Gastric emptying in Parkinson's disease

Djaldetti, Ruth; Baron, J H; Ziv, Ilan; Melamed, Eldad

doi:10.1212/wnl.46.4.1051

Cited by 186 publications

(151 citation statements)

References 13 publications

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“…Retention of levodopa in the stomach also increases its exposure to the dopa decarboxylase present in the gastric mucosa; this enzyme can convert the levodopa to dopamine, rendering it unavailable for intestinal absorption (Pfeiffer, 2003). These absorptive vagaries may constitute one mechanism for the development of motor fluctuations in individuals with Parkinson's disease (Djaldetti et al, 1996;Kurlan et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

Effects of slowed gastrointestinal motility on levodopa pharmacokinetics

Fernández

García

Diez

et al. 2010

Autonomic Neuroscience

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Autonomic disorders are often seen in Parkinson's disease, with disturbances of the gastrointestinal tract occurring most frequently. These disorders, mainly a delay in gastric emptying and slowed gastrointestinal motility, can modify the pharmacokinetics and effectiveness of drugs used to treat Parkinson's disease and administered orally. In this study, we evaluated in a rabbit model the pharmacokinetics of levodopa (administered with carbidopa) in the context of gastrointestinal motility slowed by the administration of an anticholinergic drug. Levodopa + carbidopa (20:5 mg/kg) and the anticholinergic biperiden (100 μg/kg) were orally administered to rabbits over one of two time periods (7 or 14 days) to verify the stabilization of levodopa concentrations. The values of the area under the curve (AUC) and C max were higher on the final day of treatment with an increase in AUC of 25% on day 7 and 33.4% on day 14; for C max , the increase was 15% on day 7 and 12.8% on day 14. The values of AUC and C max were lower than those obtained when levodopa was administered to rabbits with normal gastrointestinal motility. The values obtained for C min (baseline sample obtained before administration) also increased with treatment duration (24% and 47.4% on days 7 and 14, respectively). These values were higher than those obtained in the absence of anticholinergic administration. We conclude that, under our experimental conditions of slowed gastrointestinal motility, levodopa absorption diminishes, and final concentrations and C min are higher than under conditions of normal motility.

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Section: Discussionmentioning

confidence: 99%

Effects of slowed gastrointestinal motility on levodopa pharmacokinetics

Fernández

García

Diez

et al. 2010

Autonomic Neuroscience

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“…There is no conclusive data about the relation between PD stage and GE (25,27,28,31,(143)(144)(145) and it is possible that there is no strict relation between severity of motor symptoms and degree of impairment of GE in PD patients. This is supported by our results where we could see no difference of GE between the two PD groups.…”

Section: Discussionmentioning

confidence: 99%

“…Some studies have shown that delayed GE in PD patients is associated with disease severity (31,143) while other studies cannot find any association of GE and disease duration or Hoehn and Yahr clinical scale (25,27,28). Abnormalities in gastric motility have also been shown with electrogastrography in PD patients both in early and advanced stages of the disease (144,145).…”

Section: Gastric Emptyingmentioning

confidence: 99%

“…The GE has been shown to be delayed in PD patients (25)(26)(27)(28)(29)(30) resulting in an impaired bioavailability of levodopa (31)(32)(33)(34). Another factor is the competition between levodopa and other large neutral amino acids (LNAAs) that share the same active transport carrier system across the intestinal mucosa in the small intestine and a high amount of dietary proteins has been proposed to decrease the levodopa uptake (35)(36)(37).…”

Section: Levodopa In the Peripherymentioning

confidence: 99%

“…Orally given levodopa is absorbed in the proximal one-third of the small intestine and, except for the competition between levodopa and other LNAAs across the intestinal mucosa (35,36), GE is an important factor (24). It has been shown that more than 70 % of PD patients suffer from impaired gastric motility (27,31) with symptoms like early satiety, postprandial bloating and nausea and it has been suggested that this is caused by the delay in GE that has been shown in PD patients (25)(26)(27)(28)(29)(30)(136)(137)(138). Delayed GE has also been shown to impair the levodopa uptake and is therefore suggested to worsen motor complications (31)(32)(33)(34)136).…”

Section: Gastric Emptyingmentioning

confidence: 99%

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Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

Nord¹

2017

Linköping University Medical Dissertations

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Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and it is caused by a loss of dopamine (DA) producing neurons in the basal ganglia in the brain. The PD patient suffers from motor symptoms such as tremor, bradykinesia and rigidity and treatment with levodopa (LD), the precursor of DA, has positive effects on these symptoms. Several factors affect the availability of orally given LD. Gastric emptying (GE) is one factor and it has been shown to be delayed in PD patients resulting in impaired levodopa uptake. Different enzymes metabolize LD on its way from the gut to the brain resulting in less LD available in the brain and more side effects from the metabolites. By adding dopa decarboxylase inhibitors (carbidopa or benserazide) or COMT-inhibitors (e.g. entacapone) the bioavailability of LD increases significantly and more LD can pass the blood-brain-barrier and be converted to DA in the brain. It has been considered of importance to avoid high levodopa peaks in the brain because this seems to induce changes in postsynaptic dopaminergic neurons causing disabling motor complications in PD patients. More continuously given LD, e.g. duodenal or intravenous (IV) infusions, has been shown to improve these motor complications. Deep brain stimulation of the subthalamic nucleus (STN DBS) has also been proven to improve motor complications and to make it possible to reduce the LD dosage in PD patients. In this doctoral thesis the main purpose is to study the pharmacokinetics of LD in patients with PD and motor complications; in blood and subcutaneous tissue and study the effect of GE and PD stage on LD uptake and the effect of continuously given LD (CDS) on LD uptake and GE; in blood and cerebrospinal fluid (CSF) when adding the peripheral enzyme inhibitors entacapone and carbidopa to LD infusion IV; in brain during STN DBSand during oral or IV LD treatment. To conclude, LD uptake is more favorable in PD patients with less severe disease and GE is delayed in PD patients. No obvious relation between LD uptake and GE or between GE and PD stage is seen and CDS decreases the LD levels. Entacapone increases the maximal concentration of LD in blood and CSF. This is more evident with additional carbidopa and important to consider in avoiding high LD peaks in brain during PD treatment. LD in brain increases during both oral and IV LD treatment and the DA levels follows LD well indicating that PD patients still have capacity to metabolize LD to DA despite probable pronounced nigral degeneration. STN DBS seems to increase putaminal DA levels and together with IV LD treatment also increases LD in brain possibly explaining why it is possible to decrease LD medication after STN DBS surgery.Parkinsons sjukdom (PS) är en av de vanligaste s.k. neurodegenerativasjukdomarna och orsakas av förlust av dopamin(DA)producerande nervceller i hjärnan. Detta orsakar motoriska symptom såsom skakningar, stelhet och förlångsammade rörelser. Levodopa (LD) är ett ämne, som kan omvandlas till DA i hjärnan och ge symptomlindrin...

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A Randomized Controlled Trial of Etilevodopa in Patients With Parkinson Disease Who Have Motor Fluctuations

Blindauer

Shoulson²,

Oakes³

et al. 2006

Arch Neurol

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Background: Motor fluctuations are a common complication in patients with Parkinson disease (PD) receiving long-term levodopa therapy. Slowed gastric emptying and poor solubility of levodopa in the gastrointestinal tract may delay the onset of drug benefit after dosing. Etilevodopa is an ethyl-ester prodrug of levodopa that has greater gastric solubility, passes quickly into the small intestine, is rapidly hydrolyzed to levodopa, and has a shortened time to maximum levodopa concentration. Objective: To determine the efficacy, safety, and tolerability of etilevodopa in patients with PD who have motor fluctuations. Design: A double-blind, randomized, comparative clinical trial. Setting: Forty-four sites in the United States and Canada. Patients: Three hundred twenty-seven patients with PD who had a latency of at least 90 minutes total daily time to "on" (TTON) after levodopa dosing. Intervention: Treatment with either etilevodopacarbidopa or levodopa-carbidopa for 18 weeks. Main Outcome Measure: Change from baseline in total daily TTON as measured using home diaries. Results: The reduction in mean total daily TTON from baseline to treatment was 0.58 hour in the etilevodopacarbidopa group and 0.79 hour in the levodopacarbidopa group (P = .24). There was no significant difference between the etilevodopa-carbidopa and levodopa-carbidopa groups in the reduction of response failures (−6.82% vs −4.69%; P=.20). Total daily "off" time improved in the etilevodopa-carbidopa (−0.85 hour) and levodopa-carbidopa (−0.87 hour) groups without an increase in on time with troublesome dyskinesias. Conclusion: Despite the theoretical pharmacokinetic advantage of etilevodopa, there was no improvement in TTON, response failures, or off time compared with levodopa.

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Gastric emptying in Parkinson's disease

Cited by 186 publications

References 13 publications

Effects of slowed gastrointestinal motility on levodopa pharmacokinetics

Effects of slowed gastrointestinal motility on levodopa pharmacokinetics

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

A Randomized Controlled Trial of Etilevodopa in Patients With Parkinson Disease Who Have Motor Fluctuations

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