論文の公開元へSafety comparisons among monoamine oxidase inhibitors against Parkinson’s disease using FDA adverse event reporting system
概要
Title
Safety comparisons among monoamine oxidase
inhibitors against Parkinson’s disease using
FDA adverse event reporting system
Author(s)
Asano, Hiroto; Tian, Yu Shi; Hatabu, Asuka et
al.
Citation
Scientific Reports. 2023, 13(1), p. 19272
Version Type VoR
URL
rights
https://hdl.handle.net/11094/93232
This article is licensed under a Creative
Commons Attribution 4.0 International License.
Note
Osaka University Knowledge Archive : OUKA
https://ir.library.osaka-u.ac.jp/
Osaka University
www.nature.com/scientificreports
OPEN
Safety comparisons
among monoamine oxidase
inhibitors against Parkinson’s
disease using FDA adverse event
reporting system
Hiroto Asano , Yu‑Shi Tian
Kenji Ikeda
*
, Asuka Hatabu , Tatsuya Takagi , Mikiko Ueda &
Monoamine oxidase B (MAO-B) inhibitors are used to control Parkinson’s disease (PD). Selegiline,
rasagiline, and safinamide are widely used as MAO-B inhibitors worldwide. Although these drugs
inhibit MAO-B, there are pharmacological and chemical differences, such as the inhibitory activity,
the non-dopaminergic properties in safinamide, and the amphetamine-like structure in selegiline.
MAO-B inhibitors may differ in adverse events (AEs). However, differences in actual practical
clinics are not fully investigated. A retrospective study was conducted using FAERS, the largest
database of spontaneous adverse events. AE signals for MAO-B inhibitors, including selegiline,
rasagiline, and safinamide, were detected using the reporting odds ratio method and compared.
Hypocomplementemia, hepatic cyst, hepatic function abnormal, liver disorder and cholangitis were
detected for selegiline as drug-specific signals. The amphetamine effect was not confirmed for any of
the three MAO-B inhibitors. The tyramine reaction was detected as an AE signal only for rasagiline.
Moreover, the REM sleep behavior disorder was not detected as an AE signal for safinamide,
suggesting that non-dopaminergic effects might be beneficial. Considering the differences in AEs for
MAO-B inhibitors will assist with the appropriate PD medication.
Parkinson’s disease (PD) is a highlighted neurodegenerative disorder and has become one of the most serious
health problems. Based on the Global Burden of Disease 2019, a significant 155.50% global increase in the
occurrence of PD has been estimated since 1990, and the prevalence reached over 8.5 million individuals. This
upward prevalence trend demonstrated consistency from 1990 to 2 0191. During the clinical progression of PD,
motor symptoms, including tremors, rigidity, akinesia, imbalance, and numerous non-motor complications
occur. These symptoms predominantly result from altered and abnormal neurotransmission related to deficits
of predominant biogenic amines. Dopamine is the most responsible neurotransmission amine, and its relative
amount in the midbrain nigrostriatal area of patients with PD decreases due to reduced or dropped out dopaminergic neurons. So far, the principal treatment of PD is to directly supplement dopamine, such as using the
combination of carbidopa and levodopa or dopamine agonists, or to achieve therapeutic maintenance of dopamine by reducing the key metabolism, such as targeting catechol-O-methyltransferase or monoamine oxidase
B (MAO-B) using i nhibitors2.
MAO is an enzyme with two isoforms of MAO-A and -B, which are high-expressing in the brain and gut.
Selective inhibition of MAO-B in the striatum can increase dopamine levels and show anti-PD action. However,
the non-selective inhibition in the brain and gut may cause serious hypertension when taking cheese together,
termed tyramine reaction. Therefore, inhibitory selectivity is important for MAO-B inhibitor development. To
date, three MAO-B inhibitors, selegiline, rasagiline, and safinamide, have been approved for clinical use. These
inhibitors can be used as monotherapy or add-on drugs to levodopa, improve the wear-off, delay the onset of
levodopa, and prolong the mean levodopa action duration3.
Selegiline, an irreversible inhibitor, was approved for PD by the FDA in 1989 and has been widely used as a
first-generation MAO-B inhibitor. The selectivity of MAO-B over MAO-A in the brain at low doses of selegiline
Graduate School of Pharmaceutical Sciences, Osaka University, 1‑6 Yamadaoka, Suita, Osaka 565‑0871, Japan.
*
email: yushi-tian@phs.osaka-u.ac.jp
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(2023) 13:19272
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has been confirmed. However, it was also reported that when administered at high doses, the selegiline level
increased in plasma, indicating lower s electivities4. The chemical structure of selegiline contains an amphetamine
skeleton, and by first-pass metabolism, selegiline can be transformed into L-amphetamine and L-methamphetamine. Despite these aspects of selegiline, which raise the possibility of adverse effects, thus far, selegiline
has generally been considered a well-tolerated d
rug5, and its major adverse events are reported as headaches,
dizziness, insomnia, nausea, xerostomia, and c onstipation6. Furthermore, according to meta-analysis, there is
no difference in adverse event frequency between selegiline and placebo groups7. However, whether selegiline
metabolites can cause amphetamine-like adverse events, including cardiovascular and central neural system
adverse events, remains conversational. Some studies reported that cardiovascular adverse events in selegiline
users might be related to a mphetamine8–13, whereas other studies have suggested no association under ordinary
use14, 15. Moreover, in high-dose use, whether tyramine reaction occurs remains unclear.
Rasagiline is another irreversible, selective MAO-B i nhibitor16, which FDA approved in 2006. As rasagiline
does not have an amphetamine skeleton and higher selectivities of MAO-B, rasagiline has been considered to have
fewer adverse events than selegiline. Sleep disturbances have been reported to be improved by switching from
selegiline to r asagiline17. Tyramine dietary restriction was removed based on the results from clinical s tudies18.
Conversely, the package insert of selegiline still warns of the tyramine response19. It is important to clarify the
frequency and risk of tyramine reactions using pharmacovigilance data.
Safinamide, an alpha-aminoamide derivative, has recently been on the market as the newest MAO-B inhibitor.
Unlike selegiline and rasagiline, safinamide is a reversible inhibitor, and its MAO-B selectivity is much higher
than the other two drugs, which may link to higher safety profiles. Furthermore, in addition to dopaminergic
properties, safinamide has non-dopaminergic properties, such as inhibiting voltage-gated sodium and calcium
channels and glutamate release20, 21. These characteristics may also distinguish safinamide from selegiline and
rasagiline from the view of drug safety.
These MAO-B inhibitors play important roles in the current PD treatments. However, these drugs differ in
selectivity, chemical structures, and dopaminergic properties, which may affect drug safety. Although clinical
studies and meta-analyses have focused on their safety, further pharmacovigilance analyses from real-world
patient data can provide deeper comprehension and address rare but important safety concerns. Therefore,
this study applied AE signal d
etection22 to the data from the FDA Adverse Event Reporting System (FAERS)23,
compared the AE signals associated with selegiline, rasagiline, and safinamide, and provided information on
drug safety, particularly on the considered differences.
Results
Baseline information
This study involved 3784, 10,584, and 1007 records reported in FAERS (2004Q1-2022Q2) for selegiline, rasagiline,
and safinamide, respectively (Table 1). The mean ages of these reports were 68, 70, and 71, and the female rates
Selegiline
Rasagiline
Safinamide
Age in years (mean ± SD (n))
67.8 ± 12.7 (2667)
70.0 ± 10.7 (7209)
71.4 ± 9.8 (713)
Number of combination drugsa (mean ± SD)
8.5 ± 6.2
7.5 ± 5.6
7.8 ± 4.9
Monotherapyb (n, %)
34 (0.8%)
883 (8.3%)
57 (5.6%)
Female (n, %)
1517 (42.6%)
3998 (40.5%)
415 (44.3%)
Area (n, %)
Northern America
1523 (45.2%)
6082 (59.6%)
377 (40.4%)
Western Europe
201 (6.0%)
1497 (14.7%)
251 (26.9%)
Eastern Asia
991 (29.4%)
708 (6.9%)
29 (3.1%)
Northern Europe
310 (9.2%)
799 (7.8%)
62 (6.6%)
Southern Europe
231 (6.9%)
439 (4.3%)
197 (21.1%)
Eastern Europe
23 (0.7%)
169 (1.7%)
0 (0.0%)
South America
42 (1.2%)
94 (0.9%)
16 (1.7%)
Western Asia
4 (0.1%)
130 (1.3%)
0 (0.0%)
Central America
8 (0.2%)
110 (1.1%)
0 (0.0%)
Australia and New Zealand
22 (0.7%)
90 (0.9%)
1 (0.1%)
Southern Asia
5 (0.1%)
40 (0.4%)
1 (0.1%)
South-eastern Asia
11 (0.3%)
19 (0.2%)
0 (0.0%)
Southern Africa
0 (0.0%)
19 (0.2%)
0 (0.0%)
Caribbean
0 (0.0%)
5 (0.0%)
0 (0.0%)
Northern Africa
0 (0.0%)
1 (0.0%)
0 (0.0%)
Micronesia
0 (0.0%)
1 (0.0%)
0 (0.0%)
Table 1. Baseline information. In this table, unreported data were excluded from the calculation of both the
count (n) and the percentage (%). a The number of combination drugs was counted when other drugs were
reported for the same primary ID. b Monotherapy is counted when no other drugs are reported for one primary
ID.
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were 40–44%, suggesting no obvious differences among MAO-B inhibitors. For each drug, males were more
frequently reported than females. The highest reporting proportion was confirmed in Northern America for all
three MAO-B inhibitors. However, differences were observed in some reported areas. For example, selegiline
has a higher reporting proportion than rasagiline and safinamide in Eastern Asia, especially in Japan (950 cases
of 991 cases). ...
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