Intravenous levodopa administration in humans based on a two-compartment kinetic model

Gordon, Mollie; Markham, Joanne; Hartlein, Johanna; Koller, Jonathan M.; Loftin, Susan K.; Black, Kevin J.

doi:10.1016/j.jneumeth.2006.07.010

Cited by 12 publications

(14 citation statements)

References 45 publications

(52 reference statements)

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“…The intravenous levodopa infusion was dosed so as to rapidly produce and then maintain a steady plasma concentration of 600ng/ml (Gordon et al, 2007). The infusion was delivered through small-bore light-resistant Luer lock tubing (part #537235PS, Medex, Dublin, OH) from a Model 44 syringe pump (Harvard Apparatus, Holliston, MA) inside an RF-shielded copper box (Shielding Resources Group, Inc., Tulsa, OK).…”

Section: Methodsmentioning

confidence: 99%

Quantification of Indirect Pathway Inhibition by the Adenosine A_2aAntagonist SYN115 in Parkinson Disease

Black¹,

Koller²,

Campbell³

et al. 2010

J. Neurosci.

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Adenosine A 2a receptor antagonists reduce symptom severity in Parkinson disease (PD) and animal models. Rodent studies support the hypothesis that A 2a antagonists produce this benefit by reducing the inhibitory output of the basal ganglia indirect pathway. One way to test this hypothesis in humans is to quantify regional pharmacodynamic responses with cerebral blood flow (CBF) imaging. That approach has also been proposed as a tool to accelerate pharmaceutical dose finding, but has not yet been applied in humans to drugs in development. We successfully addressed both these aims with a perfusion magnetic resonance imaging (MRI) study of the novel adenosine A 2a antagonist SYN115. During a randomized, double-blind, placebo-controlled, crossover study in 21 PD patients on levodopa but no agonists, we acquired pulsed arterial spin labeling MRI at the end of each treatment period. SYN115 produced a highly significant decrease in thalamic CBF, consistent with reduced pallidothalamic inhibition via the indirect pathway. Similar decreases occurred in cortical regions whose activity decreases with increased alertness and externally focused attention, consistent with decreased self-reported sleepiness on SYN115. Remarkably, we also derived quantitative pharmacodynamic parameters from the CBF responses to SYN115. These results suggested that the doses tested were on the low end of the effective dose range, consistent with clinical data reported separately. We conclude that (1) SYN115 enters the brain and exerts dose-dependent regional effects, (2) the most prominent of these effects is consistent with deactivation of the indirect pathway as predicted by preclinical studies; and (3) perfusion MRI can provide rapid, quantitative, clinically relevant dose-finding information for pharmaceutical development.

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Section: Methodsmentioning

confidence: 99%

Quantification of Indirect Pathway Inhibition by the Adenosine A_2aAntagonist SYN115 in Parkinson Disease

Black¹,

Koller²,

Campbell³

et al. 2010

J. Neurosci.

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“…The present study provides preliminary data for a novel approach to testing presynaptic dopamine release using levodopa, the body’s natural synthetic precursor to dopamine. Exogenous levodopa boosts dopamine synthesis almost immediately in both parkinsonian and healthy brains [reviewed in 12 ]. The extra dopamine is rapidly released at the synapse in people with DA deficiency 13 , and there is evidence that this happens also in the non-parkinsonian brain.…”

Section: Introductionmentioning

confidence: 99%

“…, CNS-mediated effects 14 – 16 . Additional evidence for levodopa-induced synaptic DA release in the non-parkinsonian brain is reviewed in 12 . When given after an adequate dose of carbidopa, which prevents conversion to dopamine but does not cross the blood-brain barrier, systemic levodopa administration essentially delivers dopamine selectively to the brain, as confirmed by the fact that it does not alter quantitative whole-brain blood flow 17 – 19 , as dopamine would if it were being delivered systemically or produced outside the brain.…”

Section: Introductionmentioning

confidence: 99%

“…When given after an adequate dose of carbidopa, which prevents conversion to dopamine but does not cross the blood-brain barrier, systemic levodopa administration essentially delivers dopamine selectively to the brain, as confirmed by the fact that it does not alter quantitative whole-brain blood flow 17 – 19 , as dopamine would if it were being delivered systemically or produced outside the brain. In fact, with adequate carbidopa pretreatment, volunteers usually cannot tell whether they are receiving levodopa or a placebo 12 , 16 .…”

Section: Introductionmentioning

confidence: 99%

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Levodopa effects on [11C]raclopride binding in the resting human brain

et al. 2015

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Rationale: Synaptic dopamine (DA) release induced by amphetamine or other experimental manipulations can displace [ 11C]raclopride (RAC*) from dopamine D2-like receptors. We hypothesized that exogenous levodopa might increase dopamine release at striatal synapses under some conditions but not others, allowing a more naturalistic assessment of presynaptic dopaminergic function. Presynaptic dopaminergic abnormalities have been reported in Tourette syndrome (TS). Objective: Test whether levodopa induces measurable synaptic DA release in healthy people at rest, and gather pilot data in TS. Methods: This double-blind crossover study used RAC* and positron emission tomography (PET) to measure synaptic dopamine release 4 times in each of 10 carbidopa-pretreated, neuroleptic-naïve adults: before and during an infusion of levodopa on one day and placebo on another (in random order). Five subjects had TS and 5 were matched controls. RAC* binding potential (BP ND) was quantified in predefined anatomical volumes of interest (VOIs). A separate analysis compared BP ND voxel by voxel over the entire brain. Results: DA release declined between the first and second scan of each day (p=0.012), including on the placebo day. Levodopa did not significantly reduce striatal RAC* binding and striatal binding did not differ significantly between TS and control groups. However, levodopa’s effect on DA release differed significantly in a right midbrain region (p=0.002, corrected), where levodopa displaced RAC* by 59% in control subjects but increased BP ND by 74% in TS subjects. Discussion: Decreased DA release on the second scan of the day is consistent with the few previous studies with a similar design, and may indicate habituation to study procedures. We hypothesize that mesostriatal DA neurons fire relatively little while subjects rest, possibly explaining the non-significant effect of levodopa on striatal RAC* binding. The modest sample size argues for caution in interpreting the group difference in midbrain DA release with levodopa.

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“…At the imaging center, they took 200 mg carbidopa, and then underwent a set of clinical and MRI assessments. An intravenous levodopa infusion was then begun, dosed in such a way as to rapidly produce and then maintain a steady plasma concentration [21], with a target concentration of 600 ng/mL. At least 25 minutes after the levodopa infusion started, all MRI and clinical assessments were repeated while the levodopa infusion continued.…”

Section: Methodsmentioning

confidence: 99%

A Perfusion MRI Study of Emotional Valence and Arousal in Parkinson’s Disease

Limsoontarakul

Campbell

Black

2011

Parkinson's Disease

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Background. Brain regions subserving emotion have mostly been studied using functional magnetic resonance imaging (fMRI) during emotion provocation procedures in healthy participants. Objective. To identify neuroanatomical regions associated with spontaneous changes in emotional state over time. Methods. Self-rated emotional valence and arousal scores, and regional cerebral blood flow (rCBF) measured by perfusion MRI, were measured 4 or 8 times spanning at least 2 weeks in each of 21 subjects with Parkinson's disease (PD). A random-effects SPM analysis, corrected for multiple comparisons, identified significant clusters of contiguous voxels in which rCBF varied with valence or arousal. Results. Emotional valence correlated positively with rCBF in several brain regions, including medial globus pallidus, orbital prefrontal cortex (PFC), and white matter near putamen, thalamus, insula, and medial PFC. Valence correlated negatively with rCBF in striatum, subgenual cingulate cortex, ventrolateral PFC, and precuneus—posterior cingulate cortex (PCC). Arousal correlated positively with rCBF in clusters including claustrum-thalamus-ventral striatum and inferior parietal lobule and correlated negatively in clusters including posterior insula—mediodorsal thalamus and midbrain. Conclusion. This study demonstrates that the temporal stability of perfusion MRI allows within-subject investigations of spontaneous fluctuations in mental state, such as mood, over relatively long-time intervals.

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Intravenous levodopa administration in humans based on a two-compartment kinetic model

Cited by 12 publications

References 45 publications

Quantification of Indirect Pathway Inhibition by the Adenosine A_2aAntagonist SYN115 in Parkinson Disease

Quantification of Indirect Pathway Inhibition by the Adenosine A_2aAntagonist SYN115 in Parkinson Disease

Levodopa effects on [11C]raclopride binding in the resting human brain

A Perfusion MRI Study of Emotional Valence and Arousal in Parkinson’s Disease

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Intravenous levodopa administration in humans based on a two-compartment kinetic model

Cited by 12 publications

References 45 publications

Quantification of Indirect Pathway Inhibition by the Adenosine A2aAntagonist SYN115 in Parkinson Disease

Quantification of Indirect Pathway Inhibition by the Adenosine A2aAntagonist SYN115 in Parkinson Disease

Levodopa effects on [11C]raclopride binding in the resting human brain

A Perfusion MRI Study of Emotional Valence and Arousal in Parkinson’s Disease

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Product

Resources

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Quantification of Indirect Pathway Inhibition by the Adenosine A_2aAntagonist SYN115 in Parkinson Disease

Quantification of Indirect Pathway Inhibition by the Adenosine A_2aAntagonist SYN115 in Parkinson Disease