Showing papers in "Journal of Neural Transmission-supplement in 1988"

On tyramine, food, beverages and the reversible MAO inhibitor moclobemide.

Abstract: The pathways for the biosynthesis and metabolism of tyramine are described as a basis for the discussion of the interaction between MAO inhibitors and tyramine. While a role of endogenous tyramine in the antidepressant action of MAO inhibitors remains purely hypothetical at this time, the mechanisms leading to the potentiation of the tyramine pressor effect ("cheese effect") are well known. Experiments in animals and man have provided concordant quantitative information on the effect of irreversible and some novel reversible MAO inhibitors on the presystemic disposition of orally ingested tyramine and on the noradrenaline-releasing action of tyramine in noradrenergic nerve terminals. There is a profound difference in the magnitude of tyramine potentiation between the irreversible inhibitor tranylcypromine and the reversible inhibitor moclobemide. A systematic analysis of the tyramine content of current European food and beverage is reported and serves as a rational basis for providing advice to patients on moclobemide. Most of the food and beverages analyzed contain less tyramine than previously reported and a few rules concerning rare cheeses with high tyramine content are sufficient to eliminate the risk of hypertensive crises.

Mapping dopamine receptors in the human brain.

Abstract: We have investigated the anatomic localization of dopamine D1 and D2 receptors in the human brain using selective high affinity ligands for both types of dopamine receptors and the technique of receptor autoradiography. Dopamine D1 receptors were labeled in postmortem human brain tissue sections using the antagonist [3H]SCH 23390. Dopamine D2 receptors were labeled in consecutive tissue sections using the agonist [3H]205-502 and the antagonist [3H]spiroperidol. D1 and D2 dopamine receptors presented a heterogeneous distribution in the human brain. The highest concentrations of both D1 and D2 receptors were found in parts of the basal ganglia, particularly the nucleus caudatus and putamen. Lower concentrations were seen in other areas for example, the lateral globus pallidus was enriched in D2 receptors and the medial globus pallidus in D1 receptors. The substantia nigra contained intermediate densities of both D1 and D2, D1 receptors being present in higher concentrations. Dopamine D1 receptors were also localized in areas outside of the basal ganglia, particularly in the neocortex, amygdala and hippocampal formation. Dopamine D2 receptors were also present in areas outside of the basal ganglia, the most significant densities being found in the hippocampal formation. We observed a marked age-dependent decline in the density of D1 receptors during the first decades of life. In contrast, D2 receptor concentrations appeared to be unaltered with age. The distribution and densities of dopamine receptors were examined in 12 cases of Parkinson’s disease and compared to a control adult population. No significant differences in density and distribution were seen for either D1 nor D2 receptors.

The involvement of intestinal monoamine oxidase in the transport and metabolism of tyramine

Abstract: The monoamine oxidase activities were found to be similar in the crypt and villous cells of the different regions of rat small intestine. In all cases the activity of the A-form of the enzyme constituted more than 70% of the total. A similar proportion of that form of the enzyme was found in homogenates of biopsy samples of human intestine. Studies with everted intestines showed that at concentrations above 10 microM over 70% of tyramine was deaminated during transport and the use of selective inhibitors confirmed the A-form of monoamine oxidase to play the dominant role in that process.

Tyramine pressor effect in man: studies with moclobemide, a novel, reversible monoamine oxidase inhibitor.

Abstract: The pressor effect of tyramine (TYR) administered i.v. and orally was measured in healthy volunteers during treatment with different therapeutic doses of moclobemide, a new, reversible, preferential type A monoamine oxidase inhibitor. With moclobemide 3 X 100 mg/day the systolic blood pressure (SBP) increase produced by TYR administered i.v. was potentiated 2.4-fold and that in response to TYR p.o. in the fasting state was increased 4.1-fold, as determined from equieffective TYR doses before and during moclobemide treatment. Peak concentrations of free TYR in plasma after oral doses of TYR were increased 2.6-fold, and a 2.5-fold smaller plasma TYR concentration produced the same SBP rise as before moclobemide treatment. No SBP increase was observed at plasma TYR concentrations below 20 ng/ml or after p.o. TYR does smaller than 80 mg. The potentiation of the pressor effect of i.v. TYR by single moclobemide doses up to 300 mg had disappeared 24 hrs after moclobemide administration. Peak TYR plasma concentration and concomitant SBP increments were considerably smaller when TYR was administered with a meal than when administered as a bolus with tap water, 2.1 times higher oral TYR doses being required to achieve similar peak TYR plasma concentration as in the fasting condition. The pressor effect of TYR was further, but only slightly, increased during treatment with moclobemide 3 x 200 mg/day, however SBP rises were again significantly smaller when TYR was given together with a meal. In contrast, tranylcypromine produced a 20 to 40-fold potentiation of the pressor effect of oral TYR and this potentiation was only slightly smaller when TYR was given with a meal. In conclusion the potentiation by moclobemide of the pressor response to oral TYR corresponds roughly to a fourfold left shift of the TYR dose-pressor response curve and is about 10 times less marked than after tranylcypromine. In real life situations, the ingestion of TYR in amounts less than 100 mg is highly unlikely to produce a clinically relevant blood pressure elevation.

Psychiatric side effects during the treatment of Parkinson's disease.

Abstract: Dopaminergic agents including both levodopa and direct-acting agonists induce a variety psychiatric side-effects of which psychosis is the most significant. When this occurs early in the course of treatment, there is usually a history of prior psychotic illness. Chronic treatment can, however, elicit psychosis in individuals without such a history. The possible pathogenesis of this is reviewed.

Receptor changes during chronic dopaminergic stimulation.

Abstract: The underlying cause of the long term complications of L-DOPA or dopamine agonist therapy in Parkinson’s disease remains unknown. Previous studies of repeated administration of L-DOPA or bromocriptine to rodents have shown increases, decreases or no change in brain dopaminergic activity. For this reason we have re-examined the effects of chronic L-DOPA or dopamine agonist administration on brain dopamine receptor function in rats.

Antidepressant drug therapy: associated risks.

Abstract: Aspects of risks associated with treatment with three classes of antidepressants: tricyclic (TCA), second generation ("new") antidepressants and monoamine oxidase inhibitor (MAOI), are discussed. Moclobemide, a benzamide derivative, is a new MAOI antidepressant with reversible and preferential inhibition of the A-form of monoamine oxidase. Moclobemide is free of liver toxicity and the risk of a pressor response with tyramine-containing food is so low that strict diet restrictions are unnecessary. That MAOIs have a low incidence of side effects, particularly so called anticholinergic side effects is also true for moclobemide. A serious risk with antidepressant drugs is that the patient will use them to attempt suicide. Therefore important aspects of antidepressants are that they should take effect rapidly and be safe in overdose. No deaths from overdose have been observed with toloxatone, the only reversible MAOI antidepressant on the market to date. It is concluded that the new reversible MAOI antidepressant moclobemide is similar to other antidepressants in terms of efficacy but very noticeably superior in terms of tolerance and safety. Language: en

Interaction of moclobemide, a new reversible monoamine oxidase inhibitor with oral tyramine.

Abstract: In a double-blind placebo-controlled cross-over study in 8 healthy volunteers possible interactions between moclobemide and tyramine were studied. Eight volunteers received either moclobemide or placebo for a period of 6 days and received tyramine on day 5 and day 6 of each treatment period. Moclobemide was given in a daily dose of 450 mg to be taken in three divided doses at the end of the meals. Tyramine was administered in the form of an artificially tyramine enriched cheese (camembert) together with a meal at noon. The total tyramine doses administered were 50 mg on day 5 and 100 mg on day 6 of each treatment period. Comparisons of blood pressure and heart rate changes after tyramine ingestion between moclobemide and placebo conditions did not indicate any relevant moclobemide-tyramine interaction. It is concluded that tyramine in quantities of up to 100 mg does not lead to clinically relevant blood pressure reactions in moclobemide-treated subjects, if moclobemide is taken at the end of the meal.

Subcutaneous lisuride infusion in Parkinson's disease: clinical results using different modes of administration.

Abstract: The continuous dopaminergic stimulation provided by infusion of dopamine agonist drugs, is a very effective strategy to control ON-OFF fluctuation in Parkinson’s disease Lisuride is a potent dopamine agonist drug, very soluble in water and can be administred subcutaneously Many authors have shown that the subcutaneous infusion of lisuride can control fluctuations when applied in combination with oral levodopa as a 24 hour continuous infusion regimen In this study, lisuride was given without any other antiparkinsonian medicament and using a 12 hour infusion regimen wherever possible 13 fluctuating Parkinsonian patients were studied 6 out of these 13 were satisfactorly treated with lisuride alone and the remaining 7 with a combination of Lisuride + oral levodopa Only in 3 out of 13 patients the 24 hour infusion regimen was required

Continuous subcutaneous lisuride infusions in Parkinson’s disease

Abstract: Thirteen patients with idiopathic Parkinson’s disease and “on-off” fluctuations on oral levodopa plus dopa decarboxylase inhibitor (DDI) were treated with continuous (24 hour) subuctaneous lisuride infusions together with a reduced dose of levodopa (plus DDI). An improvement in motor performance was seen in 10 patients, with a mean increase in percentage of waking time spent “on” of 32 per cent (range 13–59 percent). However, adverse effects were common, especially psychiatric effects, leading to treatment withdrawal in 11 of 13 subjects after a mean of 40 days’ treatment.

Potentiation of tyramine pressor responses in conscious rats by reversible inhibitors of monoamine oxidase.

Abstract: Intraperitoneal injection of cimoxatone, moclobemide, amiflamine CGP 11305 A (all 5 mg/kg) increased pressor responses to intravenous tyramine (100 micrograms) in conscious, freely moving rats. Area under mean arterial pressure curve increased by 7.01, 4.28, 5.3 and 3.46 fold respectively. Clorgyline (2 mg/kg) increased area under pressor response curve by 10.4 fold. Tyramine responses returned to normal 24 hours after reversible inhibitors but were still potentiated 24 hours after clorgyline.

Continuous dopaminergic stimulation: state of the art and outlook.

Abstract: Therapy with L-Dopa was a major break-through in the treatment of Parkinson’s disease. It was an important precedent, and a stimulus for research in this and other fields of neurology. Initial side effects associated with this drug were overcome by refining the treatment schedule and by additional drugs inhibiting the peripheral conversion of L-Dopa to dopamine.

Continuous intracerebroventricular infusion of dopamine and dopamine agonists through a totally implanted drug delivery system in animal models of Parkinson's disease.

Abstract: We studied the effect of intracerebroventricular infusion of dopamine and dopamine agonists in animal models of dopamine deficiency as an experimental approach to the treatment of levodopa induced fluctuations in Parkinson's disease. Dopamine deficiency was produced in rats by unilateral lesion of the nigrostriatal pathway or by chronic treatment with reserpine. Monkeys were lesioned by intravenous injection of MPTP. The animals were treated with intracerebral infusions of dopamine (with or without associated intraperitoneal administration or intracerebroventricular infusion of pargyline), lisuride and pergolide. The intracerebroventricular infusion of these drugs was performed with osmotic minipumps in rats and with infusaid pumps in the monkeys. The infusion of dopamine or dopamine agonists in rats with unilateral lesions by 6-OH-dopamine produced a persistent rotation contralateral to the lesioned and implanted side. The infusion of dopamine reversed reserpine-induced akinesia only when pargyline was associated. In the range of concentration used, maximum allowed by solubility of compounds, the effects of dopamine were more potent than those of the agonists. In spite of the stability of dopamine "in vitro" when dissolved in antioxidants and at low pH, a pigment, product of autooxidation, was found in the brains of the animals infused with dopamine. The monkeys were implanted with infusaid pumps and infused for up to 3 weeks. The pump was not well tolerated due to its huge size for the animals. One monkey showed reversal of the MPTP-induced akinesia while the other, whose catheter had moved from the correct implantation site, remained unchanged. In both monkeys there was evidence of autooxidation of dopamine. Intracerebral infusion of dopamine agonists may be a possible experimental alternative to the treatment of levodopa induced fluctuations in Parkinson's disease but stable and soluble dopamine agonists and suitable delivery systems are needed.

Pathogenetic studies of motor fluctuations in Parkinson’s disease

Abstract: Pharmacokinetic and pharmacodynamic mechanisms for levodopa have been studied in relation to the pathogenesis of the motor fluctuations which complicate advanced Parkinson’s disease. Since levodopa clearance from the general circulation was found to be similar in patients with wearing-off or on-off phenomena and those with a stable response to levodopa, peripheral pharmacokinetic factors are unlikely to be involved. Efficacy half-time for levodopa, on the other hand, was significantly reduced in patients with mainly wearing-off fluctuations in comparison to those manifesting a stable response to oral levodopa; individuals with predominantly on-off phenomenon had an even more extreme reduction in the duration of the antiparkinsonian action of levodopa. Conversion from oral to intravenous levodopa treatment immediately stabilized plasma levodopa levels in both the wearing-off and on-off groups; motor variability also decreased, especially in those with wearing-off phenomenon. During 11 days of continuous intravenous levodopa therapy, additional reductions in motor fluctuations occurred in both groups, but at a significantly faster rate in patients with wearing-off than in those with on-off responses. These results suggest that wearing-off phenomenon may arise as a consequence of the degeneration of dopamine terminals due to natural disease progression with a resultant inability to buffer variations in levodopa availability; on-off phenomenon, may reflect additional postsynaptic dopamine receptor dysregulation, possibly in response to the resultant, nonphysiologic fluctuations in synaptic dopamine.

Subcutaneous administration of lisuride in the treatment of complex motor fluctuations in Parkinson's disease.

Abstract: 28 patients with Parkinson’s disease showing complex “on-off” fluctuations in response to chronic levodopa plus dopa decarboxylase inhibitor (po) were treated with subcutaneous lisuride using a portable infusion pump. All patients improved initially during the first weeks of treatment. Four patients abandoned the trial within the first few weeks as a consequence of psychiatric complications (2 cases), inability to understand how to use the pump (one case) and subcutaneous nodule formation plus psychological rejections to wearing a pump (one case). All other 24 patients were treated for a minimum periods of 3 months (mean 9.6 months, maximum 24 months). The average daily dose of lisuride was 2.80mg. The levodopa dose was reduced by 37%, but total withdrawal was not possible in any patient. Among the 18 patients who continued treatment at present, about 50% are independent and capable of undertaking most daily life activities. Psychiatric side-effects were present in 9 patients leading to permanent withdrawal in five.

Blood pressure response to tyramine-enriched meal before and during MAO-inhibition in man: influence of dosage regimen.

Abstract: In an open study oral tyramine in variable doses was administered to six healthy volunteers under three different conditions: 1) without moclobemide, 2) under moclobemide steady-state conditions (3 X 200 mg moclobemide daily) one hour after moclobemide intake and 3) under moclobemide steady-state conditions simultaneously with moclobemide. It was shown that the amount of tyramine effecting 30-50 mmHg systolic blood pressure increase was roughly doubled when moclobemide was administered together with tyramine instead of one hour before tyramine intake. The time interval between tyramine ingestion and maximal blood pressure increase did not differ significantly between conditions 2) and 3). The conclusion of this study is that moclobemide should always be taken at the end of a meal, which is anyway the usual time for drug intake.

Applications of new drug delivery technologies to Parkinson's disease and dopaminergic agents.

Abstract: Recent advances in drug delivery technology are creating novel therapeutic approaches to the treatment of Parkinson’s disease with levodopa and dopamine agonists. This article reviews those technologies which can be applied to Parkinson’s disease, both for targetting the central nervous system with drugs, as well as for matching the appropriate rate controlled delivery with therapeutic needs. In particular, the possibility exists for eliminating erratic highs and lows of drug delivery to the brain, and to substitute rate controlled, constant drug delivery. Clinical investigations now in progress suggest that new technologies which deliver constant dopaminergic stimulation to patients with Parkinson’s disease may not only eliminate the unpredictable swings in therapeutic efficacy in Parkinson patients with the “on/off” effect, but may even have a role in the future in preventing such fluctuations from developing in patients chronically treated with dopaminergic therapies.

Chronic s.c. Lisuride in Parkinson’s disease — motorperformance and avoidance of psychiatric side effects

Abstract: On-off fluctuations in longstanding Parkinson’s disease initially respond well to a combined drug regime of Levodopa with direct dopamine agonists and L-deprenyl. L-Dopa infusions are efficient, but not applicable for longer use. S. c.-Lisuride-infusions reduce markedly motor-response fluctuations, dystonias and hyperkinesias, but bear the risk of inducing confusion or even psychosis. In patients with coexisting response fluctuations and psychiatric disturbances a therapeutic approach is outlined to preserve still some favourable effects on motor performance avoiding severe psychosis. Side-effects and possible complications of that therapy are discussed as are some further indications for the clinical use of Lisuride in akinetic crisis, the neuroleptic malignant syndrome and in dyskinesias.

Effect of food intake on the relative bioavailability of moclobemide (Ro 11-1163).

Abstract: Twelve healthy adult volunteers received a single 100-mg tablet of moclobemide in an open-label crossover study designed to determine the influence of food on moclobemide absorption. Moclobemide was administered 30 min after a standard breakfast as well as under fasting conditions. Moclobemide absorption was rapid in the absence of food. Bioavailability parameters obtained when drug was taken 30 min after the meal suggested that the rate of absorption was slightly decreased in the presence of food (mean Tmax 0.71 h vs. 1.14 h), while the extent of absorption of moclobemide given with food was unaltered. The decreased absorption rate in the presence of food is not expected to be of clinical significance.

Agonist and antagonist actions of lisuride on dopamine neurons: electrophysiological evidence

Abstract: The effect of lisuride (LIS) on the firing rate of A 9 dopamine (DA) neurons in chloral-hydrate anesthetized and unanesthetized (paralyzed) rats was compared In both preparations, the microiontophoretic application of LIS onto DA cell bodies consistently inhibited the electrical activity of the neurons On the other hand, the effect of intravenous LIS differed in the two preparations In anesthetized rats LIS (10–100 µg/kg) inhibited in a dose-related manner the firing rate of most DA neurons tested, whereas in unanesthetized rats LIS produced a dose-related increase in firing rate The latter effect was transient, subsiding within 5 min, and was followed by the return of firing rate to baseline or slightly below it Irrespective of the animal preparation, after the initial effect of LIS had subsided, DA neurons became totally insensitive to additional doses of LIS, to apomorphine and haloperidol Such an insensitivity of DA neurons was present 1 to 6 but not 24 h after LIS (02mg/kg, subcutaneously) treatment A hypothesis is proposed to explain the different effects of LIS

Effect of moclobemide on clinical and neurochemical variables in depressed patients (preliminary findings).

Abstract: In this paper the preliminary results from an ongoing investigation on the effect of the MAO-A inhibitor moclobemide on clinicolaboratory variables (antidepressant effect, platelet MAO activity, urinary MHPG and 5-HIAA excretion, plasma prolactin and growth hormone levels and TSH response to TRH) are reported. From the total of 18 patients, 10 (2 males and 8 females) responded favourably (reduction in the HDRS 50% or more) to the treatment. Urine MHPG excretion significantly (p less than 0.001) decreased during treatment, while 5-HIAA secretion showed a less pronounced decrease (p less than 0.05). Plasma PRL and GH remained unchanged, while the TSH-response to TRH increased significantly (p less than 0.025) after 4-week treatment. A significant correlation was found between MHPG pretreatment values and treatment outcome.

Some in vitro effects of moclobemide and other MAO inhibitors on responses to sympathomimetic amines.

Abstract: The use of inhibitors of monoamine oxidase (MAO) in the treatment of some forms of depression has been marred by the occurrence of unpleasant or even fatal side effects. Of these the most serious has been the risk of sudden hypertensive crises following the ingestion of food or drink containing indirectly-acting sympathomimetic amines such as tyramine (cheese effect). This effect, due to long lasting or irreversible inhibition of MAO in the gut and vasomotor neurones is much less obvious with the new generation of reversible inhibitors. Acceptance into clinical practice of these agents will depend upon the provision of clear and unequivocal evidence that there is little or no risk of unexpected cheese effects. The use of in vitro methods has provided a most sensitive way of revealing and measuring any such propensity in these new agents including moclobemide, cimoxatone and toloxatone. Use of isolated smooth muscles, such as the vas deferens and anococcygeus muscles of the rat together with vascular smooth muscle, typified by the perfused mesenteric arterial bed may be used as reliable preliminaries to in vivo and human volunteer studies in an attempt to introduce into clinical medicine an antidepressant that acts through the inhibition of MAO but carries little or no risk of the cheese effect.

Pharmacokinetics of lisuride after subcutaneous infusion.

Abstract: Six parkinsonian patients received a constant subcutaneous infusion of 60 µg lisuride per hour in the abdominal region for 2 hours. Plasma levels of the unchanged drug were measured by radio-immunoassay. During infusion, a steady state plasma level of 0.78 ± 0.19ng/ml was achieved. After discontinuation of the infusion, concentrations declined with a half-life of 1.4 ± 0.4 hour. The total clearance of lisuride was 20 ± 6 ml/min/kg. Due to the low interpatient variability of plasma levels, a good control of clinical effects is to be expected.

Effect of chronic subcutaneous minipump infusion of lisuride upon locomotor activity of rats.

Abstract: Male Wistar rats were infused continuously for 14 days with lisuride 0.25mg/kg/day or with vehicle via subcutaneously implanted osmotic mini-pumps. Locomotor activity was measured at 5 hours, 1, 7 and 14 days after implantation. Thereafter the minipumps were removed and 1, 7 and 21 days later the locomotor activity was recorded after a subcutaneous challenge dose of lisuride 0.1 mg/kg. In the course of continuous infusion the lisuride-treated rats showed a persistent stimulation of locomotor activity which remained almost constant throughout the whole period of exposure. At all intervals after removal of the minipumps lisuride challenge produced a less pronounced locomotor stimulation in lisuride-infused rats compared to vehicle-infused animals. This observation contrasts with the findings after chronic subcutaneous bolus treatment of rats with 0.25 mg/kg lisuride once daily for 29 days which resulted (1) in a progressive enhancement of the locomotor stimulatory effect and (2) in a longlasting hyperresponsiveness towards a subcutaneous challenge dose of lisuride 0.025 mg/kg. These results are discussed with respect to the advantage of the constant availability of lisuride at central dopamine receptors for the management of patients with advanced Parkinson’s disease showing fluctuations in motor performance probably related to the kinetics of conventional oral therapy.

Parkinson’s disease and PET tracer studies

Abstract: Although the cause of Parkinson’s disease is still unknown it has become clear that dopaminergic cell loss in the substantia nigra is a prominent feature of the disease. The study of cerebral dopaminergic function — dominated by the nigrostriatal system —in relation to motor abnormalities and their response to treatment has been in the centre of research for many years. However, until recently it was not possible to approach metabolism or neurotransmitter function in brain directly in vivo. To be able to do so seems highly necessary since Parkinson’s disease is a slowly progressive condition and one wishes to know how cerebral functions are deranged in the beginning of the disease.

Pharmacokinetic studies with sustained-release formulations of levodopa in healthy volunteers.

Abstract: On the basis of the results of a large number of studies of the correlation between plasma levodopa levels and the occurrence of mobility disorders, it was concluded that side-effects such as dyskinesia, end-of-dose, peak-dose and on-off phenomena, which occur especially during levodopa long- term treatment of Parkinson patients, may be caused by fluctuations in the plasma levodopa levels. Some preliminary trials using sustained-release formulations were not up to expectations. Still, we studied the question of whether it might not be possible after all to obtain sustained plasma levodopa levels over prolonged periods of time with levodopa sustained-release (S. R.) formulations, without causing a high initial peak. For this purpose, we compared the pharmacokinetics of six different levodopa S. R. formulations with a standard preparation in two randomized cross-over trials in healthy male volunteers.

Factors contributing to fluctuations of the dopaminergic nigro-striatal feedback system in Parkinson's disease.

Abstract: The experience that the supplementation of depleted dopamine in the nigro-striatal system of parkinsonian patients with L-dopa improves the clinical triad, akinesia, rigidity and tremor, mainly applies to long-term treatment in the early phase of Parkinson’s disease. Complications in motor performance, like on-off response, wearing-off phenomena, peak-dose dyskinesia, biphasic dyskinesia, off-period dystonia and others, after more than 3 to 5 years following the onset of treatment indicate fluctuations in the dopaminergic feedback control system. It is suggested that these complications are due to progressive presynaptic degeneration and late changes in postsynaptic receptor amplification. However, as fluctuations are not imperative in all patients, an important additional aspect seems to be the topography of denervation, which involves different portions of the striatum to varying degrees. Location and extent of denervation are criteria which appear to have predictive value for the malignancy of the disease, the therapeutic response of drugs and complications in long-term treatment.

A combined regimen of subcutaneous lisuride and oral Madopar HBS in Parkinson’s disease

Abstract: At the first stage of a pilot study involving 14 parkinsonians with motor fluctuations, treatment with standard Madopar was substituted by a sustained-release form, Madopar HBS, which attenuated fluctuations in patients with end-of-dose impairment, but achieved only moderate improvement in patients with on-off phenomena.

Treatment of Parkinson's disease with subcutaneous lisuride infusions.

Abstract: Four patients with Parkinson’s disease and severe fluctuating responses to levodopa and oral dopamine agonists were treated with continuous administration of lisuride infusions, administered by means of an externally worn pump.