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Accepted Manuscript
One year safety and efficacy of inosine to increase the serum urate
level for patients with Parkinson's disease in Japan
Hirotaka Iwaki, Ando Rina, Noriyuki Miyaue, Satoshi Tada,
Tomoaki Tsujii, Hayato Yabe, Noriko Nishikawa, Masahiro
Nagai, Masahiro Nomoto
PII:
DOI:
Reference:
S0022-510X(17)34411-8
doi:10.1016/j.jns.2017.10.030
JNS 15625
To appear in:
Journal of the Neurological Sciences
Received date:
Revised date:
Accepted date:
20 August 2017
27 September 2017
23 October 2017
Please cite this article as: Hirotaka Iwaki, Ando Rina, Noriyuki Miyaue, Satoshi Tada,
Tomoaki Tsujii, Hayato Yabe, Noriko Nishikawa, Masahiro Nagai, Masahiro Nomoto ,
One year safety and efficacy of inosine to increase the serum urate level for patients
with Parkinson's disease in Japan. The address for the corresponding author was captured
as affiliation for all authors. Please check if appropriate. Jns(2017), doi:10.1016/
j.jns.2017.10.030
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ACCEPTED MANUSCRIPT
One year safety and efficacy of inosine to increase the serum urate level for patients with
Parkinson’s disease in Japan.
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1
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1
Hirotaka Iwaki , Ando Rina , Noriyuki Miyaue , Satoshi Tada , Tomoaki Tsujii , Hayato Yabe , Noriko
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Nishikawa , Masahiro Nagai , Masahiro Nomoto
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1. Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine,
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Japan
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Corresponding author:
Hirotaka Iwaki
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Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine,
Shitsukawa, Toon, Ehime 791-0295, Japan
Tel.: +81 89 960 5095
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h-iwaki@m.ehime-u.ac.jp
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Keyword:
Parkinson's disease; Inosine; Urate; Uric Acid; Clinical trial; Oxidative stress; Antioxy dant;
Asian;
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Abstract
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Background: Epidemiological studies have repeatedly reported that increased serum urate
level is associated with a slower progress of Parkinson’s disease (PD). The urate precursor,
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inosine, raises the serum urate level and is therefore a candidate for a disease modifying
treatment. However, an elevated serum urate level is a risk factor for gout, urolithiasis, and
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cardiovascular diseases. Although there have been previous clinical studies, the use of
inosine in a clinical setting is still limited, and its safety is unclear, especially in an Asian
population.
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Methods: We conducted a single-arm, single-center clinical trial to assess the safety of
inosine for PD patients with relatively low urate levels. After informed consent, 10 subjects
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were orally administered inosine to maintain a target urate level between 6.0 mg/dl and 8.0
mg/dl for one year. All adverse effects were recorded and categorized by severity. Also, the
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efficacy of using inosine to raise the serum urate level was reported.
Results: We did not observe any adverse events requiring termination or reduction of the
study drug, although uric acid crystalluria was transiently observed in a single subject. An
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inosine dosage of 1070 (SD=501) mg/day significantly raises the urate level from 3.5 (0.84)
mg/dl at baseline to 6.68 (1.11) mg/dl at the 52nd week.
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Conclusions: Inosine was safely used for one year and effectively raised urate levels in a
small group of subjects. Our study is the first report to use inosine for patients with PD in
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an Asian population.
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Introduction
Parkinson’s disease (PD) is one of the most prevalent neurodegenerative diseases, affecting
about 0.4 % of the general population between the ages of 60 to 69, and 1.0 % of those
between 70 and 79. 1 The mechanism of developing PD is unknown but there is much
evidence that an oxidative process is involved. 2–4 The most abundant antioxidant in the
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human body is urate5,6. High serum urate levels have been shown to be associated with
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lower incidence as well as slower progression of PD 7– 11. Moreover. recent studies of urate
supporting the causal link between urate and PD.
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transporter SNPs and PD support the hypothesis that urate is protective against PD, 12–14
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Urate is also regarded as a potential protective agent for Multiple Sclerosis (MS), and there
have been several studies to investigate its potential. To raise serum urate levels in MS
patients, a urate precursor, inosine, was orally administered in the clinical trials. 11 It has
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been used for up to three years for patients with MS,15,16 and successfully raised serum
urate levels. The only serious adverse event was urolithiasis, which was safely controlled
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with hydration and the cessation of inosine medication. Although a high serum urate level
can result in gout and urolithiasis; and it is also reported to be associated with kidney
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dysfunction, stroke, and coronary heart disease1 7; these previous research results may
advocate inosine usage in PD patients. In fact, after the initiation of our study, a clinical
trial to apply inosine for PD patients (SURE-PD study) was reported from the United
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States.
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However, even combining MS patients and PD patients together, the total number of
patients reported to have used inosine is only 206, 15,16,18–21, too few to conclude the safety
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profile for inosine. And most of those were MS patients (156 people), who are a relatively
young population than those with PD. Moreover, all these studies were conducted in either
Europe or the United States, illustrating the need for additional safety information,
especially in an Asian population.
We conducted rigorous safety assessments of the use of inosine for PD patients, as well as
an assessment of the efficacy of using inosine to increase the serum urate level among
Japanese PD patients, in a single-arm, single-center trial. This is the first report of clinical
usage of inosine in PD patients in Asian population.
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Method
Stu dy design and participants
The study was a single-center, non-randomized, open-label trial conducted in Ehime
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University Hospital in Ehime, Japan, from October 9th, 2012 to August 3rd, 2016. We
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enrolled patients older than 20 years old of age with idiopathic PD, diagnosed by UK
Parkinson’s disease Brain Bank criteria, with lower serum urate levels than the average in
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the PD cohort of Ehime University Hospital (male 5.5 mg/dL, female 4.2 mg/dL). We
excluded patients with low pH urine at baseline (< 5.0) or with a history of gout,
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urolithiasis, chronic heart diseases or kidney diseases, due to the possibility of a higher risk
of adverse events. All the participants gave informed consent to a protocol approved by
Ehime University’s institutional review board of clinical research ethics. The outline of the
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protocol has been avalable as of October 9th, 2012, on the public database UMIN-CTR,
editors
(ICMJE).
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which complies with recommendations of the International committee of medical journal
(Publishing
site;
https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000010637).
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Upon enrolment, patients undertook medical checkups as well as assessments of the
severity of Parkinson’s disease using Hoehn and Yahr’s Stage and Unified Parkinson’s
disease rating scale part II and III. Their medical history, other comorbidities, and
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medications were also recorded.
Procedures
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In the study phase, oral inosine of 1000mg/day (morning and evening, 500 mg/tablet each)
was administered to participants. Blood and urine samples were taken at each visit
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(usually 3-5 hours after inosine medication; Approximate peak 20). According to their serum
urate levels, the dose was titrated between 500 and 2000 mg per day with a 250 mg ladder
to achieve a serum urate level between 6.0 mg/dL to 8.0 mg/dL. The initial 12 weeks were
defined as a titration period, where they visited us 2, 4, 8, and 12 weeks after initiation of
the medication. Then, participants were scheduled to visit the study site with an interval of
8 weeks at the longest, for 52 weeks. The research investigators were allowed to change the
dosage of inosine according to the participants’ serum urate levels in this maintenance
period, if necessary. Inosine medication was finished at the visit in the 52nd week and,
barring complications, participants were discharged from the study after the safety
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check-ups at the 56th week.
Measurements
At each visit, participants had routine medical examinations and any new symptoms or
possible inosine complications were recorded in case reports. Because the doctors were able
to adjust anti-Parkinson’s medications, any prescription change was also recorded at each
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visit. Routine assessments of the severity of the disease were scheduled at the visits in the
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4th, 16th, 36th, 52nd and 56th weeks. The complete blood counts and general lab tests such
as liver enzymes and kidney function markers were checked. Urine analysis included
urine pH, urate concentrations and urine density. Also,
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microscopic observation for stones,
physiological studies such as kidney echogram, echocardiogram, and electrocardiograms
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were checked every three months. Participants left the study when they withdrew informed
consent or didn’t comply with the protocol at all (e.g., < 50% drug compliance), or when
investigators found it difficult or harmful to continue the study.
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Statistical analysis
For the safety analysis, we summarized all of the adverse events we observed and their
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severity as: “severe” in cases of death, hospitalization, or any condition that would
necessitate the subject being withdrawn from the study or told to stop taking the
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medication because of safety concerns; “moderate” when the dose of inosine should be
reduced other than to achieve the target urate range; and “mild” as symptoms or
phenomena that could be followed-up without intervention. To detect any asymptomatic or
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unnoticed adverse events, we also compared patients’ laboratory and physiological data as
well as disease-specific scores at the 52nd week to baselines. The efficacy of inosine
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increasing serum urate levels in a target dose is described by the serum urate level at the
52nd week compared with the baseline. Also, the achievement ratio was calculated as
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follows: if the urate level was within the target level on a particular visit, the whole
duration from one day after the last visit to the present day were counted as achieved, and
it was divided by the entire duration of the maintenance period.
Test results at the 52nd week (the end of medication) were compared between those at
baseline with a paired t-test for continuous variables or signed rank test for non-parametric
variables. We used the double-sided significance level of 0.05 in the analyses conducted
with SAS® (version 9.4, SAS Institute Inc., Cary, NC, U.S.A).
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Results
Among 23 screened, a total of 10 patients (4 males and 6 females) participated in the study.
They all finished the last scheduled visit at the 56th week. Their baseline demographics are
summarized in Table 1. Regarding safety, no severe or moderate complications were
observed. All the adverse events defined as mild were transient, and these incidents were
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likely unrelated to inosine (Table 2). Among lab tests of urine and blood, one patient had
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uric acid crystalluria, but it was only observed once and never again.
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When we compared the baseline data with those at the 52nd week, the urine pH at the
52nd week compared with the baseline showed a marginal difference (p = 0.07, Table 1),
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and the chronological boxplots seemed to change downward after the initiation of inosine
medication (Figure 1C). Also, the amount of urate per 1.0 g of urine creatinine increased as
the serum level of urate increased. Vital signs such as body weight, blood pressure, heart
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rate, and the lab test results of the blood and the urine did not show significant changes at
the 52nd week from the baseline. The disease-specific symptomatic markers did not differ
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significantly between the baseline and the 52nd week with a similar level of treatment
strength (Table 1 and Figure 1D). The physiological tests using echography or electric
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cardiograms did not detect any abnormality either.
At the 52nd week, the mean serum urate level was 6.68 (SD; 1.11) mg/dL, which was
significantly different from the baseline of 3.50 (0.84) mg/dL (p < 0.001), with the inosine
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dosage of 1075 (501) mg/day (Table 1). The ratio of achieving the serum urate level within
the target range of 6.0-8.0 during the maintenance period was 61%. The mean urate levels,
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as well as the prescription dosage, were relatively stable over the medication period, with
the swift return to baseline level as soon as four weeks from the termination of the
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medication (Figures 1A/B).
Discussion
We used inosine medication to raise the serum urate levels of patients with PD and with
lower urate levels for one year, and did not observe any adverse events that required
stopping or decreasing inosine. We adjusted the individual dosage to maintain the target
serum urate level between 6.0 – 8.0 mg/dL, and the serum urate level was effectively
increased by inosine. But the ratio of achieving the target range during maintenance period
was 61%, lower than expected. We assume this was partially because we were trying to
avoid the possible complications of high urate levels. In fact, participants had serum urate
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levels between 5.5 and 5.9 mg/dL, a little lower than the target range, in 16% (16/100) of
the visits in the maintenance period. Serum urate fluctuations might also have affected the
achievement. 11% of all visits (17/150) had more than a 1.5 mg/dL difference in the serum
urate level from the previous visit with the same inosine dosage. If a subject forgot their
morning medication, the serum urate level would on average decrease by 1.0 mg/dL from
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the previous reports20, in addition to 0.5 mg fluctuations within individuals. 22 Therefore,
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the duration between the last medication and blood sampling mattered although we do not
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have the data to confirm this.
We conducted post-hoc analysis of the dose response relationship and it indicates that the
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serum urate level measured at the first visit after the initiation of inosine is useful to
predict the maintenance dose (Supplement table). There may be other variables such as
body weight and baseline urate levels, but our date size was too small to develop a full
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prediction model. Such an approach may be taken for future study.
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The major difference of our study from previous studies is its population’s characteristics.
Our participants were all Asians (Japanese) and the oldest among all the studies using
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inosine. Epidemiological studies reveal that the prevalence of gout in Japan is rarer than in
western countries and the prevalence of patients with gout by age and sex are also
different.23,24 In addition, the distribution of urate transporter related SNPs is different. 25
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Yet despite these differences, we did not find any problematic comp lications, including the
associated diseases. When using inosine, the most common adverse event reported is
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urolithiasis, but we did not observe this. It may relate to the small number of participants,
but the relatively modest elevation of urate in our participants may be a reason, too. For
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example, SURE-PD study reported zero events in the placebo group, one event among 24 in
the mild (6.1-7.0) urate elevation group, and two events among 26 in the moderate (7.1-8.0)
urate elevation group.20 Another difference is that we observed a marginal decline in urine
pH after inosine initiation. Considering our small study size, it is more likely an
observation by chance, but can be a population difference. Acidic urine is a known risk
factor for urolithiasis, 26 as well as a high concentration of urate in urine, which was
observed in our analysis (Table 1).
Also, the average increase in the serum urate level of inosine was larger in our study (+3.2
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mg/dL by 1.08 g/day of inosine) than observed in SURE-PD (+2.3 mg/dL by 1.18 g/day and
+3.0 mg/dL by 1.51 g/d ), which may reflect the population difference. Again, we stress the
importance of titration according to individuals. In the secondary analysis of SURE-PD
study, it showed UPDRS based non-futility of inosine as a disease modifier. Interestingly,
our 10 participants did not show disease progression during the study period, and it made
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us feel more optimistic about the disease-modifying potential of inosine.
One limitation of our study was its small size. However, as this was the first study using
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inosine in an Asian PD population, we intentionally chose a small sample size. Although we
don’t have enough data to conclude the safety of inosine, the sample size was still sufficient
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to assess the efficacy of inosine to raise serum urate levels. Another limitation was the
single-arm design, which precluded us from assessing the association of inosine medication
and the incidence of adverse events by comparing them to a placebo group. However, we did
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not find any clinically relevant adverse events other than uric acid crystalluria, and as we
described all the adverse events, the information may be useful for combined safety
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analysis in the future.
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Out strength was that our vigorous safety assessment of using inosine for PD patients
supports the safety of inosine in an older, Asian population, one that is distinct from the
European and North American populations that have already been studied. These results
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warrant inosine application for wider populations, and support the next step of larger
clinical trials to assess the further safety as well as efficacy of inosine for preventing or
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Conclusion
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modifying the development of Parkinson’s disease.
We conducted the safety and efficacy assessment of using inosine for PD patients for the
first time in an Asian population. Inosine effectively raised serum urate levels of
participants with relatively low dosages than in other studies in Europe and the U.S., and
we have not observed any problematic adverse effect. This study will encourage the next
step in the assessment of the efficacy and the safety of using inosine for PD patients.
Acknowledgment
We thank Kanno Mari for her precise data handling and management. We also appreciate
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insight and advice of Donald Halsted and Karen Dobson, who were kind enough to review
this manuscript.
Contributors
Dr. Iwaki and Dr. Nomoto contribute to the conception of the study. Dr.Iwaki also designed
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the study and analyzed and interpreted the results. Dr. Ando, Dr.Miyaue, Dr.Tada, Dr. Tsujii, Dr.
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Yabe, Dr.Nishikawa, Dr. Nagai and Dr. Nomoto acquired the data and all of them contributed to the draft
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and gave the final approval of the manuscripts.
Disclosure
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Dr. Nomoto has received speaker's honoraria from Dainippon Sumitomo Pharma Co., Ltd., Hisamitsu
Pharmaceutical Co., Inc., Kyowa Hakko Kirin Co., Ltd., Novartis Pharma K.K., and Otsuka
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Pharmaceutical Co., Ltd. The other authors have nothing to disclose.
Funding
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This work was financially supported by a hospital research grant from Ehime University
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Hospital.
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At 52nd week
P value
N
10, female 6
-
-
Race – Asian (%)
10 (100 %)
-
-
Age, years
67.3 (10.9)
-
-
BMI, kg/cm2
21.7 (2.5)
-
-
Disease duration, years
8.7 [1.5, 13.0]
-
Wearing Off, N (%)
4 (40%)
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Inosine dosage, mg/day
-
1075 (501)
-
Serum level of urate, mg/dL
3.50 (0.84)
6.68 (1.11)
<0.001
Urine pH
7.0 [6.0, 7.5]
6.5 [5.0, 7.0]
0.07
eGFR, ml/min/m2
79.0 (10.7)
73.5 (7.2)
0.108
Urine urate, mg /1.0 g creatinine
0.53 (0.18)
0.92 (0.29)
0.011
Hoehn and Yahr Scale
2.5 [2.0, 5.0]
2.5 [2.0, 4.0]
1.00
UPDRS part II
6.5 (4.1)
6.8 (4.2)
0.56
UPDRS part III
14.4 (7.5)
11.3 (6.6)
0.29
400 (225)
420 (224)
0.17
699 (417)
715 (420)
0.39
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Levodopa Equivalent Dose, mg/day
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Levodopa Medication, mg/day
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Baseline
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Table 1 Summary Characteristics
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Values are means(SD) or Median [range], unless specified.
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BMI, body mass index; eGFR, estimated glomerular filtration rate; UPDRS, unified
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Parkinson’s disease rating scale.
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Table 2 Adverse events
N (out of 10)
0
Moderate
0
Mild
15
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Severe
4
(3 unknowns, 1 herpes simplex virus)
Pain
3
(1 back pain, 1 pelvic pain, 1 knee pain)
Glucose Resistance
1
Nausea
1
Dizziness
1
Overacting bladder
1
Cyst formation under a lib bone
1
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Tinea pedis
1
1
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Hemorrhoids
Asymptomatic
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Uric acid crystalluria
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Virus infection
1
1
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Figure 1 Legend:
The trend of the key measurements over the study duration.
A: The serum urate level over the study period. (Error bar; SD)
B: The mean inosine dosage over the study period. (Error bar; SD)
C: Boxplot of urine pH over the study period.
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D: UPDRS part III score over the study period.(Error bar; SD)
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Figure 1
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Highlights

Inosine was used for the first time in clinical research with an Asian population
with Parkinson’s disease.
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There were no problematic adverse effects in a small group of patients.
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Inosine effectively raised serum urate levels of participants with relatively lower
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dosages than in other studies in Europe and the U.S.
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