Delayed gastric emptying (GE) affects over 70% of PD patients (1, 2). In other words, food or medicines may take longer than normal to leave the stomach. This may be a problem on many fronts. First, there is the discomfort of a stomach that does not empty. There is the issue of early satiety, or loss of appetite, too soon in the meal. This may mean a person is not getting enough calories. Additionally, there is the effect on absorption of nutrients and medications, which may be impaired for several reasons. The stomach and the intestines have very specialized jobs to do, and these may be sidelined by slow emptying. In the case of levodopa, absorption takes place just after leaving the stomach and entering the first part of the small intestine. Delay of GE is associated with poor absorption of levodopa and subsequent delayed ON time (the time medications are working and symptoms are controlled), and worsening motor fluctuations (for example, unexpected medication failures such as doses that do not work at all, or suddenly stop working before they should) (3, 4).
For years, researchers have attempted to deal with the problem of GE. In the 1990s, investigators showed that cisapride (Propulsid), a prescription drug FDA approved for severe nighttime heartburn in patients with gastroesophageal reflux disease (GERD), was associated with fewer motor fluctuations in PD (5-7). The implication was that earlier emptying of stomach contents would improve drug absorption, and therefore function, in PD patients. However, Janssen Pharmaceuticals Inc., made a voluntary action to withdraw the drug from the U.S. market after noting that as of December 31, 1999, use of cisapride had been associated with 341 reports of heart rhythm abnormalities, including 80 reports of death. Per the press release, most of these adverse events occurred in patients who were taking other medications, or suffering from underlying conditions known to increase risk of cardiac arrhythmia associated with cisapride (8).
The problem is that there are not many drugs available to help GE. In the U.S., the drug metoclopramide (Reglan) improves GE, but is also a very potent dopamine receptor blocker which can exacerbate symptoms of PD, and is generally not used in this population for that reason. To be clear, metoclopramide is possibly the most common cause of drug-induced parkinsonism in the U.S., even among those who do not have underlying PD.
Outside of the U.S., domperidone is used, and generally does not alter PD motor symptoms because it affects serotonin, rather than dopamine, receptors. Movement disorder and gastroenterology specialists in the U.S. still frequently prescribe the drug. However, because there is no FDA approval, it is not covered by Medicare and patients must pay out of pocket. Most of the time the drug is obtained by patients from Canada, though compounding pharmacists may also fill capsules in the U.S., and that is likely a more expensive option. Interestingly, use of domperidone is associated with increases in plasma levodopa concentration among PD patients (9).
What is approved in the U.S.? Erythromycin, an antibiotic FDA approved to treat infection, has long been known to assist in gastric motility and GE. However, there are side effect and adverse event concerns, such as the development of bacterial resistance to antibiotics, and kidney and ototoxicity. Erythromycin has been reported in some patients to cause severe and permanent damage to the inner ear, resulting in hearing loss, deafness, and severe vertigo. The drug was trialed NCT02005029 (10) at Virginia Commonwealth University Parkinson’s Center, Richmond, Virginia, and results were posted online at ClinicalTrials.gov in February 2017, though it does not appear the data was published in a medical journal. The study included 4 participants who received a single dose of erythromycin and 4 who received placebo. There was a modest improvement of GE in the erythromycin group (105 minutes) versus placebo (180 minutes). Also reported was a small increase in plasma levodopa concentration. The drug is used off-label by some physicians and obviously requires monitoring of side effects.
There may be a better mechanism on the horizon. In February 2018, international researchers in the United Kingdom, Europe, and Australia published a study in the journal Movement Disorders which tested another agent, camicinal (GSK962040), a “gastroprokinetic” drug (11).
Camicinal improves GE by binding to motilin receptors in the gut. The primary outcome of the study was to evaluate the effect of camicinal on levodopa pharmacokinetics (the movement of drugs within the body) in PD patients. The study was multicenter (11 sites). Participants had PD with suboptimal control of motor function while taking levodopa. Motor fluctuations were defined in the study as wearing off, peak-dose dyskinesia, and delayed or absent ON periods that impacted functional status or quality of life. Patients had to have a stable levodopa dosing regimen for at least four weeks prior to screening, and therapy could not be altered during the study. Participants further had to have a delayed GE of 70 or more minutes.
Nineteen patients who had been randomized to placebo, and 37 patients to caminical 50 mg once daily, completed the study. This was a double-blinded investigation (patients and raters were blinded to whom was receiving placebo or study drug). Patients were treated from seven to nine days, and there was a 14-day follow up period. GE improved by an average of 5.3 minutes in the treatment group. Though this seems modest, there were other measures which indicated improvement, and the trend toward improvement at the end of the study would seem to indicate that a longer duration trial would be in order. For example, by the eighth day of the study the time for maximum level of levodopa in the plasma was 23 minutes sooner with camicinal than placebo. And, MDS-UPDRS III scores (measures of motor function in PD) improved an average of 9 points by the eighth day. With camincinal, there was a nearly two hour improvement in ON time.
This study was the first to describe the motilin receptor agonist camicinal motor response to levodopa in PD patients with motor fluctuations.
REFERENCES
- Cloud, et al. Gastrointestinal features of Parkinson’s disease. Curr Neurol Neursci Rep. 2011;11:379-384.
- Heetun, et al.Gastroparesis and Parkinson’s disease: a systematic review. Parkinsonism Relat Disord 2012;18:433-440.
- Doi, et al. Plasma levodopa peak delay and impaired gastric emptying in Parkinson’s disease. J Neurol Sci 2012;319:86-88.
- Muller, et al. Impact of gastric emptying on levodopa pharmacokinetics in Parkinson disease patients. Clin Neuropharmacol 2006;29:61-67.
- Djadldetti, et al. Effect of cisapride on response fluctuations in Parkinson’s disease. Mov Disord 1995;10:81-84.
- Cisapride was shown to improve plasma levodopa levels and therefore the motor function in patients with PD.
- Neira, et al. the effects of cisapride on plasma L-DOPA levels and clinical response in Parkinson’s disease. Mov Disord. 1995;10-66-70.
- https://www.fda.gov/ohrms/dockets/ac/00/backgrd/3634b1a_tab4a.htm
- Nishikawa, et al. Coadministration of domperidone increases plasma levodopa concentration in patients with Parkinson’s disease. Clin Neuropharmacol 2012;35:182-184.
- https://clinicaltrials.gov/ct2/show/NCT02005029?term=erythromycin&cond=Parkinson+Disease&rank=1
- Marrinan, et al. A randomized, double-blind, placebo-controlled trial of carmicinal in Parkinson’s disease. Movement Disord. 2018;33(2):329-332.
