Low Doses Of Levodopa Research Articles

Rapidly Progressive Dementia and Myoclonus

Back to table of contents Previous article Next article LetterFull AccessRapidly Progressive Dementia and MyoclonusEmmanuel Sagui, M.D., Michel Bregigeon, M.D., Christian Brosset, M.D., , Celine Tilignac, M.D., Jean Louis Kemeny, M.D., Pierre Clavelou, M.D., , and Jean Francois Pellissier, M.D., Emmanuel SaguiSearch for more papers by this author, M.D., Michel BregigeonSearch for more papers by this author, M.D., Christian BrossetSearch for more papers by this author, M.D., Hôpital Laveran, Marseille, France, Celine TilignacSearch for more papers by this author, M.D., Jean Louis KemenySearch for more papers by this author, M.D., Pierre ClavelouSearch for more papers by this author, M.D., Hôpital Frontmaure, Chamalières, France, and Jean Francois PellissierSearch for more papers by this author, M.D., Hôpital de la Timone, Marseille, FrancePublished Online:1 Aug 2000AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail SIR: Dementia with Lewy bodies (DLB) is a lately identified concept based on a clinical and pathological correlation: progressive disabling mental impairment with peculiar features such as hallucinations, fluctuating cognition or motor parkinsonism, and cortical with or without subcortical Lewy bodies.1 We report briefly two cases with unusual features of DLB.Case ReportsCase 1. A 74-year-old woman with no significant medical history but with depression 1 year ago began complaining of slowness of movements. Examination disclosed mild features of parkinsonism, including reduced armswing, rigidity, and bradykinesia, without resting tremor. Mini-Mental State Examination (MMSE) score was 30/30. Shortly after low doses of levodopa (150 mg) were given, parkinsonian features receded, but visual complex hallucinations arose. These hallucinations were not recognized as unreal and even worsened after levodopa was stopped or clozapine was given. Cognitive impairment appeared 7 months later. Hospitalization then occurred as myoclonus became evident. MMSE was 6/30, with perseveration and rigid-akinetic signs at examination. Decline was markedly rapid, and the patient died 8 months after the onset of the symptoms. Brain computed tomography (CT) revealed cerebral atrophy. EEG showed triphasic complexes without periodicity. 14-3-3 protein was not detected in the cerebrospinal fluid (CSF). Diffuse cortical Lewy bodies were found at autopsy.Case 2. A 72-year-old man with history of tobacco addiction and asbestosis presented with a 1-year history of progressive forgetfulness. Examination disclosed mild temporospatial confusion, dressing and ideomotor apraxia, and bilateral cogwheel rigidity. Language and attention were well preserved. Brain CT was normal. Six months later, the patient came to the hospital for cognitive impairment with shuffling gait. Examination showed akinesia and rigidity. MMSE was 9/30. Routine biological investigations were unrevealing, with no changes on brain CT. EEG showed slow left activities. Four months later, the patient was admitted to the hospital bedridden in the course of continuous and progressive decline. He was alert but unresponsive to voice. Examination disclosed rest myoclonus increased by noise, with no pyramidal features or focal signs. There was biological evidence of dehydration, with elevated natremia and creatinemia. CSF was germ-free, without pleocytosis. EEG showed slow delta activity without periodic discharges. The patient died 5 days after admission. Autopsy disclosed numerous senile plaques, neurofibrillary tangles, and cortical and subcortical Lewy bodies without spongiform changes.CommentBoth of these case reports are of particular interest because the patients evolved very rapidly to a fatal outcome (8 and 22 months) and had myoclonus in the late stage. Mean duration of DLB ranges from 5 to 8 years,2 although a 22-month duration has been described.3 Myoclonus is uncommon in DLB and was not mentioned in the first clinical descriptions.4,5 Although not excluded, it is not a feature essential to or supportive of the diagnosis of DLB.1 Myoclonus in patients with a rapidly progressive form of dementia raises the suspicion of Creutzfeldt-Jacob disease. Once a prion disease is ruled out, DLB should be considered in such patients.References1 McKeith IG, Galasko D, Kosaka K et al: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996; 47:1113–1124Google Scholar2 Gomez-Tortosa E, Ingraham AO, Irizarry MC, et al: Dementia with Lewy bodies. J Am Geriatr Soc 1998; 46:1449–1458Google Scholar3 Litvan I, McKee A: Clinicopathologic case report: dementia with Lewy bodies (DLB). J Neuropsychiatry Clin Neurosci 1999; 11:107–112Link, Google Scholar4 Ala TA, Yang KH, Sung JH, et al: Hallucinations and signs of parkinsonism help distinguish patients with dementia and cortical Lewy bodies from patients with Alzheimer's disease at presentation: a clinicopathological study. J Neurol Neurosurg Psychiatry 1997; 62:16–21Crossref, Medline, Google Scholar5 Kosaka K: Diffuse Lewy body disease in Japan. J Neurol 1990; 237:197–204Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited ByNone Volume 12Issue 3 August 2000Pages 412-412 Metrics PDF download History Published online 1 August 2000 Published in print 1 August 2000

Dystonia.

Therapy for most people with dystonia is symptomatic, directed at lessening the intensity of the dystonic contractions. For a small minority of patients (eg, those with dopa-responsive dystonia, Wilson's disease, or psychogenic dystonia), specific therapy directed at one of the many causes of dystonia is available. Before initiating treatment, clinicians need to decide if a patient has a form of dystonia amenable to such therapy. The most sensitive and least costly method to diagnose DRD is a therapeutic trial of levodopa. It is, therefore, recommended to treat all those with dystonia beginning in childhood or adolescence with low-dose levodopa. For patients with generalized or segmental signs who do not respond to levodopa, other oral medications, including anticholinergics, baclofen, and benzodiazepines, may provide mild to moderate relief; these medications are often given in combinations. For those with focal dystonia, most having adult-onset disease, botulinum toxin A injections often effectively control contractions. The injections produce transient weakness and need to be repeated, generally every 3 to 5 months. There is growing renewed interest in surgical treatment. Peripheral denervating procedures may be helpful for patients with torticollis who do not obtain adequate benefit with botulinum toxin A. The central procedures of pallidotomy and pallidal stimulation are under study; their place in the treatment of the many dystonia subtypes (eg, limb vs axial, generalized vs focal, primary vs secondary) still needs to be established. There are very few studies evaluating physical and psychological therapies or the impact of diet or lifestyle in dystonia. Most clinicians consider physical therapy, including massage, a potential adjunct to medical therapy, and psychological support and stress reduction may help individuals cope with this chronic and frequently disabling condition.

Combined Use of the Adenosine A2A Antagonist KW-6002 with [formula omitted]-DOPA or with Selective D1 or D2 Dopamine Agonists Increases Antiparkinsonian Activity but Not Dyskinesia in MPTP-Treated Monkeys

The novel selective adenosine A2A receptor antagonist KW-6002 improves motor disability in MPTP-treated parkinsonian marmosets without provoking dyskinesia. In this study we have investigated whether KW-6002 in combination with l-DOPA or selective D1 or D2 dopamine receptor agonists enhances antiparkinsonian activity in MPTP-treated common marmosets. Combination of KW-6002 with the selective dopamine D2 receptor agonist quinpirole or the D1 receptor agonist SKF80723 produced an additive improvement in motor disability. Coadministration of KW-6002 with a low dose of l-DOPA also produced an additive improvement in motor disability, and increased locomotor activity. The ability of KW-6002 to enhance antiparkinsonian activity was more marked with l-DOPA and quinpirole than with the D1 agonist. However, despite producing an enhanced antiparkinsonian response KW-6002 did not exacerbate l-DOPA-induced dyskinesia in MPTP-treated common marmosets previously primed to exhibit dyskinesia by prior exposure to l-DOPA. Selective adenosine A2A receptor antagonists, such as KW-6002, may be one means of reducing the dosage of l-DOPA used in treating Parkinson's disease and are potentially a novel approach to treating the illness both as monotherapy and in combination with dopaminergic drugs.

Tyrosine hydroxylase deficiency with severe clinical course: Clinical and biochemical investigations and optimization of therapy

Tyrosine hydroxylase deficiency was diagnosed after determination of cerebrospinal fluid neurotransmitters and DNA analysis in a child with severe axial hypotonia and hypokinesia associated with dystonic and ballistic movements. L-dopa therapy was unsuccessful, whereas a combination with selegiline, a selective monoamine oxidase-β inhibitor, with low-dose L-dopa markedly improved the severe clinical picture.

Putaminal necrosis presenting with hemidystonia

A 7-year-old female presented with putaminal necrosis associated with hemidystonia. Cranial magnetic resonance imaging revealed bilateral putaminal lesions appearing as hypointense signals on T 1-weighted images and hyperintense signals on T 2-weighted images. After a differential diagnosis of basal ganglial degeneration was made, putaminal necrosis was diagnosed. Low doses of levodopa (0.5 mg/kg daily) were administered, but her clinical signs worsened. Positron emission tomography scanning with [ 18F]-6-fluoro- l-dopa revealed asymmetric uptake and right-sided dominant decreases of [ 18F]-6-fluoro- l-dopa uptake of the putamen. On the basis of these findings, standard doses of levodopa (10 mg/kg daily) were administered, and her clinical signs improved. These results suggest that hemidystonia is associated with a disturbance of the dopamine system.

Four novel mutations in the Tyrosine Hydroxylase gene in patients with infantile parkinsonism

Mutation detection in the Tyrosine Hydroxylase gene (TH) was performed in patients from two families. DNA sequencing revealed the presence of four novel missense mutations (exon 9 and 14 in family A, exon 8 and 9 in family B); the mutations were confirmed with restriction enzyme analysis, and did not occur in control alleles. Three mutations are in the catalytic domain of the enzyme and one may disturb tetramerization. At the moment, all patients are in the fourth decade of life. For more than 30 years they have been able to live a normal life with low‐dose l‐DOPA medication.

Biochemical and Molecular Genetic Characteristics of the Severe Form of Tyrosine Hydroxylase Deficiency

Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of the catecholamines dopamine, norepinephrine, and epinephrine. Recently, mutations were identified in cases of autosomal recessive dopa-responsive dystonia and infantile parkinsonism. We describe a patient with severe symptoms and a new missense mutation in TH. Relevant metabolites in urine and cerebrospinal fluid were measured by HPLC with fluorometric and electrochemical detection. All exons of the TH gene were amplified by PCR and subjected to single-strand conformation polymorphism analysis. Amplimers displaying aberrant migration patterns were analyzed by DNA sequence analysis. The patient presented with severe axial hypotonia, hypokinesia, reduced facial mimicry, ptosis, and oculogyric crises from infancy. The major metabolite of dopamine, homovanillic acid, was undetectable in the patient's cerebrospinal fluid. A low dose of L-dopa produced substantial biochemical but limited clinical improvement. DNA sequencing revealed a homozygous 1076G-->T missense mutation in exon 10 of the TH gene. The mutation was confirmed with restriction enzyme analysis. It was not present in 100 control alleles. Secondary structure prediction based on Chou-Fasman calculations showed an abnormal secondary structure of the mutant protein. We describe a new missense mutation (1076G-->T, C359F) in the TH gene. The transversion is present in all known splice variants of the enzyme. It produces more severe clinical and biochemical manifestations than previously described in TH-deficient cases. Our findings extend the clinical and the biochemical phenotype of genetically demonstrated TH deficiency.

Restless Legs Syndrome.

With suitable pharmacotherapy, patients with any degree of restless legs syndrome (RLS) should be able to obtain substantial relief of symptoms. The best therapeutic success is attained when the physician tailors therapy to the patient's specific symptoms and can flexibly try a variety of agents, if needed. Therapy should be reserved for those in whom RLS cannot be managed with just sleep hygiene and related practices. It should not be withheld, however, if a patient reasonably believes that his or her quality of life is being impaired by RLS. The optimal initial approach to RLS in the general patient is usually the use of a dopaminergic agent: low-dose levodopa in milder cases, a dopamine agonist in more severe ones. Patients whose problems are primarily sleep related can initially be treated with a benzodiazepine. Patients who have symptoms primarily while awake can initially be treated with a dopaminergic agent or an opioid. Patients whose RLS discomfort is truly painful can initially be treated with gabapentin. Combination therapy with two or three agents from different classes can be useful as well. Determination of iron status is the most important initial laboratory evaluation in patients with RLS. Iron supplementation should be used as indicated. In the future, delivery modes other than oral administration of medications may be of significant benefit, especially in more severe cases.

Renal Effects of L-DOPA in Heart Failure

We examined whether low-dose L-DOPA treatment induces natriuresis and diuresis in patients with congestive heart failure who have cardiac decompensation despite treatment with digoxin, a diuretic, and an angiotensin-converting enzyme inhibitor and who respond acutely to intravenously infused dopamine. In a randomized, double-blind, placebo-controlled crossover study, 11 patients with severe congestive heart failure received L-DOPA (0.10 g, p.o., t.i.d., for 1 day and then 0.25 g, p.o., t.i.d., for 2 days after a washout period of > or = 1 day), with assessments of plasma and urinary levels of catechols, urinary volume, and sodium content, and clinical and laboratory measures of improvement of congestive heart failure. L-DOPA elicited short-term, dose-related increases in urinary volume and sodium excretion. At the 0.10-g dose, L-DOPA increased plasma L-DOPA levels and urinary L-DOPA excretion by about fivefold, whereas at the 0.25-g dose, L-DOPA increased plasma and urinary L-DOPA by >50-fold. Twenty-four-hour urinary dopamine excretion increased by about fivefold after the low dose of L-DOPA and approximately 50-fold after the high dose. The results demonstrate that oral L-DOPA treatment can produce beneficial natriuretic and diuretic effects in selected patients with congestive heart failure. The bioavailability of oral L-DOPA appears to vary with the dose. These results support findings from previous studies about beneficial cardiac functional effects of L-DOPA in patients with refractory heart failure.

Ropinirole: A dopamine agonist for the treatment of Parkinson’s disease

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, dosage and administration, and formulary considerations of ropinirole are reviewed. Ropinirole is a nonergoline dopamine agonist that binds to dopamine D2-receptors; the drug is indicated for use in the symptomatic treatment of early and late Parkinson's disease (PD). Ropinirole is rapidly absorbed after oral administration and undergoes extensive hepatic metabolism to active metabolites. The elimination half-life averages about six hours. Ropinirole has a low potential to interact with other drugs likely to be administered to PD patients. In patients with early PD, initial monotherapy with ropinirole was more effective than placebo or bromocriptine in the absence of selegiline and was as effective as bromocriptine in the presence of selegiline. Ropinirole was as effective as levodopa in patients with earlier stages of PD. In one subset of patients with advanced PD not adequately controlled by levodopa, adjunctive ropinirole was more effective than placebo and bromocriptine. Ropinirole was more effective than bromocriptine in patients previously given high-dose levodopa and was as effective in patients previously given low-dose levodopa or adjunctive dopamine agonist therapy. The most frequent adverse effects are nausea, somnolence, and dizziness; the dosage should be increased gradually to minimize adverse effects. Ropinirole is less expensive than bromocriptine and pergolide and similar in cost to pramipexole. Ropinirole appears to be a useful addition to existing therapeutic approaches to PD and is approved for both early and later stages of the disease.

Molecular genetics of dopa-responsive dystonia.

The causative genes of two types of hereditary dopa-responsive dystonia (DRD) due to dopamine (DA) deficiency in the nigrostriatum DA neurons have been elucidated. Autosomal dominant DRD (AD-DRD) was originally described by Segawa as hereditary progressive dystonia with marked diurnal fluctuation (HPD). We cloned the human GTP cyclohydrolase I (GCH1) gene, and mapped the gene to chromosome 14q22.1-q22.2 within the HPD/DRD locus, which had been identified by linkage analysis. GCH1 isthe rate-limiting enzyme for the biosynthesis of tetrahydrobiopterin (BH4), the cofactor for tyrosine hydroxylase (TH), which is the first and rate-limiting enzyme of DA synthesis. We proved that the GCH1 gene is the causative gene for HPD/DRD based on the identification of mutations of the gene in the patients and decreases in the enzyme activity expressed in mononuclear blood cells to 2-20% of the normal value. About 60 different mutations (missense, nonsense, and frameshift mutations) in the coding region or in the exon-intron junctions of the GCH1 gene have been reported in patients with AD-DRD all over the world. Recent findings indicate that the decreased GCH1 activity in AD-DRD may be caused by the negative interaction of the mutated subunit with the wild-type one, i.e., a dominant negative effect, and/or by decreases in the levels of GCH1 mRNA and protein caused by inactivation of one allele of the GCH1 gene. Autosomal recessive DRD (AR-DRD) with Segawa's syndrome was discovered in Germany. The AR-DRD locus was mapped to chromosome 11p15.5 in the chromosomal site of the TH gene. In the AR-DRD with Segawa's syndrome, a point mutation in TH (Gln381Lys) resulted in a pronounced decrease in TH activity to about 15% of that of the wild type. Several missense mutations in the TH gene have been found in AR-DRD in Europe. The phenotype of AR-DRD with the Leu205Pro mutation in the TH gene, which produces a severe decrease in TH activity to 1.5% of that of the wild type, was severe, not dystonia/Segawa's syndrome, but early-onset parkinsonism. However, a marked improvement of all clinical symptoms with a low dose of L-dopa was reported in AR-DRD/parkinsonism patients. These findings on DRD indicate that the nigrostriatal DA neurons may be most susceptible to the decreases in GCH1 activity, BH4 level, TH activity, and DA level, and that DRD is the DA deficiency without neuronal death in contrast to juvenile parkinsonism or Parkinson's disease with DA cell death.

Amantadine reduces levodopa-induced dyskinesias in parkinsonian monkeys.

The antidyskinetic potential of the glutamate NMDA receptor channel blocker amantadine was evaluated in four levodopa-primed parkinsonian monkeys using two different regimens (1.25 or 2.5 mg/kg administered subcutaneously twice daily for 3-6 days). When administered with a relatively low dose of levodopa, amantadine produced a near-total suppression of choreiform dyskinesias and a substantial reduction in dystonic dyskinesias at the expense of a significant reduction in antiparkinsonian response. With a high dose of levodopa, amantadine had a smaller but still significant effect on dyskinesias without altering the antiparkinsonian response. These results lend support to the view that glutamate receptor-mediated mechanisms contribute to levodopa-induced dyskinesias. They also suggest that amantadine could alleviate such complications in parkinsonian patients, especially with careful dose optimization.

Early introduction of dopamine agonists in the long-term treatment of Parkinson's disease.

Recent efforts in treatment of Parkinson's disease (PD) have focused on the development of agents or strategies that suppress or delay disease progression and levodopa-induced adverse reactions. In the past decade, many reports have demonstrated advantages of the early introduction of a dopamine (DA) agonist or early combination therapy with a DA agonist and levodopa. In the search for available clinical information, most long-term studies of early treatment with a DA agonist have used bromocriptine. Although DA agonist monotherapy is effective for a majority of patients for a year or less, only a small proportion of patients (approximately 10%) obtain benefits for as long as 4-5 years. Those patients on long-term monotherapy with a DA agonist exhibited a few or no adverse reactions, such as the wearing-off phenomenon or dyskinesia. DA agonist monotherapy may avoid unnecessary levodopa administration to the special subpopulation of PD patients who have very slowly progressing disease and who can be maintained for the long-term on DA agonist monotherapy. In contrast to the high incidence of adverse reactions in patients receiving high-dose levodopa monotherapy, many trials have demonstrated that early combination therapy for PD using partial substitution of levodopa by bromocriptine can inhibit the development of motor fluctuations and/or dyskinesia. In these trials, good symptomatic effects with few adverse reactions were achieved by >25% substitution of levodopa by bromocriptine. In addition, in patients receiving bromocriptine plus levodopa therapy, disease progression appeared to be slowed for a few years. Although the mechanism by which the action of DA agonists combined with levodopa remains to be clarified, the lower incidence of levodopa-related adverse reactions in patients receiving early combination therapy suggests that continued use of a DA agonist is beneficial for patients with PD. In summary, because levodopa-induced adverse reactions can be reduced by combined use of a DA agonist with low-dose levodopa, introduction of a DA agonist at an early stage of PD, or with restricted use of additional levodopa, may be useful for long-term treatment of PD.

Advances in the treatment of Parkinson's disease.

Pharmacological treatment of Parkinson's disease has been advanced by a better understanding of how to use currently existing drugs as well as by the introduction of newer drugs. Three new dopaminergic agonists, ropinirole, pramipexole and cabergoline, have been introduced recently for the treatment of Parkinson's disease. A new class of drugs, COMT inhibitors, such as tolcapone, also have been introduced into clinical practice. These drugs extend the effect of levodopa therapy. The results of clinical trials such as the 5-year Sinemet study indicate that low-dose levo-dopa therapy can control motor symptoms up to 5 years with the minimal prevalence of adverse reactions. Pharmacology, efficacy and adverse reactions of these compounds will be discussed as well as their place in the treatment of Parkinson's disease.

Pharmacological effects of dopaminergic drugs on in vivo binding of [99mTc]TRODAT-1 to the central dopamine transporters in rats.

The purpose of this study was to investigate the influence of drugs competing for the dopamine transporter (DAT) or changing intra- and/or extracellular dopamine levels on the binding of a novel technetium-99m labeled tropane derivative, technetium, [2-[[2-[[[3-(4-chloro- phenyl)-8-methyl-8-azabicyclo[3, 2, 1]oct-2-yl]methyl] (2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3)]-oxo-[1R-(exo -exo)]-, [99mTc]TRODAT-1, to DAT. This paper describes the further characterization of [99mTc]TRODAT-1 binding sites in rats under conditions which may exist in patients receiving various drug treatments. All experiments were carried out using an i.v. injection of [99mTc]TRODAT-1 into male Sprague-Dawley rats. Measurements of % dose/gram ratio of (striatum-cerebellum)/cerebellum at 1 h post injection were used as an indicator for specific DAT binding. The biodistribution studies were performed in the presence of drugs which compete for the binding site, such as CFT (WIN 35,428) and methylphenidate, drugs which influence dopamine levels, such as L-DOPA, gamma-hydroxybutyrolactone, and alpha-methyl-p-tyrosine, and d-amphetamine, which both acts as a competitor for DAT binding and increases dopamine levels. Additionally, the influence of dopamine receptor agonists, such as apomorphine and (+)bromocriptine, on biodistribution was tested. Binding of [99mTc]TRODAT-1 to DAT was found to be inhibited by CFT, methylphenidate, and d-amphetamine in a dose-dependent manner. The specific binding of [99mTc]TRODAT-1 was not altered by dopamine receptor agonists or by drugs which cause minor changes in dopamine levels. When administered in high doses (634 micromol/kg), L-DOPA also decreased the binding of [99mTc]TRODAT-1. It is likely that a low dose of L-DOPA (normally needed in the treatment of Parkinson's disease) will not affect the results on [99mTc]TRODAT-1 single-photon emission tomographic (SPET) imaging studies. In conclusion, the results clearly demonstrate the specificity of [99mTc]TRODAT-1 binding to DAT in vivo. Competition for [99mTc]TRODAT-1 binding was observed only with drug treatment that significantly increases dopamine levels or actively competes for binding at DAT. The results suggest that prior knowledge of whether patients are receiving various drug treatments may assist in the interpretation of DAT status as assessed by SPET imaging studies using [99mTc]TRODAT-1.

Positron emission tomography (PET) measurements of striatal D2 receptors in untreated Parkinson's disease patients with follow-up after 6 and 12 months' treatment with SINEMET® or SINEMET® CR

Untreated Parkinson's disease (FD) patients typically demonstrate an upregulation in striatal D(2) receptor binding. Reduced D(2) binding is found in levodopa-treated patients with a fluctuating response to this drug. Using PET and (11)C-raclopride, we determined striatal:background uptake ratios to provide a measure of D(2) receptor binding in 10 untreated, newly diagnosed PD patients who were treated subsequently with levodopa for 1 yr. At baseline, we found increased striatal D(2) receptor uptake ratios in patients (3.89) in comparison to normal controls (3.22; p < 0.02). Furthermore, the ratio between caudate and putamen D(2) uptake was significantly reduced in patients (0.86 vs. 0.98 in normals, p < 0.01). Patients were subsequently randomized to treatment with either SINEMET((R)) (300 mg of levodopa/d) or SINEMET((R)) CR (400 mg of levodopa/d). Patients in both groups received similar symptomatic benefit following treatment, and none developed motor fluctuations. All patients were rescanned after 6 months of treatment. There were no significant differences in striatal (or caudate and putamen considered singly) raclopride binding between the first and 6 month post-treatment scans. Similarly, there were no significant differences between pre- and 6 month post-treatment scans on the basis of levodopa preparations. Patients were subsequently treated with the other Sinemet preparation for another 6 month period before rescanning. Again, no differences in raclopride binding were found compared to pre-treatment or between type of levodopa preparation. We conclude that there is no evidence for downregulation of D(2) receptor binding after 1 yr of low-dose levodopa therapy in patients who receive symptomatic benefit without motor fluctuations, regardless of type of preparation. Follow-up of such individuals may permit determination of when and in what context D(2) receptor downregulation occurs.

Combined effects of cabergoline and L-dopa on parkinsonism in MPTP-treated cynomolgus monkeys.

The behavioral effects of L-dopa or cabergoline alone were compared with those of the joint administration of the two drugs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys with attention to the induction of hyperactivity and dyskinesia. Cabergoline alone at 0.2 mg/kg or less improved in a dose-dependent fashion the parkinsonism without inducing hyperactivity and dyskinesia following a single subcutaneous injection. L-dopa alone improved the parkinsonism, but induced hyperactivity and dyskinesia, depending on the dose applied. Doses required for 50% amelioration by L-dopa and cabergoline were 10 and 0.038 mg/kg, s.c., respectively. With low doses (50%-amelioration doses), cabergoline or L-dopa alone improved the parkinsonism without induction of hyperactivity and dyskinesia, but the duration of action was brief. Cabergoline in combination with L-dopa was highly effective in improving motor disability without induction of hyperactivity and dyskinesia. Moreover, the duration of action was more prolonged with the coadministration than with the single administration of each drug. These findings suggest that the combined therapy with low doses of L-dopa and cabergoline is beneficial for treating patients with advanced Parkinson's disease.

Behavioral and neurochemical effects induced by chronic L-DOPA administration

L-DOPA, in combination with benserazide, in the ratio 4:1 (w/w), was administered orally to rats. In the staircase maze test a low dose of L-DOPA (3 mg/kg/day) reduced the increase in errors caused by 20 days interruption of daily training, while a higher dose (30 mg/kg/day) was ineffective. A decrease in levels of dopamine in the olfactory system and DOPAC in the striatum was seen at all tested doses of L-DOPA, while an increase in 5-HT levels was seen in the hippocampus and in the striatum. 5-HIAA levels did not change. Levels of ACh in the olfactory system were reduced at all doses of L-DOPA, while in the hippocampus this effect was seen only at the dose of 90 mg/kg/day. The density of muscarinic receptors was not altered. AI1 tested doses of L-DOPA caused norepinephrine levels to fall in the hippocampus and increase in the striatum. The density of α 1-adrenoceptors was reduced only at the two lower doses of L-DOPA. A comparison of the neurochemical results with the behavioral modifications seen in the staircase maze test suggests that the catecolaminergic systems are implicated in the memory process.

Effect of Levodopa and Carbidopa on Recovery of Visual Function in Patients With Nonarteritic Anterior Ischemic Optic Neuropathy of Longer Than Six Months' Duration

We conducted a pilot clinical trial to determine the efficacy of levodopa in promoting visual recovery in eyes with nonarteritic anterior ischemic optic neuropathy of greater than six months' duration. This prospective, randomized, double-masked, placebo-controlled clinical trial involved 20 subjects with nonarteritic anterior ischemic optic neuropathy of 30 months' mean duration. Subjects were randomly assigned to receive either low-dose levodopa and carbidopa or a placebo for three weeks. At 12 weeks after the baseline visit, the levodopa group then was provided a higher, conventional dose of levodopa and carbidopa for three more weeks. Change in visual function was monitored at four, 12, 16, and 24 weeks after the baseline visit. At 12 weeks after the baseline visit, the levodopa group experienced a significant (P = .016) mean difference in improvement of visual acuity of 5.9 letters from the placebo group. At 24 weeks after the baseline visit, a significant treatment effect (P = .036) for visual acuity was still evident; the levodopa group had a mean gain in improvement of 7.5 letters difference from baseline from the placebo group. Three subjects in the levodopa group experienced a doubling of the visual angle as denoted by a gain of at least 15 letters. Significant improvement was not observed for color vision (P = .82) or mean deviation of visual field loss (P = .82). The study found significant improvement of visual acuity among subjects receiving levodopa and carbidopa despite long-standing visual loss from nonarteritic anterior ischemic neuropathy. Confirmation of our results is awaited from larger population studies and with a longer follow-up time interval regarding the efficacy of levodopa in reversing visual loss in this disease.

Effect of the competitive NMDA antagonist, CGP 40 116, and a low dose of l-Dopa on the motor activity deficit of MPTP-treated mice.

Three experiments were performed to investigate the effects of combining the active D-stereoisomer of CGP 37 849, i.e. the glutamatergic antagonist, CGP 40 116, with l-dopa, in mice that had undergone treatment with the neurotoxin, MPTP. In the first experiment, the decreased motor activity in MPTP-treated mice was alleviated by the administration of a low dose of l-dopa (5mg/kg, s.c.) together with a low dose of CGP 40 116 (30µg/kg). This dose was inactive in the control (saline-treated) mice. The highest dose of CGP 40 116 used (3000µg/kg) stimulated activity in the control mice. In Experiment 2, the inactive L-stereoisomer, i.e., CGP 40 117, was found to be inactive at doses (3 and 30µg/kg) effective with CGP 40 116. The effects of CGP 40 116 and l-dopa on the 24-h activity of mice tested under either day-night or night-day conditions, were more marked and longer lasting in the night-day condition. Taken together, the results from all three experiments show that CGP 40 116 in a dose range of 1-30µg/kg in combination with l-dopa (5mg/kg, s.c.) alleviated the reduced motor activity in MPTP-treated mice whereas higher doses of CGP 40 116 (100, 300, or 3000µg/kg) or lower doses (0.1 and 0.3µg/kg) were without effect. These experiments are interpreted as support for current views on glutamatergic-dopaminergic interactions in Parkinsonism and offer further evidence for the MPTP mouse model of the disease.