The effects of L-threo-3,4-dihydroxyphenylserine on the total norepinephrine and dopamine concentrations in the cerebrospinal fluid and freezing gait in parkinsonian patients

Tohgi, Hideo; Abe, Takashi; Takahashi, Satoshi

doi:10.1007/bf02260912

Cited by 62 publications

(47 citation statements)

References 18 publications

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“…Beneficial effects on freezing, gait impairment, retropulsion, and postural instability were noted in small, poorly controlled studies. 93,94 Pending further evidence, there is presently no place for L-threo-DOPS or other nondopaminergic compounds in daily clinical practice. …”

Section: Treatment Drug Treatmentmentioning

confidence: 99%

Falls and freezing of gait in Parkinson's disease: A review of two interconnected, episodic phenomena

et al. 2004

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Falls and freezing of gait are two "episodic" phenomena that are common in Parkinson's disease. Both symptoms are often incapacitating for affected patients, as the associated physical and psychosocial consequences have a great impact on the patients' quality of life, and survival is diminished. Furthermore, the resultant loss of independence and the treatment costs of injuries add substantially to the health care expenditures associated with Parkinson's disease. In this clinically oriented review, we summarise recent insights into falls and freezing of gait and highlight their similarities, differences, and links. Topics covered include the clinical presentation, recent ideas about the underlying pathophysiology, and the possibilities for treatment. A review of the literature and the current state-of-the-art suggests that clinicians should not feel deterred by the complex nature of falls and freezing of gait; a careful clinical approach may lead to an individually tailored treatment, which can offer at least partial relief for many affected patients.

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Section: Treatment Drug Treatmentmentioning

confidence: 99%

Falls and freezing of gait in Parkinson's disease: A review of two interconnected, episodic phenomena

et al. 2004

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“…Other agents that are being considered as nondopaminergic PD therapeutics include modulators of the noradrenergic system. In small open-label studies, the epinephrine precursor L-threo-DOPS was found to have beneficial effects on freezing and gait disturbances in PD patients (Tohgi et al, 1993;Giladi, 2008;Devos et al, 2010). Furthermore, methylphenidate, a mixed dopamine and noradrenaline reuptake inhibitor, was found to show benefit on gait and freezing scores in a randomized controlled trial of 17 advanced PD patients , but results of a more recent trial in 27 PD patients revealed that methylphenidate did not improve gait and tended to worsen measures of motor functions, sleepiness, and quality of life (Espay et al, 2011).…”

Section: Non-dopaminergic Therapiesmentioning

confidence: 99%

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Smith

Wichmann

Factor

et al. 2011

Neuropsychopharmacol

194

137

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The demonstration that dopamine loss is the key pathological feature of Parkinson's disease (PD), and the subsequent introduction of levodopa have revolutionalized the field of PD therapeutics. This review will discuss the significant progress that has been made in the development of new pharmacological and surgical tools to treat PD motor symptoms since this major breakthrough in the 1960s. However, we will also highlight some of the challenges the field of PD therapeutics has been struggling with during the past decades. The lack of neuroprotective therapies and the limited treatment strategies for the nonmotor symptoms of the disease (ie, cognitive impairments, autonomic dysfunctions, psychiatric disorders, etc.) are among the most pressing issues to be addressed in the years to come. It appears that the combination of early PD nonmotor symptoms with imaging of the nigrostriatal dopaminergic system offers a promising path toward the identification of PD biomarkers, which, once characterized, will set the stage for efficient use of neuroprotective agents that could slow down and alter the course of the disease.

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“…From preclinical and clinical studies involving measurements of plasma and CSF levels of NE and metabolites after systemic L-DOPS administration, it appears that relatively little of circulating L-DOPS enters the central nervous system unchanged (40,103). In rats, L-DOPS has only about 1/4 the ability of L-DOPA to traverse the blood-brain barrier (48), and the amount of increase of central NE by L-DOPS is actually less than that from L-DOPA.…”

Section: Clinical Pharmacokinetics and Metabolic Fate Of L-dopsmentioning

confidence: 99%

“…In rats, L-DOPS has only about 1/4 the ability of L-DOPA to traverse the blood-brain barrier (48), and the amount of increase of central NE by L-DOPS is actually less than that from L-DOPA. In humans, CSF levels of NE do increase, especially in patients treated concurrently with carbidopa (103,104).…”

Section: Clinical Pharmacokinetics and Metabolic Fate Of L-dopsmentioning

confidence: 99%

“…In the late 1980s there was a flurry of research activity on the potential usefulness of L-DOPS in these areas. Several small, uncontrolled clinical trials or case reports supported benefit of L-DOPS to treat freezing of gait, dysarthria, or depressed mood (75,79,103,109). Clinical research on these topics was presented at a Satellite Symposium of the Tenth International Symposium on Parkinson's Disease, in Tokyo in 1991, and the Proceedings of the Symposium were published in the volume,…”

Section: Clinical Use Parkinson's Diseasementioning

confidence: 99%

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L‐Dihydroxyphenylserine (L‐DOPS): A Norepinephrine Prodrug

Goldstein

2006

Cardiovascular Drug Reviews

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L-threo-3,4-dihydroxyphenylserine (L-DOPS, droxydopa) is a synthetic catecholamino acid. When taken orally, L-DOPS is converted to the sympathetic neurotransmitter, norepinephrine (NE), via decarboxylation catalyzed by L-aromatic-amino-acid decarboxylase (LAAAD). Plasma L-DOPS levels peak at about 3 h, followed by a monoexponential decline with a half-time of 2 to 3 h. Plasma levels of NE and of its main neuronal metabolite, dihydroxyphenylglycol (DHPG) peak approximately concurrently but at much lower concentrations. The relatively long half-time for disappearance of L-DOPS from plasma, compared to that of NE, explains their very different attained plasma concentrations. In patients with neurogenic orthostatic hypotension, L-DOPS increases blood pressure and ameliorates orthostatic intolerance. Inhibition of LAAAD, such as by treatment with carbidopa, which does not penetrate the blood-brain barrier, prevents the blood pressure effects of the drug, indicating that L-DOPS increases blood pressure by augmenting NE production outside the brain. Patients with pure autonomic failure (which usually entails loss of sympathetic noradrenergic nerves), and patients with multiple system atrophy (in which noradrenergic innervation remains intact) have similar plasma NE responses to L-DOPS. This suggests mainly non-neuronal production of NE from L-DOPS. L-DOPS is very effective in treatment of deficiency of dopamine-beta-hydroxylase (DBH), the enzyme required for conversion of dopamine to NE in sympathetic nerves. L-DOPS holds promise for treating other much more common conditions involving decreased DBH activity or NE deficiency, such as a variety of syndromes associated with neurogenic orthostatic hypotension.

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The effects of L-threo-3,4-dihydroxyphenylserine on the total norepinephrine and dopamine concentrations in the cerebrospinal fluid and freezing gait in parkinsonian patients

Cited by 62 publications

References 18 publications

Falls and freezing of gait in Parkinson's disease: A review of two interconnected, episodic phenomena

Falls and freezing of gait in Parkinson's disease: A review of two interconnected, episodic phenomena

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

L‐Dihydroxyphenylserine (L‐DOPS): A Norepinephrine Prodrug

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