Clinical implications of gastric complications on levodopa treatment in Parkinson's disease

Abstract

Disorders of the gastrointestinal (GI) tract are common and distressing nonmotor symptoms of Parkinson's disease (PD) that can adversely affect levodopa absorption and lead to OFF periods, also known as motor fluctuations. Gastroparesis, which is primarily defined as delayed gastric emptying (DGE), and Helicobacter pylori infection, which is present with increased frequency in PD, are among the most common and important GI disorders reported in PD that may impair oral levodopa absorption and increase OFF time. Symptoms of gastroparesis include nausea, vomiting, postprandial bloating, fullness, early satiety, abdominal pain, and weight loss. DGE has been reported in a substantial fraction of individuals with PD. Symptoms of H. pylori infection include gastritis and peptic ulcers. Studies have found that DGE and H. pylori infection are correlated with delayed peak levodopa plasma levels and increased incidence of motor fluctuations. Therapeutic strategies devised to minimize the potential that gastric complications will impair oral levodopa absorption and efficacy in PD patients include treatments that circumvent the GI tract, such as apomorphine injection, levodopa intestinal gel delivery, levodopa inhalation powder, and deep brain stimulation. Other strategies aim at improving gastric emptying in PD patients, primarily including prokinetic agents.

The gut-brain axis and Parkinson disease: clinical and pathogenetic relevance

“…The pathophysiology of this phenomenon is complex and likely multifactorial. The damage to, and a-synuclein deposition in the VN and ENS likely play a major role in DGE, whereas more controversial is the involvement of Cajal interstitial cells (the gastric pacemaker cells) [70,71]. Common medications used in PD, such as levodopa and anticholinergics, can contribute to DGE in a dosedependent manner [71,72], and the interaction of some macronutrients (especially fats) with receptors in the small intestine can further inhibit gastric emptying [73].…”

“…In advanced PD stages, redistribution of daily protein intake (limited to evening hours) and/or restriction of daily protein intake, have been shown to increase levodopa bioavailability [78], reduce plasma levels of LNAA [78,79], improve motor fluctuations in 30-90% of PD patients [79][80][81][82] and reduce levodopa daily dose in 75% [78]. However, careful monitoring is necessary with long-term adherence to low-protein regimens, as these may increase the risk of nutritional complications such as weight loss and malnutrition [71]. Administration of dietary herb extract Rikkunshito has been evaluated in two small open-label trials.…”

“…Prokinetic agents are a mainstay treatment for gastroparesis [71]. Of all the available prokinetics, domperidone, a D2 dopamine receptor blocker that does not cross the BBB, has been shown to be efficacious in the management of gastroparesis in PD, without worsening motor symptoms [85], and it increases levodopa bioavailability when co-administered with levodopa [86].…”

“…The updated recommendations on PD treatment released by the International Parkinson and Movement Disorder Society (MDS) Evidence-Based Medicine (EBM) Committee, consider domperidone "possibly useful" in the treatment of PD-related gastroparesis but specialised monitoring is required due to potentially life-threatening arrythmias secondary to QT elongation [87]. Metoclopramide, the only FDAapproved medication for gastroparesis in the United States, is contraindicated in PD due to its ability to cross the BBB and block central dopaminergic receptors [71]. Other prokinetics which have been under investigation in PD include mosapride, a selective 5hydroxytryptamine type 4 (5-HT 4 ) agonist, which was beneficial at reducing gastric emptying rates, prolonging "on" time and reducing motor fluctuations in a small open-label trial on 5 patients with advanced PD [88].…”

From the Gut to the Brain and Back: Therapeutic Approaches for the Treatment of Network Dysfunction in Parkinson's Disease

“…Improvements have also been observed on non-motor symptoms, such as sleep/fatigue, urinary and sexual functions, gastrointestinal motility, and cognitive and affective comorbidities (105,106). Adverse events occur more frequently during the early stages of implantation, but these appear to be related to the surgical procedure and stoma inflammation (107). The contribution of dopaminergic as well as noradrenergic, glutamatergic, and GABAergic pathways provide insights into the intricacy of the PD phenomenology and the development of novel disease-modifying approaches in addition to dopamine-replacing therapies.…”