DM than with SM (p < 0.001), whereas the duration of “on” was similar with the two preparations. The post-prandial delayed- “on” in the 14 patients who responded to therapy was significantly shorter for DM than for SM (p < 0.001). In the long-term study, the mean latency to “on” in all patients was significantly shorter than at baseline (p < 0.001). Time spent in “on” during the active day increased significantly, and remained stable during the 36-month study. No changes were apparent in the mean dosage of levodopa/day or the number of doses/day, and no acute or long-term adverse events were reported. In conclusion, these results confirm the long-term safety of the dispersible formulation, and its improved efficacy compared with standard levodopa formulations, as monotherapy and in association with slow-release formulations.     

Controlled-release levodopa/benserazide (Madopar HBS): clinical observations and levodopa and dopamine plasma concentrations in fluctuating parkinsonian patients

Summary In five levodopa (l-dopa)-treated patients with Parkinson's disease with severe fluctuations of motor performance, plasma l-dopa as well as dopamine levels were measured during 2 days, first under optimal standard l-dopa with peripheral decarboxylase inhibitor (PDI) and then after a dose adjustment period using slow-release l-dopa/benserazide (Madopar HBS) in an open inpatient trial. Three patients benefited from the slow-release preparation; two patients deteriorated with a tendency to have an unpredictable response, a delay to turn on with the first dose in the morning, as well as an increase in dyskinesia corresponding to l-dopa cumulation during the day. These problems were subsequently also seen during the follow-up period of 1 year in those patients who benefited from Madopar HBS as inpatients. This might indicate that patient compliance is more difficult with the new formulation. After 1 year all patients had returned to their previous standard l-dopa/PDI treatment. l-Dopa levels continued to fluctuate, but to a lesser degree with Madopar HBS. The equivalent l-dopa dosage had to be increased by 56% (29–100%) with Madopar HBS while mean dopamine levels increased in four patients (by 47–257%) without the occurrence of peripheral side-effects. This implies that with the new formulation more l-dopa is metabolized to dopamine and explains the necessity to increase the equivalent l-dopa dosage.     

A comparison of the effects of controlled-release levodopa (Madopar CR) with conventional levodopa in late Parkinson''s disease.

In this multicentre study a controlled-release formulation of levodopa and the decarboxylase inhibitor benserazide (Madopar CR) was evaluated in patients with Parkinson's disease exhibiting dose-related fluctuations in motor performance in response to conventional levodopa preparations. The effect of Madopar CR, with or without conventional levodopa/benserazide, on the proportion of time spent "on", "off" or "intermediate" was compared with that of previous conventional levodopa/decarboxylase inhibitor therapy. Evaluation of the two periods of optimum therapy was based on both patient diary data and investigator opinion. Forty seven patients completed the study but full patient diaries were available for only 37. The mean optimum total daily dosage of conventional Madopar was 820 mg taken in a mean of 6.4 doses, compared with a mean optimum daily dosage of combined Madopar CR and conventional Madopar of 1088 mg, taken in a mean of 5.2 doses. Conventional Madopar was taken in addition to Madopar CR in all but eight patients. Madopar CR was felt to be advantageous in 83% and disadvantageous in 11% of patients completing the study. Considering the 37 patients for whom diary data were available, Madopar CR therapy resulted in an increase in the mean time spent "on" (p = 0.016) and a decrease in the mean time spent "off" (p = 0.029) compared with conventional Madopar alone. Individually 25 out of 37 had an increase in "on" time and 19 out of 37 experienced a decrease in "off" time. Thus Madopar CR was found to be beneficial in a significant proportion of patients experiencing fluctuations in response to conventional levodopa.     

Madopar HBS in fluctuating parkinsonian patients: two-year treatment

In an open-label study, we substituted conventional levodopa plus benserazide: 100/25 (Madopar) with a controlled-release form (HBS) in 18 fluctuating parkinsonian patients for 24 months. Significantly positive results were obtained in both peak-dose and diphasic dyskinesias up to 12 months of treatment; morning akinesias were also improved up to 6 months. A general trend of deterioration, compared to the first 3-6 months of HBS treatment, was observed in "off" fluctuations after 1 year: akinesias due to a delayed response worsened after 1 year of treatment also when compared with the conventional treatment. Positive results were obtained with new HBS on standard Madopar-related psychiatric disorders.     

A randomised controlled study of bromocriptine versus levodopa in previously untreated Parkinsonian patients: a 3 year follow-up.

The long term effects of a de novo treatment with levodopa versus bromocriptine were compared in respectively 13 and 15 previously untreated patients with Parkinson's disease in a prospective randomised trial. Thirteen patients were treated with levodopa alone (mean dose 444, SEM 63 mg daily) whereas 15 others received bromocriptine alone (mean dose 50, SEM 6 mg daily) during 37, SEM 4 and 32, SEM 4 months respectively. For a similar decrease in the Columbia rating scale, the nature of long term side effects was different in the two groups: three patients on levodopa developed peak-dose dyskinesias and one other dystonia. With bromocriptine, one patient developed a severe psychosis whereas 3 others suffered from primary lack of efficacy (1 case) or late decrease in efficacy (2 cases). These results demonstrate the potential of D2 dopamine agonists (like bromocriptine) in the de novo treatment of Parkinson's disease; however, their use is limited by their lack of efficacy and/or the occurrence of neuropsychiatric side effects.     

Diurnal motor variations to repeated doses of levodopa in Parkinson's disease

Patients with Parkinson's disease (PD) in long-term levodopa therapy often complain of worsening of motor symptoms in the afternoon and evening. The pathophysiology of this phenomenon is not known. We evaluated the motor response to repeated doses of levodopa during a 12-hour period in 52 parkinsonian patients (19 de novo, 20 stable, and 13 wearing-off). On the day of the study, all patients received standard doses of levodopa/carbidopa at 8:00 a.m., 12:00 noon, and 4:00 p.m. Motor measurements such as tapping test, walking time, and tremor score, and blood samples for levodopa and 3-O-methyldopa (3OMD) plasma analysis, were performed hourly. Mean motor scores and pharmacokinetic data, evaluated for a period of 3 hours after each levodopa dose, were compared. In de novo patients, we did not observe diurnal changes in motor score, whereas a progressive daytime worsening was visible in stable and wearing-off patients. No significant difference in levodopa pharmacokinetics after each levodopa dose was observed within each patient group, whereas 3OMD plasma levels significant increased with repeated levodopa administrations. However, no significant correlation between motor scores and 3OMD plasma levels was observed, suggesting that the diminishing motor response to afternoon and evening doses of levodopa in patients in long-term levodopa therapy does not relate to the pharmacokinetics of the drug. It is possible that this phenomenon may be an expression of the occurrence of tolerance to repeated doses of levodopa.     

Madopar HBS and the decompensated phase of Parkinson disease

The most important current problem in the treatment of Parkinson disease in the so-called L-dopa long-term-treatment syndrome. We present here the results of our experience with Madopar HBS in the treatment of two groups of patients suffering from L-dopa long-term treatment syndrome. In the first study we replaced the standard Madopar with Madopar HBS. In the second study, after identifying the most disabling “off” periods, we added Madopar HBS to the previous treatment in such a way as to control these “off” phases. Our study suggests that Madopar HBS is useful in reducing typical fluctuation phenomena in the majority of patients.

---

Sommario Attualmente il problema più importante nel trattamento del morbo di Parkinson è costituito dalla cosiddetta “sindrome da trattamento cronico con L-dopa”. Presentiamo qui di seguito i risultati della nostra esperienza con Madopar HBS nel trattamento di 2 gruppi di pazienti affetti da tale sindrome. Nella prima parte dello studio abbiamo sostituito del tutto il Madopar standard con Madopar HBS, nella seconda parte, dopo aver identificato il periodo “off” maggiormente invalidante, abbiamo aggiunto Madopar HBS al trattamento precedente in modo che fosse efficace sulla fase off così identificata. Il nostro lavoro suggerisce che il Madopar HBS è utile nel ridurre le fluttuazioni motorie nella maggioranza dei pazienti parkinsoniani.

     

Combination of selegiline and controlled release levodopa in the treatment of fluctuations of clinical disability in parkinsonian patients

Abstract– Thirteen parkinsonians with a long duration of the disease and long-term dopa therapy, seven of them showing severe on-off oscillations and 6 an "end—of—dose impairment", were treated with a controlled release (HBS) preparation of L-DOPA/benserazide for more than 3 years.
Thereafter, selegiline was added in a progressively increasing dosage up to a maximum of 10 mg/day during 4 months, with the aim of a) further improving the long-term results and b) reducing the doses of the new formula of L-DOPA.
A significant decrease of early morning parkinsonism and reduction of motor disability throughout the day were observed; "wearing-off'cases showed better results compared with those presenting "on-off'oscillations. A mean reduction of 20% in the doses of levodopa was achieved. Likewise, a mild reduction of dyskinesias and a mild-moderate enhancement of dystonias were recorded. Only one patient did not tolerate selegiline and two others received lower doses due to side-effects.
Selegiline was capable of enhancing the antiparkinsonian effect of the new formula of L-DOPA, while allowing a reduction of the doses administered. It must also be emphasized that such improvement was achieved in complicated patients, most of whom showed some deterioration of response in the late stages of long-term sustained release levodopa treatment.     

Selegiline as the primary treatment of Parkinson's disease — a long-term double-blind study

Introduction – To assess the therapeutic efficacy of selegiline combined with levodopa in the long-term treatment of Parkinson's disease (PD). Material and methods – A randomized, prospective, double-blind study on 44 patients with PD needing levodopa therapy after the initial double-blind treatment with placebo or selegiline was carried out. The patients were followed-up for 5 years under combination therapy. Results – Selegiline induced a significant ( P < 0.001) slowing in the need to increase the daily levodopa dose in order to compensate for the progression of the disease. After 5 years of combination therapy the mean dose of levodopa was on average 320 mg lower in the selegiline group (405 ± 59 mg vs 725 ± 78 mg). The difference in the levodopa doses between the two groups increased along with follow-up time, as also the ratio of the levodopa doses (placebo/selegiline group). The number of daily levodopa doses needed to compensate for the occurrence of motor fluctuations was significantly lower in the selegiline group. The parkinsonian disability did not differ between the two groups because the clinical condition was kept as optimal as possible by adjusting the levodopa dosage. Nine patients in the placebo group needed initiation of additional dopaminergic therapy in comparison to one in the selegiline group ( P =0.004). During the 5-year follow-up period 11 patients were withdrawn from the selegiline group, 7 due to adverse events. There was no difference in mortality between the two groups. Conclusion – Selegiline therapy offers beneficial long-term effects in the treatment of PD.     

The clinical efficacy of oral levodopa methyl ester solution in reversing afternoon "off" periods in Parkinson's disease

We compared the efficacy of a single dose of an oral solution of levodopa methyl ester (ME) to that of standard levodopa, in the form of a single dose of Madopar, in reversing afternoon "off" periods in 12 patients with Parkinson's disease (PD). The highly soluble ME solution led to a significantly more rapid reversal of "off" periods. This preparation may therefore convey a clinical advantage in patients experiencing motor fluctuations whilst taking multiple daily dosages of levodopa, particularly in those with long or highly variable latency to the next "on" period.     

Twelve-month safety of entacapone in patients with Parkinson's disease

The safety of entacapone combined with levodopa and a dopadecarboxylase (DDC) inhibitor was tested in a 12-month double-blind study of 326 patients with idiopathic Parkinson's disease (PD). The study population represented 'typical' PD outpatients, including patients with varying disease severity and with various concomitant medications. Two-thirds of the patients were randomized to receive 200 mg of entacapone with each of 2--10 daily levodopa doses, and one-third to receive placebo. All entacapone patients were included in the safety evaluation of adverse events (AEs), vital signs, ECG, and laboratory parameters. Entacapone was well tolerated with a discontinuation rate due to AEs of 14% compared with 11% with placebo (NS). As expected, due to dopaminergic enhancement, dyskinesia was more frequent as an AE with entacapone than with placebo. Dryness of mouth, urine discoloration and diarrhoea were more frequent non-dopaminergic AEs with entacapone than with placebo. Entacapone had no adverse effects on hepatic enzyme activity, ECG or haemodynamic parameters, and there was no evidence of any toxicity. As an indication of levodopa enhancement with entacapone, patients taking 5--10 doses of levodopa, most likely representing predominantly fluctuating patients, showed a significant decrease in their mean daily levodopa dose of 94 mg in the entacapone group compared with a decrease of 39 mg in the placebo group (P < 0.01). The interval between the first two morning doses of levodopa increased by 17% with entacapone, whereas with placebo no extension was observed (P < 0.05). Despite levodopa dose reduction, efficacy of entacapone was maintained. As further evidence of efficacy, Parkinsonian symptoms markedly worsened in all patients after withdrawal of entacapone. We conclude that entacapone is safe in optimizing levodopa in long-term treatment of idiopathic Parkinson's disease. Monitoring of liver or other safety parameters during entacapone treatment is not required.     

Five-year efficacy and safety of levodopa/DDCI and entacapone in patients with Parkinson’s disease

This was a retrospective pooled analysis of data from four comparably designed, double-blind, placebo-controlled, Phase III studies and their long-term open-label extensions. Patients on levodopa and a dopa decarboxylase inhibitor (DDCI) were randomized to entacapone or to placebo in the 6-month, double-blind phase, with all patients subsequently receiving entacapone in the extension phase. UPDRS III motor scores improved by -2.1 points during the first 6 months of levodopa/DDCI and entacapone therapy, and remained below baseline for up to 2 years. Increased daily 'ON' time, together with response duration to a single morning dose of levodopa and clinical global evaluation, also supported the long-term efficacy of levodopa/DDCI and entacapone. The mean daily dose of levodopa did not increase over the 5-year follow-up period. Long-term therapy with levodopa/DDCI and entacapone was well-tolerated.     

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.     

Onset of dyskinesia with adjunct ropinirole prolonged‐release or additional levodopa in early Parkinson's disease

Levodopa‐induced dyskinesia can result in significant functional disability and reduced quality of life in patients with Parkinson's disease (PD). The goal of this study was to determine if the addition of once‐daily ropinirole 24‐hour prolonged‐release (n = 104) in PD patients not optimally controlled with levodopa after up to 3 years of therapy with less than 600 mg/d delays the onset of dyskinesia compared with increasing doses of levodopa (n = 104). During the study, 3% of the ropinirole prolonged‐release group (mean dose 10 mg/d) and 17% of the levodopa group (mean additional dose 284 mg/d) developed dyskinesia (P < 0.001). There were no significant differences in change in Unified Parkinson's Disease Rating Scale activities of daily living or motor scores, suggesting comparable efficacy between the two treatments. Adverse events were comparable in the two groups with nausea, dizziness, insomnia, back pain, arthralgia, somnolence, fatigue, and pain most commonly reported. Ropinirole prolonged‐release delayed the onset of dyskinesia with comparable efficacy to increased doses of levodopa in early PD patients not optimally controlled with levodopa. © 2010 Movement Disorder Society