Levodopa therapy for Parkinson's disease: Pharmacokinetics and pharmacodynamics

LeWitt, Peter A.

doi:10.1002/mds.26082

Cited by 273 publications

(235 citation statements)

References 71 publications

(78 reference statements)

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“…Current therapeutic approaches rely upon levodopa and dopamine agonists. Levodopa, the precursor of dopamine moves across the BBB and combines with the peripherally-acting decarboxylase inhibitors such as benserazid and carbidopa to ensure its bioavailability in the CNS and thereby its clinical effectiveness in patients (161). However, it does not relieve other disabling symptoms of PD possibly derived from alterations in other neurotransmitter systems, such as cholinergic, noradrenergic, and serotonergic systems (162, 163).…”

Section: Clinical Aspects Of Dopaminergic Therapymentioning

confidence: 99%

“…Even though the pharmacokinetic profile of levodopa is often blamed as the source of these complications, the exact cause is still far from understood (167). With conventional formulation of L-DOPA, irregular absorption and rapid catabolism are the basis of these long-term complications, which triggered the development of various other techniques including sustained-release oral formulations (161). Even though the correlation between L-DOPA therapy and the occurrence of long-term side effects was apparently stated as essential in many studies, the recent view considers the clinical phenotype and the individualized course as an even more important factor (168).…”

Section: Clinical Aspects Of Dopaminergic Therapymentioning

confidence: 99%

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Deep Brain Stimulation and L-DOPA Therapy: Concepts of Action and Clinical Applications in Parkinson's Disease

et al. 2018

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L-DOPA is still the most effective pharmacological therapy for the treatment of motor symptoms in Parkinson's disease (PD) almost four decades after it was first used. Deep brain stimulation (DBS) is a safe and highly effective treatment option in patients with PD. Even though a clear understanding of the mechanisms of both treatment methods is yet to be obtained, the combination of both treatments is the most effective standard evidenced-based therapy to date. Recent studies have demonstrated that DBS is a therapy option even in the early course of the disease, when first complications arise despite a rigorous adjustment of the pharmacological treatment. The unique feature of this therapeutic approach is the ability to preferentially modulate specific brain networks through the choice of stimulation site. The clinical effects have been unequivocally confirmed in recent studies; however, the impact of DBS and the supplementary effect of L-DOPA on the neuronal network are not yet fully understood. In this review, we present emerging data on the presumable mechanisms of DBS in patients with PD and discuss the pathophysiological similarities and differences in the effects of DBS in comparison to dopaminergic medication. Targeted, selective modulation of brain networks by DBS and pharmacodynamic effects of L-DOPA therapy on the central nervous system are presented. Moreover, we outline the perioperative algorithms for PD patients before and directly after the implantation of DBS electrodes and strategies for the reduction of side effects and optimization of motor and non-motor symptoms.

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Section: Clinical Aspects Of Dopaminergic Therapymentioning

confidence: 99%

Section: Clinical Aspects Of Dopaminergic Therapymentioning

confidence: 99%

Deep Brain Stimulation and L-DOPA Therapy: Concepts of Action and Clinical Applications in Parkinson's Disease

et al. 2018

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“…To date, L-dopa is the most effective drug for treating the signs and symptoms of Parkinson's disease (PD) and is still considered the standard therapeutic agent 1,2 . However, after several years of treatment, L-dopa-induced dyskinesia (LID) occurs in the majority of patients 1,[3][4][5] .…”

Section: Introductionmentioning

confidence: 99%

Validation of a New Scoring Scale for Behavioral Assessment of L-Dopa-Induced Dyskinesia in the Rat: A New Tool for Early Decision-Making in Drug Development

Loiodice¹,

Denibaud²,

Deffains³

et al. 2017

ACS Chem. Neurosci.

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The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated non-human primate (NHP) has been described as the most translatable model for experimental reproduction of L-dopa-induced dyskinesia (LID). However, from a drug discovery perspective, the risk associated with investment in this type of model is high due to the time and cost. The 6-hydroxydopamine (6-OHDA) rat dyskinesia model is recommended for testing compounds but relies on onerous, and non-standard behavioral rating scales. We sought to develop a simplified and sensitive method aiming at assessing LID in the rat. The purpose was to validate a reliable tool providing earlier insight into the antidyskinetic potential of compounds in a time/cost-effective manner before further investigation in NHP models.Unilaterally 6-OHDA-lesioned rats were administered L-dopa (20 mg/kg) and benserazide (5 mg/kg) daily for 3 weeks starting 4 weeks post-lesion, then co-administered with amantadine (20-30-40 mg/kg). An adapted rating scale was used to score LID frequency and a severity coefficient was applied depending on the features of the observed behavior.A gradual increase (about 3-fold) in LID score was observed over the 3 weeks of L-dopa treatment.The rating scale was sensitive enough to highlight a dose-dependent amantadine-mediated decrease (about 2.2-fold) in LID score.We validated a simplified method, able to reflect different levels of severity in the assessment of LID and, thus, provide a reliable tool for drug discovery.

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“…Chronic use of the dopamine (DA) precursor l -3,4-dihydroxyphenylalanine ( l -DOPA) for effective noninvasive treatment of Parkinson's disease (LeWitt 2015) induces abnormal involuntary motor movements known as l -DOPA-induced dyskinesia (LID). In mice, these abnormal involuntary movements appear in the limbs as hyperkinetic and jerky stepping movements of the forelimbs or small circular movements of the forelimb to and from the snout.…”

Section: Introductionmentioning

confidence: 99%

Human COMT over-expression confers a heightened susceptibility to dyskinesia in mice

Solís

García-Montes

García‐Sanz

et al. 2017

Neurobiology of Disease

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Catechol-O-methyltransferase (COMT) degrades dopamine and its precursor L-DOPA and plays a critical role in regulating synaptic dopamine actions. We investigated the effects of heightened levels of COMT on dopamine-regulated motor behaviors and molecular alterations in a mouse model of dyskinesia. Transgenic mice overexpressing human COMT (TG) and their wildtype (WT) littermates received unilateral 6-OHDA lesions in the dorsal striatum and were treated chronically with L-DOPA for two weeks. L-DOPA-induced dyskinesia was exacerbated in TG mice without altering L-DOPA motor efficacy as determined by contralateral rotations or motor coordination. Inductions of FosB and phospho-acetylated histone 3 (molecular correlates of dyskinesia) were potentiated in the lesioned striatum of TG mice compared with their WT littermates. The TG mice had lower basal levels of dopamine in the striatum. In mice with lesions, L-DOPA induces a greater increase in the dopamine metabolite 3-methoxytyramine in the lesioned striatum of dyskinetic TG mice than in WT mice. The levels of serotonin and its metabolite were similar in TG and WT mice. Our results demonstrate that human COMT overexpression confers a heightened susceptibility to L-DOPA-induced dyskinesia and alters molecular and neurochemical responses in the lesioned striatum of mice.

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Levodopa therapy for Parkinson's disease: Pharmacokinetics and pharmacodynamics

Cited by 273 publications

References 71 publications

Deep Brain Stimulation and L-DOPA Therapy: Concepts of Action and Clinical Applications in Parkinson's Disease

Deep Brain Stimulation and L-DOPA Therapy: Concepts of Action and Clinical Applications in Parkinson's Disease

Validation of a New Scoring Scale for Behavioral Assessment of L-Dopa-Induced Dyskinesia in the Rat: A New Tool for Early Decision-Making in Drug Development

Human COMT over-expression confers a heightened susceptibility to dyskinesia in mice

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