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Ambroxol, a drug used in cough syrup to break up phlegm, may be worthy of further study as a neuroprotective compound in Parkinson's disease, results suggested.

In a small, open-label, single-center study of Parkinson's patients, ambroxol crossed the blood-brain barrier and boosted β-glucocerebrosidase (GCase) enzyme protein levels, reported Anthony Schapira, MD, DSc, of University College London, and colleagues in .

"The results of the AiM-PD study indicate that ambroxol is safe, well tolerated, and able to increase GCase levels in the spinal fluid of people with Parkinson's," Schapira told 麻豆传媒. "This is an important step to now allow us to find out whether this drug can slow the progress of Parkinson's."

Glucocerebrosidase (GBA) gene mutations occur in about 10% of Parkinson's patients and are the biggest genetic risk factor for the disease. These mutations lower GCase production, causing . Although GCase activity is reduced in Parkinson's patients with and without GBA1, it's lower in people with the mutations.

Mutations in GBA also are causal for Gaucher's disease, a lysosomal storage disorder, noted J. William Langston, MD, of Stanford University in California, who was not involved in the study.

"For many years, we saw a connection between Gaucher's and Parkinson's that we didn't think was random," Langston said in an interview with 麻豆传媒. "But population studies unequivocally showed that Gaucher's increased the risk for Parkinson's disease. And in autopsies, Gaucher looked very much like Parkinson's, even under the microscope."

Ambroxol to its mature form and has been shown to and reduce alpha-synuclein levels in mice. The drug may modulate alpha-synuclein through several mechanisms, Schapira and colleagues noted: GCase may have a direct role in alpha-synuclein disposal, or alternatively, GBA1 mutations may prevent GCase from being transported to the lysosome, a structure within mammalian cells that digests unneeded proteins.

In this nonrandomized, non-controlled trial, Schapira and colleagues treated 18 Parkinson's patients with escalating doses of oral ambroxol to 1.26 g per day (420 mg 3 times a day) from January 2017 to April 2018. Primary outcomes were ambroxol detection in cerebrospinal fluid (CSF) and change in CSF GCase activity at 186 days.

Participants had an average age of about 60 and 83% were men. Of 17 people included in the primary analysis, eight had GBA1 mutations and nine did not (one patient was excluded due to red blood cell contamination). All were taking dopaminergic therapy. Throughout the study, ambroxol appeared to be well tolerated, with no serious adverse events.

In 186 days, CSF levels of ambroxol levels increased by 156-ng/mL (lower 95% confidence limit 129 ng/mL, P<0.001.) In the same period, CSF GCase activity decreased by 19% (0.059 nmol/mL per hour, 95% CI –0.115 to –0.002, P=0.04). Changes occurred in patients with and without GBA1 mutations.

Patients also showed a 13% increase in CSF alpha-synuclein concentration over time. What that means is unknown, Langston observed: "One theory is alpha-synuclein should go down. Another is that, as you get rid of abnormal alpha-synuclein, it gets kicked out into the spinal fluid," he said. "I don't think anybody knows the real answer to that."

Mean scores on part III of the Movement Disorders Society Unified Parkinson Disease Rating Scale improved by 6.8 points, but placebo effects are "a big issue" in Parkinson's trials, especially open-label ones, Langston noted.

"This study provides us with the proof of concept that we can raise levels of GCase in humans with ambroxol," Simon Stott, PhD, of The Cure Parkinson's Trust in London, told 麻豆传媒. "The Cure Parkinson's Trust, in collaboration with the Van Andel Institute and the John Black Charitable Foundation, is now exploring the next steps in the development of this novel therapeutic approach for Parkinson's."

In addition, a group in Canada is studying ambroxol in . The also is testing an investigational oral therapy known as GZ/SAR402671 in Parkinson's patients who carry a single copy of GBA.

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