Continuous dopaminergic stimulation reduces risk of motor complications in parkinsonian primates

Bibbiani, Francesco; Costantini, Lauren C.; Patel, Raj; Chase, Thomas N.

doi:10.1016/j.expneurol.2004.11.013

Cited by 119 publications

(64 citation statements)

References 29 publications

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“…296,297 Of particular importance is the observation that the same short-acting dopaminergic agent that induces dyskinesia when administered in a pulsatile manner does not induce dyskinesia when administered continuously. 298,299 For example, intermittent doses of the short-acting dopamine agonist apomorphine induce severe dyskinesia in MPTP primates, whereas continuous infusion of the same agent does not 299 ( figure 15). These different patterns (pulsatile and continuous) of dopamine receptor stimulation are likely to elicit different functional responses, because they activate different signal transduction pathways in postsynaptic neurons.…”

Section: 242mentioning

confidence: 99%

The scientific and clinical basis for the treatment of Parkinson disease (2009)

Olanow¹,

Stern²,

Sethi³

2009

Neurology

737

649

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Parkinson disease (PD) is an age-related neurodegenerative disorder that affects as many as 1-2% of persons aged 60 years and older. With the aging of the population, the frequency of PD is expected to increase dramatically in the coming decades. Current therapy is largely based on a dopamine replacement strategy, primarily using the dopamine precursor levodopa. However, chronic treatment is associated with the development of motor complications, and the disease is inexorably progressive. Further, advancing disease is associated with the emergence of features such as freezing, falling, and dementia which are not adequately controlled with dopaminergic therapies. Indeed, it is now appreciated that these nondopaminergic features are common and the major source of disability for patients with advanced disease. Many different therapeutic agents and treatment strategies have been evaluated over the past several years to try and address these unmet medical needs, and many promising approaches are currently being tested in the laboratory and in the clinic. As a result, there are now many new therapies and strategic approaches available for the treatment of the different stages of PD, with which the treating physician must be familiar in order to provide patients with optimal care. This monograph provides an overview of the management of PD patients, with an emphasis on pathophysiology, and the results of recent clinical trials. It is intended to provide physicians with an understanding of the different treatment options that are available for managing the different stages of the disease and the scientific rationale of the different approaches. 1 PD is the second most common neurodegenerative disorder, with an average age at onset of about 60 years. An estimated 5 million people throughout the world have PD, with 1 million individuals each in the United States and in Europe with the disorder. PD affects approximately 0.3% of the population and 1% to 2% of those older than 60 years.2 With the aging of the population and the substantial increase in the number of at-risk individuals older than 60 years, it is anticipated that the prevalence of PD will increase dramatically in the coming decades.

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Section: 242mentioning

confidence: 99%

The scientific and clinical basis for the treatment of Parkinson disease (2009)

Olanow¹,

Stern²,

Sethi³

2009

Neurology

737

649

View full text Add to dashboard Cite

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“…This invokes alternative mechanisms, other than solely the plasma half-life on which CDS relies, to explain increased incidence of motor complications with levodopa relative to agonists. Experiments with MPTP-lesioned primates showed that subjects receiving continuous subcutaneous delivery of apomorphine remained in the 'on' state for the duration of the study with minimal dyskinetic movements, while subjects given intermittent apomorphine injections developed both peak dose dyskinesias and wearing off effect [29]. Thus, changing the delivery profile of an identical drug, even one with a half-life shorter than levodopa, seems to be able to lower the risk of motor complications.…”

Section: Cds and The Transition To Cddmentioning

confidence: 99%

“…Another hypothesis is that continuous intestinal infusion interferes with absorption of vitamins necessary for normal homocysteine metabolism. Some authors have recommended that patients using intraintestinal levodopa infusion (as well others taking high doses of oral levodopa) be given B12/B6 supplementation and have the appropriate serum labs monitored regularly [29]. Further studies are required to obtain a better understanding of this rare adverse event, and more information will be gathered as clinical experience with the infusion system accumulates.…”

Section: Continuous Duodenal Levodopa Infusionmentioning

confidence: 99%

“…Several studies have linked increased incidence of neuropathy in PD patients with cumulative levodopa dose and elevated serum methylmalonic acid levels [47,48]. It has been proposed that levodopa may disrupt the metabolic pathway of colabamin (B12), leading to elevation of serum methylmalonic acid and homocysteine, as well as B12 deficiency [29]. Another hypothesis is that continuous intestinal infusion interferes with absorption of vitamins necessary for normal homocysteine metabolism.…”

Section: Continuous Duodenal Levodopa Infusionmentioning

confidence: 99%

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Continuous dopaminergic delivery to minimize motor complications in Parkinson’s disease

Wright

Waters²

2013

Expert Review of Neurotherapeutics

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“…The occurrence of dyskinesias, or involuntary movements, is one of the most troublesome and debilitating side effects of prolonged treatment with L-dopa, occurring in up to one-third of all patients. In preclinical studies, SZ was effective in induced Parkinson syndrome in monkeys (Bibbiani et al, 2005). In clinical studies, SZ demonstrated proof of concept in an open pilot study and in a placebo-controlled dose-finding study.…”

mentioning

confidence: 92%

In Vitro Characterization of Sarizotan Metabolism: Hepatic Clearance, Identification and Characterization of Metabolites, Drug-Metabolizing Enzyme Identification, and Evaluation of Cytochrome P450 Inhibition

Gallemann

Wimmer²,

Höfer³

et al. 2010

Drug Metab Dispos

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ABSTRACT:In vitro biotransformation studies of sarizotan using human liver microsomes (HLM) showed aromatic and aliphatic monohydroxylation and dealkylation. Recombinant cytochromes P450 (P450) together with P450-selective inhibitors in HLM/hepatocyte cultures were used to evaluate the relative contribution of different P450s and revealed major involvement of CYP3A4, CYP2C9, CYP2C8, and CYP1A2 in sarizotan metabolism. The apparent K m, u and V max of sarizotan clearance, as investigated in HLM, were 9 M and 3280 pmol/mg/min, predicting in vivo hepatic clearance of 0.94 l/h, which indicates that sarizotan is a low-clearance compound in humans and suggests nonsaturable metabolism at the targeted plasma concentration (<1 M). This finding is confirmed by the reported human clearance (CL/F of 3.6-4.4 l/h) and by the doselinear area under the curve increase observed with doses up to 25 mg. The inhibitory effect of sarizotan toward six major P450s was evaluated using P450-specific marker reactions in pooled HLM. K i, u values of sarizotan against CYP2C8, CYP2C19, and CYP3A4 were >10 M, whereas those against CYP2D6 and CYP1A2 were 0.43 and 8.7 M, respectively. Based on the estimates of sarizotan concentrations at the enzyme active sites, no clinically significant drug-drug interactions (DDIs) due to P450 inhibition are expected. This result has been confirmed in human DDI studies in which no inhibition of five major P450s was observed in terms of marker metabolite formation.Sarizotan (SZ) hydrochloride is an aminomethyl-chromane that underwent clinical development for levodopa therapy-associated dyskinesia in patients with Parkinson's disease. The occurrence of dyskinesias, or involuntary movements, is one of the most troublesome and debilitating side effects of prolonged treatment with L-dopa, occurring in up to one-third of all patients. In preclinical studies, SZ was effective in induced Parkinson syndrome in monkeys (Bibbiani et al., 2005). In clinical studies, SZ demonstrated proof of concept in an open pilot study and in a placebo-controlled dose-finding study. Single-and multiple-dose studies in healthy volunteers with orally administered SZ hydrochloride revealed rapid absorption (t max 0.5-2.3 h). Subsequently, plasma levels declined polyexponentially with a terminal elimination half-life of 5 to 7 h. C max and t max varied slightly with formulation and food intake, whereas the area under the curve (AUC) was unaffected by these factors. AUC and C max increased dose proportionally over the tested dose range of 0.5 to 25 mg (Kroesser et al., 2006a(Kroesser et al., , 2007.The Food and Drug Administration (FDA) recommends that all new chemical entities (NCEs) in development be characterized with respect to metabolic properties before administration to humans (FDA Guidance for Industry: Drug Interaction Studies-Study Design, Data Analysis and Implications for Dosing and Labeling, http://www.fda. gov/cber/guidelines.htm, 2006). The in vitro characterization involves estimation of the role of metabolism in the clear...

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Continuous dopaminergic stimulation reduces risk of motor complications in parkinsonian primates

Cited by 119 publications

References 29 publications

The scientific and clinical basis for the treatment of Parkinson disease (2009)

The scientific and clinical basis for the treatment of Parkinson disease (2009)

Continuous dopaminergic delivery to minimize motor complications in Parkinson’s disease

In Vitro Characterization of Sarizotan Metabolism: Hepatic Clearance, Identification and Characterization of Metabolites, Drug-Metabolizing Enzyme Identification, and Evaluation of Cytochrome P450 Inhibition

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