Low Doses Of Levodopa Research Articles

Low-dose Levodopa Therapy in Japanese Patients with Parkinson's Disease: A Retrospective Study

To investigate the efficacy and the rate of adverse events of chronic low-dose levodopa-carbidopa therapy in Japanese patients with Parkinson's disease (PD). A total of 92 Japanese PD patients treated with low doses of levodopa from the outset were studied. Both disease-specific motor disabilities and quality of life (QOL) in the patients were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) and the Parkinson's Disease 39 Quality of Life Questionnaire (PDQ39), respectively. In the overall patient group, the mean duration of treatment, the mean daily dose of levodopa, the disability scores and the motor scores of UPDRS were 6.2 years, 186.4 mg, 8.0 and 19.2, respectively. The rates of motor fluctuations, dyskinesias and hallucinations were 8.7%, 6.5% and 14.1%, respectively. The mean summary index of PDQ39 scores was 23.1. Patients with motor fluctuations showed a significantly earlier disease onset. Dose of levodopa, age at onset, and treatment duration were not associated with the occurrence of dyskinesias. Patients with hallucination had higher doses of levodopa and dopamine agonist. Our results demonstrate that chronic administration of a low-dose levodopa preparation can provide satisfactory benefit with a low incidence of motor complications, and can result in good QOL in Japanese patients with PD. The concomitant use of a small amount of dopamine agonist and amantadine from the outset has partly contributed to a reduced dose of levodopa and the lesser occurrence of motor complications.

Sydney multicenter study of Parkinson's disease: Non‐L‐dopa–responsive problems dominate at 15 years

One-third of the 149 people recruited 15 to 18 years ago in the Sydney Multicenter Study of Parkinson's disease have survived. The original study compared low-dose levodopa with low-dose bromocriptine. We now report the problems experienced by people who survive 15 years from diagnosis. The standardized mortality ratio is significantly elevated at 1.86 and is not significantly different between treatment arms. Falls occur in 81% of patients, and 23% sustained fractures. Cognitive decline is present in 84%, and 48% fulfill the criteria for dementia. Hallucinations and depression are experienced by 50%. Choking has occurred in 50%, symptomatic postural hypotension in 35%, and urinary incontinence in 41%. No patient is still employed, and 40% of patients live in aged care facilities. Although approximately 95% have experienced L-dopa-induced dyskinesia/dystonia and end of dose failure of medication, in the majority, these symptoms are not disabling. Dyskinesia and dystonia were delayed by early use of bromocriptine, but end-of-dose failure appeared at a similar time once L-dopa was added. The rate of disease progression is similar in both arms of the study. We conclude that the most disabling long-term problems of Parkinson's disease relate to the emergence of symptoms that are not improved by L-dopa. Neuroprotective interventions in Parkinson's disease should be judged by their ability to improve non-L-dopa-responsive aspects of the disease, rather than just by their capacity to delay the introduction of L-dopa or reduce its associated side effects.

Long-term course of l -dopa-responsive dystonia caused by tyrosine hydroxylase deficiency

The authors report the long-term course of two siblings with L-dopa responsive dystonia (DRD) associated with a compound heterozygous mutation in the tyrosine hydroxylase (TH) gene. Both siblings manifested with lower-limb onset generalized DRD and had a sustained response to low-dose L-dopa therapy for over 35 years. Although the l-dopa therapy was delayed up to 20 years after disease onset, there were no cognitive or neurologic sequelae of the long-term catecholamine deficit.

Misdiagnoses in children with dopa-responsive dystonia

Dystonia is a state of continuous contraction of groups of agonist and antagonist muscles resulting in a sustained abnormal posture. Dopa-responsive dystonia was first described in 1976 by Segawa. Patients typically have diurnal variation of their symptoms with worsening at the end of the day and a dramatic response to low-dose L-dopa. This report presents five consecutive children with dopa-responsive dystonia who were misdiagnosed initially as spastic diplegic cerebral palsy, intractable epilepsy, hereditary spastic paraplegia, or a neurodegenerative disorder. There were two males and three females aged 3-13 years (mean 8.6 years). They were monitored for up to 2 years (mean 14.8 months). One had focal, one axial, one segmental, and two generalized dystonia. The dystonia was paroxysmal in two (tiptoe walking and opisthotonus), and all had a progressive course. All children responded dramatically to L-dopa (mean 200 mg/day), including three who were wheelchair-bound for several years. The difficulties in early diagnosis, variability of clinical presentation, and dramatic response to L-dopa will be illustrated. To conclude, dopa-responsive dystonia should be considered in any child who presents with paroxysmal or progressive hypertonia of unknown etiology, because it responds so dramatically to L-dopa.

The effect of monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) polymorphisms on levodopa therapy in patients with sporadic Parkinson's disease.

The etiology of sporadic idiopathic Parkinson's disease (PD) is considered multifactorial with both genetic and environmental factors modifying the disease expression. Recent studies suggest that polymorphism in monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) might influence the risk and treatment of PD. The aim of the study was to evaluate the effect of MAOB and COMT genetic polymorphism on effective daily dose of levodopa applied during the first 5 years of treatment, and to find out if a relationship exists between MAOB and COMT haplotypes and motor disturbances onset in PD patients treated with levodopa preparations. A total of 95 patients (40 females and 55 males) of Polish origin diagnosed with sporadic PD were enrolled into the study, and were divided into two groups. Group 1 - patients treated with doses of levodopa below 500 mg/day during the first 5 years of treatment. Group 2 - patients requiring levodopa doses exceeding 500 mg/24 h during the first 5 years of treatment. Low activity alleles of MAOB and COMT, i.e. MAOB allele A and COMT(L) as well as high activity ones, i.e. MAOB allele G and COMT(H), were determined using PCR-RFLP method. No statistically significant differences were found in MAOB and COMT allele distribution in the two groups. However, the frequency of COMT(L/L) homozygotes was higher in the group treated with low doses of levodopa when compared with the second group. MAOB and COMT AG-HH haplotype predominated in the group of females treated with high daily doses of levodopa when compared with AG-LL haplotype in the group of females treated with low daily doses of levodopa (<500 mg/24 h). The results of the study suggest that patients with COMT(L/L) genotype and possibly MAOB genotype A may benefit from more efficient and safer levodopa therapy.

Therapeutic factors causing hallucination in Parkinson's disease patients, especially those given selegiline

Selegiline protects nigral dopaminergic neurons and is recommended for the treatment of patients in the early stage of Parkinson's disease (PD). We treated 112 PD patients and noted that those given selegiline had a high incidence of hallucination. Our objective was to determine which clinical therapeutic factors cause such hallucinations. The Kruskal-Wallis and χ 2 test showed that in 94 patients, the severity of the hallucinations was significantly related to the duration of illness, Hoehn and Yahr stage, doses of levodopa and cabergoline, whether or not selegiline was used, and whether or not medication for constipation was required. In addition, patients who were treated with a low dose of levodopa (≤300 mg/day), who had a low Hoehn and Yahr stage, and a short duration of illness (≤8 years) together with a high dose of selegiline or cabergoline also tended to have hallucinations. MRI findings were not related to the incidence of hallucination. When selegiline is given to patients who have PD of long duration and a high Hoehn and Yahr stage, and who already are receiving levodopa and a dopamine agonist, the doses of levodopa and the dopamine agonists given, as well as the presence of constipation, may be related to the incidence of hallucination.

Effects of pulsatile l-DOPA treatment in the double lesion rat model of striatonigral degeneration (multiple system atrophy)

We examined the role of a striatal lesion in the development of l-DOPA-induced abnormal involuntary movements (AIMs) using the double lesion rat model of striatonigral degeneration (SND), the underlying neuropathological substrate of parkinsonism associated with multiple system atrophy (MSA-P), in comparison to a Parkinson's disease (PD) rat model. l-DOPA administration reliably induced AIMs in SND and PD rats in a dose-dependent fashion. AIMs occurred significantly earlier in SND compared to PD rats. There was a mild, but significant, transient increase of orolingual AIMs during the first week of low-dose l-DOPA treatment in SND. Whereas l-DOPA significantly improved contralateral forelimb akinesia in PD rats, there was no beneficial effect in SND rats. Striatal FosB/ΔFosB up-regulation in SND and PD rats correlated with the severity of l-DOPA-induced dyskinesias. Pulsatile l-DOPA administration in the double lesion SND rat model replicates salient features of the human disease MSA-P, including loss of the anti-akinetic l-DOPA response and induction of dyskinesias with transient orolingual predominance.

Management of Parkinson Disease

Parkinson disease is a movement disorder caused by progressive dopaminergic neuron degeneration in the substantia nigra and characterized by four cardinal symptoms: resting tremor, bradykinesia, rigidity, and postural instability. Levodopa has been considered the first-choice intervention for Parkinson disease for more than three decades. However, up to 50–90% of levodopa-treated patients develop motor complications within 5–10 years of starting treatment. It is important, therefore, to delay the initiation and/or reduce the dosage requirements of levodopa. The non-ergoline dopamine agonist ropinirole (Requip®) is used as monotherapy or in combination with low-dose levodopa in patients with early disease, and as an adjunct to levodopa in patients with advanced Parkinson disease.

Subcutaneous Apomorphine

Apomorphine, a short-acting dopamine D1 and D2 receptor agonist, was the first dopamine receptor agonist used to treat Parkinson's disease. Subcutaneous apomorphine is currently used for the management of sudden, unexpected and refractory levodopa-induced 'off' states in fluctuating Parkinson's disease either as intermittent rescue injections or continuous infusions. Other indications include the challenge test for determining the dopaminergic responsiveness and finding the appropriate dose of the drug in intermittent subcutaneous administration. Except for a rapid on- and offset of the antiparkinsonian response with subcutaneous apomorphine, the magnitude and pattern of the motor response to single dose of subcutaneously administered apomorphine is qualitatively comparable to that of oral levodopa. Seventy-five percent of patients achieve a clinically significant improvement with a dose of apomorphine 4mg. The efficacy of intermittent subcutaneous apomorphine injections as an add-on to levodopa therapy in advanced Parkinson's disease was explored in one short-term, randomised, double-blind, placebo-controlled trial, one short-term and six long-term, open-label, uncontrolled studies, including a total of 195 patients. These studies provide evidence that this mode of administration was successful in aborting 'off' periods and improving Parkinson's disease motor scores, but tended to increase dyskinesias. No levodopa-sparing effect was observed. Eleven long-term, open-label, uncontrolled studies, including a total of 233 patients evaluated the efficacy of continuous subcutaneous apomorphine infusions in monotherapy or as an add-on to levodopa therapy in advanced Parkinson's disease. These studies proved that subcutaneous apomorphine infusions are successful in aborting 'off' periods, reducing dyskinesias and improving Parkinson's disease motor scores with the added benefit of a substantial levodopa-sparing effect. The apomorphine challenge test has at least 80% overall predictive ability to clinically diagnose Parkinson's disease across the different stages of the disease and parkinsonian syndromes. Similarly, those data also indicate that the apomorphine challenge test has a >80% ability to predict dopaminergic responsiveness across all stages of Parkinson's disease. Adverse events are usually mild and consist predominantly of cutaneous reactions and neuropsychiatric adverse effects. The incidence of adverse effects is higher in patients receiving continuous infusion than in those receiving intermittent pulsatile administration. Based on the results of these studies it is recommended that subcutaneous apomorphine either as intermittent injections or continuous infusions should be offered to any suitable Parkinson's disease patient who has difficulties in his/her management with conventional therapy. Low-dose levodopa therapy in combination with waking-day hours subcutaneous apomorphine infusion would probably be the most efficient treatment. Continuous subcutaneous apomorphine infusions should be evaluated before more invasive measures or neurosurgical interventions are contemplated.

Dopa-Responsive Dystonia with Different Phenotypes in Monozygotic Twins

Dopa-responsive dystonia (DRD) is typically characterized by dystonia of the lower extremities beginning in childhood, with progression to involve the entire body, marked worsening of symptoms during the day, improvement in symptoms with sleep, and a dramatic response to low-dose levodopa. Inheritance usually is autosomal-dominant. The affected gene encodes for the enzyme GTP-cyclohydrolase 1(GCH1); more than 70 …

Translating A2A antagonist KW6002 from animal models to parkinsonian patients.

Improving the translation of novel findings from basic laboratory research to better therapies for neurologic disease constitutes a major challenge for the neurosciences. This brief review of aspects of the development of an adenosine A2A antagonist for use in the management of Parkinson's disease (PD) illustrates approaches to some of the relevant issues. Adenosine A2A receptors, highly expressed on striatal medium spiny neurons, signal via kinases whose aberrant activation has been linked to the appearance of parkinsonian signs after dopaminergic denervation and to the motor response complications produced by dopaminomimetic therapy. To assess the ability of A2A receptor blockade to normalize certain of these kinases and thus benefit motor dysfunction, the palliative and prophylactic effects of the selective antagonist KW6002 were first evaluated in rodent and primate models. In hemiparkinsonian rats, KW6002 reversed the intermittent L-dopa treatment-induced, protein kinase A-mediated hyperphosphorylation of striatal alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor GluR1 S845 residues and the concomitant shortening in motor response duration. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys, coadministration of KW6002 with daily apomorphine injections acted prophylactically to prevent dyskinesia onset. These and related preclinical observations guided the design of a limited, randomized, controlled, proof-of-concept study of the A2A antagonist in patients with moderately advanced PD. Although KW6002 alone or in combination with a steady-state IV infusion of optimal-dose L-dopa had no effect on parkinsonian severity, the drug potentiated the antiparkinsonian response to low-dose L-dopa with fewer dyskinesias than produced by optimal-dose L-dopa alone. KW6002 also safely prolonged the efficacy half-time of L-dopa. The results suggest that drugs capable of selectively blocking adenosine A2A receptors could confer therapeutic benefit to L-dopa-treated parkinsonian patients and warrant further evaluation in phase II studies. They also illustrate a strategy for successfully bridging a novel approach to PD therapy from an evolving research concept to pivotal clinical trials.

Effect of pulsatile administration of levodopa on dyskinesia induction in drug-naïve MPTP-treated common marmosets: effect of dose, frequency of administration, and brain exposure.

Levodopa (L-dopa) consistently primes basal ganglia for the appearance of dyskinesia in parkinsonian patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -treated primates. This finding may reflect its relatively short duration of effects resulting in pulsatile stimulation of postsynaptic dopamine receptors in the striatum. We have compared the relationship between L-dopa dose and frequency of administration on dyskinesia initiation in drug-naïve, MPTP-treated common marmosets. We have also studied the effect of increased brain exposure to pulsatile administration by combining a low-dose of L-dopa with the peripheral catechol-O-methyltransferase inhibitor (COMT-I), entacapone. Pulsatile administration of a low (dose range, 5.0-7.5 mg/kg p.o.) or a high (12.5 mg/kg) dose of L-dopa plus carbidopa b.i.d. produced a dose-related reversal of motor deficits. Repeated administration of low and high doses of L-dopa for 26 days to drug-naïve, MPTP-treated animals also caused a dose-related induction of peak-dose dyskinesia. Repeated administration of high-dose L-dopa b.i.d. compared to once daily caused a frequency-related improvement of motor symptoms, resulting in a more rapid and initially more intense appearance of peak-dose dyskinesia. Administration of low-dose L-dopa b.i.d. for 26 days in combination with entacapone enhanced the increase in locomotor activity and reversal of disability produced by L-dopa alone, but with no obvious change in duration of L-dopa's effect. However, combining entacapone with L-dopa resulted in the more rapid appearance of dyskinesia, which was initially more severe than occurred with L-dopa alone. Importantly, increasing pulsatile exposure of brain to L-dopa by preventing its peripheral breakdown also increases dyskinesia induction.

Effect of Late Initiation of Levodopa Treatment in Patients With Long-Standing Parkinson's Disease

The time of initiation of levodopa therapy in patients with Parkinson's disease (PD) is still debatable, as is the hypothesis of levodopa toxicity Some researchers argue that late initiation of treatment will delay the appearance of response fluctuations. In the present study, 11 patients in whom treatment with low doses of levodopa was delayed for a mean of 7.9 +/- 3.1 years were followed for a mean of 15.7 +/- 3.3 years. Time of onset of response fluctuations and disease severity were compared with those in 17 patients with fluctuating PD who were treated with levodopa from disease onset. There was no significant change in time to onset of response fluctuations and dyskinesias once levodopa treatment was started, and late initiation of levodopa did not affect disease progression. The authors conclude that the decision of when to initiate levodopa treatment should be taken according to the patient's needs.

Treatment of Parkinson's disease: levodopa as the first choice

The introduction of levodopa in the 1960s revolutionised the treatment of Parkinson's disease (PD), and it continues to be the most effective symptomatic therapy. The vast majority of PD patients who start treatment with L-dopa experience good to excellent functional benefit. In vitro studies with high doses of L-dopa and absent glia had shown that it may be neurotoxic, but other tissue culture studies show L-dopa to be neuroprotective. Most studies in animal models and clinico-pathological and mortality studies in humans failed to show evidence in favour of accelerated dopaminergic neuronal loss with long-term L-dopa therapy.L-dopa continues to be beneficial throughout the course of PD, although as the disease progresses, escape of some symptoms from adequate control may occur and refractory disabilities such as impaired balance, dysarthria, cognitive decline and hallucinations may emerge. Treatment of advanced PD may also be complicated by the emergence of motor fluctuations and dyskinesias. Studies in animal models and in humans show that these motor complications are not specific to a particular dopaminergic agent, but that they are related both to the extent of the striatal lesion and to the mode of application of dopaminergic agents: Pulsatile administration of L-dopa and of the dopamine agonist apomorphine causes more motor complications than continuous striatal dopaminergic receptor stimulation, and continuous administration can alleviate existing dyskinesias and fluctuations. Several controlled studies comparing levodopa and dopamine agonists as initial treatment have attempted to answer the question whether delaying L-dopa therapy can reduce the occurrence of motor complications. Three medium-term (3-5 years) and one 10-year study showed less dyskinesia in the first five years of treatment in patients who had started therapy with a dopamine agonist. However, these studies also consistently showed that levodopa provided better functional improvement in the first years of treatment. Ten-year follow-up data in patients randomised to L-dopa or bromocriptine also showed a slightly lower incidence of motor complications in the bromocriptine arm. However, this difference was not significant for the clinically relevant moderate and severe forms of dyskinesias and fluctuations, and was achieved at the expense of significantly worse disability scores during the first years of therapy. Furthermore, the relative impact of motor disability and dyskinesias on patients' quality of life remains to be established. Concordance is essential in the optimum treatment of PD and patients should be informed of the various therapeutic options available. Treatment should respect individual patients' needs and take into account their particular functional disabilities and specific handicaps. Low-dose L-dopa therapy (up to 400 mg/day), however, remains the most effective initial treatment of choice for the majority of patients.

Parkinson's disease: medical treatment of moderate to advanced disease.

Parkinson's disease, a common neurodegenerative disorder, results in significant morbidity 10 to 15 years after disease onset and increased mortality. Levodopa is the mainstay of therapy and provides benefit for the duration of the illness. However, within 5 years, up to 50% of individuals develop fluctuations, including dyskinesias, wearing off, and "on/off" effects. Optimal management of Parkinson's disease patients requires careful titration of medications, with use of polypharmacy, including levodopa, dopamine agonists, catechol-O-methyltransferase inhibitors, amantadine, and anticholinergics in order to maintain good motor function and quality of life. With advancing disease, problems such as dysphagia, dysarthria, and gait and balance abnormalities occur, which are not responsive to dopaminergic medication. Due to extradopaminergic neuronal system degeneration, autonomic dysfunction can also be prominent. Recognition and management of these problems is helpful in improving quality of life in late-stage disease. In very late stages, dementia may complicate treatment, requiring discontinuation of combination therapy and use of low-dose levodopa with atypical neuroleptics.

Decreased phasic EMG activity during rapid eye movement sleep in treatment-naïve Parkinson's disease: effects of treatment with levodopa and progression of illness.

Rapid eye movement (REM) sleep behavior disorder (RBD) is frequently associated with Parkinson's disease (PD) and may anticipate its diagnosis by several years. We assessed the presence of motor dyscontrol during REM sleep in treatment-naïve PD patients and investigated the putative effect of levodopa (L-dopa) treatment on motor activity. Overnight sleep studies were performed on 15 previously untreated PD patients and 14 controls at baseline, again after a 3- to 9-month treatment period with a low dose of L-dopa, and 2 to 5 days after treatment discontinuation (in 8 patients). No differences in sleep parameters were observed across groups or treatment conditions. None of the patients met criteria for RBD at baseline, whereas 5 patients were symptomatic at the time of the second sleep study. A quantitative analysis of electromyographic (EMG) activity during REM sleep showed a lower phasic twitching activity in untreated PD than in controls. However, an increase in both phasic twitching and tonic activity was found after treatment with L-dopa. Discontinuation of treatment resulted in a return to pretreatment values of phasic but not of tonic EMG activity. Thus, the increase in phasic activity seems to depend on the effects of L-dopa, whereas the increase in tonic EMG activity during REM sleep might be caused by other factors such as the progression of disease. Potential implications for the understanding of the relationship between RBD and PD are discussed.

Persistent Behavioral Sensitization to Chronic l-DOPA Requires A2AAdenosine Receptors

To investigate the role of A(2A) adenosine receptors in adaptive responses to chronic intermittent dopamine receptor stimulation, we compared the behavioral sensitization elicited by repeated l-DOPA treatment in hemiparkinsonian wild-type (WT) and A(2A) adenosine receptor knock-out (A(2A) KO) mice. Although the unilateral nigrostriatal lesion produced by intrastriatal injection of 6-hydroxydopamine was indistinguishable between WT and A(2A) KO mice, they developed strikingly different patterns of behavioral sensitization after daily treatment with low doses of l-DOPA for 3 weeks. WT mice initially displayed modest contralateral rotational responses and then developed progressively greater responses that reached a maximum within 1 week and persisted for the duration of the treatment. In contrast, any rotational behavioral sensitization in A(2A) KO mice was transient and completely reversed within 2 weeks. Similarly, the time to reach the peak rotation was progressively shortened in WT mice but remained unchanged in A(2A) KO mice. Furthermore, daily l-DOPA treatment produced gradually sensitized grooming in WT mice but failed to induce any sensitized grooming in A(2A) KO mice. Finally, repeated l-DOPA treatment reversed the 6-OHDA-induced reduction of striatal dynorphin mRNA in WT but not A(2A) KO mice, raising the possibility that the A(2A) receptor may contribute to l-DOPA-induced behavioral sensitization by facilitating adaptations within the dynorphin-expressing striatonigral pathway. Together these results demonstrate that the A(2A) receptor plays a critical role in the development and particularly the persistence of behavioral sensitization to repeated l-DOPA treatment. Furthermore, they raise the possibility that the maladaptive dyskinetic responses to chronic l-DOPA treatment in Parkinson's disease may be attenuated by A(2A) receptor inactivation.

Antiparkinsonian activity and dyskinesia risk of ropinirole and L‐DOPA combination therapy in drug naive MPTP‐lesioned common marmosets (Callithrix jacchus)

De novo administration of long-acting dopamine agonists, such as ropinirole, to patients with Parkinson's disease or to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated subhuman primates produces a lower incidence of dyskinesia than occurs with L-DOPA. This study compares the intensity of dyskinesia produced by combinations of L-DOPA and ropinirole and by these drugs alone, using the MPTP-treated common marmoset model of Parkinson's disease. The objective is to determine the optimum therapeutic strategy for the long-term control of Parkinson's disease with a minimal risk of dyskinesia. MPTP-treated marmosets received either L-DOPA alone, ropinirole alone, or one of two combinations of these drugs (either L-DOPA dominant or ropinirole dominant) daily for 28 days in doses titrated to produce a similar improvement in disability and increase in locomotion. In the group receiving L-DOPA alone, there was a trend for peak dose locomotor activity to increase and the duration of drug effect to decline over the period of the study. L-DOPA alone induced marked dyskinesia over the period of treatment, in contrast to ropinirole which produced a low intensity of involuntary movements. The L-DOPA dominant combination initially produced little dyskinesia, but this became increasingly intense as the study progressed. In contrast, the ropinirole dominant combination produced no greater intensity of dyskinesia than was produced by ropinirole alone. These data suggest that in early Parkinson's disease, the use of ropinirole alone or in combination with a low-dose L-DOPA might delay the induction of dyskinesias while improving motor performance.

Pharmacological effects of cabergoline against parkinsonism

The pharmacological effects of cabergoline, a novel ergot alkaloid, against parkinsonism were assessed by comparing its effects with those of bromocriptine and pergolide. The affinities of cabergoline and pergolide for the D2 receptor were about the same, about 7 times stronger than that of bromocriptine. The affinity of each compound for the D1 receptor was markedly lower than its affinity for the D2 receptor. However, other data suggest that cabergoline and pergolide would have D1-receptor agonist activity, whereas bromocriptine would act as a D1-receptor antagonist. In MPTP-lesioned parkinsonian monkeys, cabergoline improved motor disability, and its effect lasted longer than those of bromocriptine and pergolide. Moreover, cabergoline induced no behavioral abnormalities even though at the highest dose used, in contrast to bromocriptine and pergolide, both of which induced hyperactivity. This beneficial effect of cabergoline did not attenuate on prolonged administration. Combined treatment with a low dose of L-dopa and a low dose of cabergoline improved motor disability without inducing the hyperactivity and dyskinesia seen during treatment with L-dopa alone at high doses. From these results, we suggest that cabergoline promises to be a useful anti-parkinsonian agent with a long lasting effect that survives prolonged administration and without the side effects induced by L-dopa.

Pharmacokinetic Optimisation of Dopamine Receptor Agonist Therapy for Parkinson??s Disease

Dopamine receptor agonists were originally developed as adjunctive therapies to ‘smooth out’ motor response fluctuations to levodopa in patients with advanced Parkinson’s disease. However, they are now used in the early stages of the disease, in monotherapy or combination with low doses of levodopa, to delay the onset of levodopa therapy and its complications. Oral dopamine agonists currently available worldwide for Parkinson’s disease include the older ergot derivatives bromocriptine and pergolide and the second generation non-ergoline compounds ropinirole and pramipexole. Other dopamine agonists that are used less frequently include cabergoline (a new ergoline drug, only recently released in some European countries as an antiparkinsonian drug), lisuride (an ergot derivative) and piribedil (an older non-ergot compound). Data on the pharmacokinetics of oral dopamine agonists, especially the older ergot derivatives, are scarce and mostly refer to small groups of healthy young individuals. All these agents, with the exception of pramipexole, are subject to extensive enterohepatic first-pass metabolism. Their bioavailability is low and shows high intra- and interindividual variability. The pharmacodynamic properties of dopamine agonists relevant to their antiparkinsonian effect have not been clearly defined. As a result, an optimal dosage schedule for the treatment of Parkinson’s disease is generally identified using highly individualised empirical assessment. This involves considerable time expenditure and creates difficulty for patients, who have to follow complex titration schedules. Dopamine agonists appear to have a low potential for pharmacokinetic interaction with levodopa. Few data have been reported on the effect of coadministration on the pharmacodynamics of levodopa. The available data indicate that pergolide and bromocriptine significantly increase the duration of the motor response to levodopa, while baseline motor effects and the magnitude of motor response are substantially unchanged. Cabergoline also significantly prolongs the motor response to a dose of levodopa in patients experiencing motor fluctuations, but baseline motor scores are also significantly improved, suggesting a long-lasting effect. Subcutaneous apomorphine is currently the only non-oral formulation of a dopamine agonist available; it is used as add-on rescue therapy for patients who have advanced Parkinson’s disease and a wide spectrum of complex motor, sensory, autonomic and cognitive ‘wearing-off ’ phenomena not controlled by optimal oral dopaminergic therapy. Attempts to deliver apomorphine and other soluble dopamine agonists by more practical non-oral routes, such as intranasally or transdermally, have so far been of limited clinical utility or are currently still under investigation.