Expert Opinion on Therapeutic Patents

ISSN: 1354-3776 (Print) 1744-7674 (Online) Journal homepage: https://www.tandfonline.com/loi/ietp20

Technological prospection: Patents mapping

involving compounds for the treatment of L-DOPA-
induced dyskinesias

Sheilla da Silva Barroso, Lorenna Emília Sena Lopes, Klebson Silva Santos &
Margarete Zanardo Gomes

To cite this article: Sheilla da Silva Barroso, Lorenna Emília Sena Lopes, Klebson Silva Santos
& Margarete Zanardo Gomes (2019): Technological prospection: Patents mapping involving
compounds for the treatment of L-DOPA-induced dyskinesias, Expert Opinion on Therapeutic
Patents, DOI: 10.1080/13543776.2019.1690453

To link to this article: https://doi.org/10.1080/13543776.2019.1690453

Accepted author version posted online: 06

Nov 2019.

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 Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis
Group

Journal: Expert Opinion on Therapeutic Patents

DOI: 10.1080/13543776.2019.1690453
Technological prospection: Patents mapping involving compounds for the
treatment of L-DOPA-induced dyskinesias

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Sheilla da Silva Barroso1,2, Lorenna Emília Sena Lopes2,3, Klebson Silva
Santos2 and Margarete Zanardo Gomes1,2,3

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1
Northeast Biotechnology Network Post-Graduating, Tiradentes University,

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Aracaju, Sergipe, Brazil
2
Research and Technology Institute, Brazil
3
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Health and Environment Post-Graduating Program, Tiradentes University,
Aracaju, Sergipe, Brazil
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Corresponding author:
Sheilla da Silva Barroso,
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Laboratory of Morphology and Experimental Pathology, Research and

Technology Institute, 300 Murilo Dantas Avenue, Aracaju, Sergipe, 49032-490,
Brazil
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Tel.: +55 79 3218 2664

Email: sheillassb@hotmail.com
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Information Classification: General

 Abstract

Introduction: Parkinson's disease (PD), is a disorder debilitant characterized

by the reduction of nigrostriatal dopaminergic neurons within the midbrain,
specifically in the substantia nigra pars compacta, which results for the
dopamine (DA) depletion in the striatum. Dopamine replacement therapies with
the 3,4-dihydroxy-L-phenylalanine (Levodopa or L-DOPA) represent the most
common strategy to treat PD. However, chronic administration of L-DOPA

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results in abnormal involuntary movement (AIMs). Thus, the present study

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aimed to prospect patents of alternative treatment strategies for L-DOPA-
induced dyskinesias.

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Areas covered: This review covers the therapeutic patents published over the

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2001-2019 period in the WIPO, INPI, and ESPACENET, which report treatment
strategies for L-DOPA induced dyskinesias (LIDs).
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Expert opinion: In recent years, several pharmaceutical companies, as well as
universities and researchers have tested effective compounds for LIDs
treatment, showing substances that act on central pathways as antagonists and
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agonists of the serotonergic system, which may result in the key to onset of
LIDs in animal models of PD. Future works aiming to elucidate the L-DOPA,
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Flibanserin, Eltoprazine, and Pridopidina mechanisms of action on the receptors

of the serotonergic system and D2 receptors of the indirect pathway, will allow
the development of effective therapies for LIDs.
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Key words: patents, dyskinesias, technological prospection, abnormal

involuntary movement
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Information Classification: General

 Article highlights

• Parkinson’s disease (PD) therapy is centered to replace the loss of

striatal dopamine

• L-DOPA-induced dyskinesias are common and serious complications of

long‐term treatment with L-dopa

• The etiopathogenesis mechanisms underlying of the LID and involuntary

movements are still largely unclear, though pulsatile stimulation of post-

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synaptic striatal receptors appears to be important in their genesis

• The pharmacological effect of these compounds was evaluated in pre-

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clinical studies and the exact mechanism of action and safety should be
further evaluated

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• There is hope that new drugs for the L-dopa-induce dyskinesia are
presented and launched in the market in the next years
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Information Classification: General

 1. Introduction
Parkinson's disease (PD) is illness neurodegenerative, associated with a
motor deficit, with loss of pigmented dopaminergic neurons and subsequent
decrease of dopamine in axon terminals in the striatum [1]. The available
treatments for PD are still focused DA replacement therapy, which only
ameliorating symptoms and does not halt the neurodegenerative process [2]. In
fact, despite it was introduced almost 50 years, the use of l-3,4-
dihydroxyphenylalanine precursor (levodopa or L-DOPA) has been considered

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most common to strategies for the symptomatic treatment of PD [3,4]. However,
chronic L-DOPA use and ingestion resulting in the development of dyskinetic

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movements and in non-physiological pulsed dopamine D1 receptors pulsatile
stimulation [5,6]. These are abnormal and involuntary movements (AIMs)

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discomforting affecting about 40% - 90% of patients undergoing treatment with
worsening of the condition over time treatment with L-DOPA [7].
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Motor complications (wearing-off, dose failure, beginning of dose
worsening, end-of-dose rebound) are a consequence of chronic use of oral
formulations of L-DOPA, and its daily intake, implies in a non-physiological
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structural plasticity in the dendrites and the spines of striatal medium spiny
neurons causing alterations of glutamatergic and dopaminergic transmission
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[8,9] (Figure 1). The clinical manifestations of LID can include individual
hyperkinetic movements choreic, ballistic, or dystonic or a combination of these
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can appear as well [10].

The phenomenology and pattern of LID movements can be classified
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according to the plasma concentration of L-DOPA in, “peak-dose” dyskinesia,

which is related to the peak or highest levels of L-DOPA, occurring 1 - 2 h post-
dose. Peak‐dose dyskinesias are usually choreiform, though in the later stage’s
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dystonia can superimpose [11]. Diphasic dyskinesia occurs a few minutes after
taking the L-DOPA, or at the end of a dose, and is related with rising and
decreasing plasma concentrations of L-DOPA. This type of dyskinesias is
associated with repetitive non-purposeful behaviors, relational with L-DOPA
use. Although ON dyskinesia is usually not painful, in severe cases, some
patients may have a combination of the movements choreic, ballism, and
dystonic [12] and OFF dyskinesia, appears early in the morning or at night,

Information Classification: General

 predominantly characterized by movements dystonic, becomes more severe
when plasma L-DOPA levels are low [2]. The so-called low-dose dyskinesia that
includes OFF-period and diphasic dyskinesia responds to an increase in
dopamine stimulation and involves an approach including reducing OFF-times
and extending L-DOPA action [12].
Despite technological advances, the etiopathogenesis mechanisms
underlying of the LID and involuntary movements are still largely unclear [13]. In
rat models of PD, maladaptive plasticity resulting in supersensitive excitatory

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transmission at the pre- and post-synaptic levels [5,14], changes in extracellular
concentrations of glutamate. Among the mechanisms suggested in the

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etiopathogenesis of LIDs, oxidative stress-related to neuroinflammation [15,16].
Literature evidence indicates that chronic L-DOPA administration affects the

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synaptic transmission in the striatum that promotes changes in the firing
capacity of neurons to the exit routes of the ganglia of the base [17]. The
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present study aimed to prospect patent applications for the treatment of
dyskinesias induced by L-DOPA in the period 2001-2019.
1.1 Existing treatment for LID
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In the last decades, the treatment of LID or its prevention is a challenge

for the treatment of PD [2]. To date, the majority of novel therapies that have
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been investigated for LID are targeting peak-dose dyskinesia. Studies

conducted and validated in animal models have helped to provide information
on the mechanism of action as well as the pharmacokinetics (concentration vs.
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time) and pharmacodynamics (effect vs. time) of drugs for the treatment of LID
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[5,18]. Approaches based on the use of DA agonists reduce the risk of motor
complications and the improvement of symptoms of PD. The DA agonists show
a reduced effect in comparison to L-DOPA. The advantage of DA agonists is
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the late complications of L-DOPA, since the durant of PD treatment doses of L-

DOPA needs to be increased, improving the postsynaptic activation of the
receptors and delay the occurrence of LID [12, 19].
There are three strategies designed to improve L-DOPA-induced
dyskinesias: 1) reduction of L-DOPA doses intake at the beginning of treatment,
2) using dopamine receptor agonists, and 3) reverting dyskinesias by
stimulation of dopamine receptors for improving LID [11]. Several drugs,
clozapine, levetiracetam, aripiprazole, dextromethorphan, sarizotan and

Information Classification: General

 including amantadine (AMAN), exhibit antidyskinetic effect on the advanced
stage of PD [12].
Increased extracellular levels of dopamine and glutamate are implicated
in LIDs and N-methyl-D-aspartate (NMDA) glutamate receptor antagonists,
such as amantadine (AMAN), evidenced have been antidyskinetic effects [20-
22]. Nevertheless, treatment with AMAN may result in adverse effects such as
depression, hallucinations, and confusion mental [23,24].
The Sarizotan (5-HT 1A partial agonist) has been tested for its

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antidyskinetic properties in MPTP-treated monkeys. The data about the
sarizotan and its antidyskinetic properties expressed in the literature indicate

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that the 5HT 1A recepts not sufficient to control an L-DOPA-derived of
dopamine release and that simultaneous activation of the 5-HT 1A and 5-HT 1B

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receptors results in a potent synergistic and side effects that are minimizer of L-
DOPA medication [25]. Despite promising results in the pre-clinical studies, a
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large phase III clinical trial was terminated for lack of efficacy [26].

2. Methods
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In this review, the specialized databases such as the World Intellectual

Property Organization (WIPO), European Patent Office (EPO - Espacenet –
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Worldwide) and Instituto Nacional de Propriedade Industrial (INPI) were used to

prospect patent applications for the treatment of dyskinesias induced by L-
DOPA. The strategy used to search patents were based on inclusion criteria:
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international patents published in English or Portuguese containing the keyword

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dyskinesias in the title or abstract; with clinical or pre-clinical trials, and as

exclusion criteria: duplicate/cross-patent patents in databases; patents
unrelated to the topic; non-pharmacological treatment or genetic
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testing/modification.
The search occurred in April 2019 and included patents deposited over
the period from January 2001 to April 2019. The documents researched were
from analyzed computed individually, considering the International Patent
Classification (IPC), year and country of deposit. The limitations respecting of
confidentiality were respected.
Through the search conducted in the three databases cited, a total of
586 patients were identified in the preliminary evaluation of the data (Figure 2).

Information Classification: General

 After application of inclusion and exclusion criteria, 421 duplicate patents and
149 patents were outside the focus of the review (patents related to genetic
modification and/or were not in English at the international patents) were
excluded. Hence, was collected 16 patents that have therapeutic possibilities in
pharmacological treatment for L-DOPA induced dyskinesias (L-DOPA). For
graphics construction, Microsoft Office Excel® software was used, version
2016.

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3. Therapeutic compounds for the treatment of LIDs
This review described 18 components for the treatment of LIDs that are

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specified in the patents reviewed (Supplemental material). The compounds
efficacy here described been tested in a particular time-window from the

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nigrostriatal pathway degeneration and repetitive administration of L-DOPA
combined with benserazide in hemiparkinsonian rats for 21 days, which induces
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the occurrence of abnormal involuntary movements (AIMs). Once established,
the dyskinetic condition remains for an extended duration even in the absence
of treatment with L-DOPA, and dyskinesias appear with constant intensity each
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time the animal is acutely treated with L-DOPA [27].

In 2002, were four patents found, in which different compounds are
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described for the treatment of LIDs. The first patent selected AU2002310813
B2, assessed the effect of Flibanserin [1-(2-{4-[3-
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(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)-1,3-dihydro-2H-benzimidazol-2-one]
an antidepressant, described as a promising compound in the treatment of
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LIDs. The inventors tested Flibanserin in a model of RGS9 knockout mice,

induced by reserpine (0.5 mg/kg) and L-DOPA (10 mg/kg) intraperitoneally (i.p)
once daily, for three consecutive days. Quantification of the abnormal
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involuntary movements (AIMs) was performed after administration (i.p) of L-

DOPA, L-DOPA + Flibanserin (1 or 10 mg/kg) or L-DOPA + Buspirone (1 or 10
mg/kg), three days after from reserpine induction. The animals treated with L-
DOPA + Flibanserin 10 mg/kg showed a 64% reduction in the dyskinetic scores,
demonstrating that Flibanserin had advantages over L-DOPA + Buspirone in
the treatment of LID, where the mechanism of action is based on a synergistic
interaction with two different types of serotonergic receptors (5-HT1A agonism
and 5HT-2 antagonism) [28].

Information Classification: General

 A patent of the company AstraZeneca Pharmaceuticals LP Global
Intellectual Property in the invention WO 2002049652 A1, evaluated the
compound 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4]
-thiazepine, known as quetiapine is a typical antipsychotic agent considered to
be of good efficacy and tolerability in the treatment of schizophrenia. Applicants
after behavioral testing have observed that quetiapine could have a positive
effect on the treatment of dyskinesias associated with dopaminergic therapy.
The inventors tested the quetiapine administered subcutaneously in

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cynomolgus monkeys at doses of (2 and 4 mg/Kg). For the dyskinesias
inducing, the monkeys received 1-methyl-4phenyl-1,2,3,6-tetrahydropyrudine

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(MPTP) and treated with a dose of L-DOPA either sufficient to produce
moderate dyskinesias or sufficient to produce maximum dyskinesia. The results

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demonstrated that quetiapine administered subcutaneously at the dose of 4
mg/kg reduced the LIDs moderately (57%), where a maximum decrease of the
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LIDs was 41%. The quetiapine at a dose of 2 mg/Kg was less effective when
compared to a dose of 4 mg/Kg. The inventors propose that the most suitable
formulations be quetiapine fumarate tablets and/or capsules [29].
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In the same year, the companies MOR-Research Applications Ltd. and

NST Neuro Survival Technologies Ltd. proposed the use of the compound 2-
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amino-6-trifluoromethoxybenzothiazole, called riluzole as the treatment method

for LIDs. Patients this study filled up dyskinesias diaries in which they marked at
every waking hour whether involuntary movements were present and their
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severity (mild/moderate and severe). During the clinical trial, the patients were
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treated with riluzole having an initial dosage of 25 mg twice a day, and after a
week, the dosage increased to 50 mg twice a day. The results showed a 30%
reduction in daily vigils when dyskinetic movements were described as severe.
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In this preliminary study, showed the administration of riluzole (50 mg) can
attenuate LIDs in patients with PD without aggravating Parkinsonian symptoms
and/or suppressing the efficacy of L-DOPA. Furthermore, in this study, riluzole
use during six weeks had no adverse effects [30].
The company Newron Pharmaceuticals S.P.A. in the document
WO2004098585 A1, evaluated the effect of kynurenine-3-hydroxylase inhibitors
for the treatment of motor disorders associated with chronic treatment with L-
DOPA. The cynomolgus (Macaca fascicularis) monkeys received MPTP to

Information Classification: General

 induced parkinsonian syndrome and dyskinesias. The monkeys receiving
chronic treatment with L-DOPA (100 mg/kg) plus Benserazide (25 mg/kg; i.p)
for 3 consecutive days. The results showed kynurenine-3-hydroxylase inhibitors
RO-618048 administration alone at increasing doses (10, 30, 100 mg/kg) did
not have any effect on the locomotor activity compared to administration before
and after treatment with RO-618048. The simultaneous administration of L-
DOPA (30 mg/kg) and RO-618048 (25 mg/kg) for three consecutive days,
significantly reduced dyskinetic response to L-DOPA, in about 20%. Thus, the

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results showed that the substance L-DOPA plus RO-618048 reduced the LIDs
without side effects [31].

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In another document also in 2004, Acadia Pharmaceuticals INC through
the document WO 2004064738 A2, evaluated the effect of [N- (1-

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methylpiperidin-4-yl) -N- (4-fluorophenylmethyl) -N '- (4- (2-methylpropyloxy)
phenylmethyl), the compound known as carbamide, an inverse agonist of the
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5HT2A receptor, an effective compound for treating severe dyskinesias induced
by L-DOPA. The inventors in order to determine the potential anti-dyskinetic
activity, tested the compound carbamide in an animal model (MPTP) to induce
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parkinsonism in monkeys, coupled with prolonged administration of L-DOPA to

induces severe dyskinesias. The compound carbamide, when administered s.c
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in dyskinetic primates was found to significantly decrease L-DOPA induced

dyskinesias at the dose of 0.3 mg/kg when compared to the vehicle substance
[32].
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In 2008, Universita' Degli Studi di Ferrara, proposed the use of the

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compound receptor peptide agonist UFP-112 and RO 65-6570 as the treatment

method for LIDs. The rats were lesioned with 6-OHDA in MFB and two weeks
after lesion, the degree of DA depletion is assessed through behavioral tests.
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Four weeks after lesion, the animals selected, i.e. those with a >95% lesion of
the DA system, received subcutaneously injected with L-DOPA (6 mg/kg) plus
benserazide (15 mg/kg), once daily for 21 days. The results showed that the
receptor peptide agonist UFP-112 at a dose of 0.01 pmol/L evident an
antidyskinetic effect in about 50%. In the same study, a 70% decrease in
dyskinesias was shown for compound RO 65-6570 at a dose of 0.01 mg/kg, the
antidyskinetic effect was evident at 20 min following L-DOPA administration,
with maximum peak after 60 min and after this time the effect gradually declined

Information Classification: General

 in 120 min. During the AIMs 180 min test period, the dyskinetic animals showed
abnormal movements that affected the body axis, limbs, orolingual and
locomotion [33].
The patent document US 20080260825 A1 evaluated the nicotine effect
on the dyskinesias in a non-human primate model. Squirrel monkeys (Saimiri
sciureus) subcutaneously received 2.0 mg/kg MPTP and were rated for
parkinsonism 3-4 weeks after MPTP administration. All monkeys in the treated
group received a solution containing nicotine and Gatorade to drink for 3 weeks,

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while the control group ingested only Gatorade. Nicotine dosing was started at
50 pg/mL for 1 week, and the concentration, increased by 150 ptg the following

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a few weeks, up to 650 ptg/mL. Monkeys were treatment L-DOPA/carbidopa (5
mg/kg and 1.25 mg/kg, respectively), for 8 weeks. During levodopa treatment,

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the monkeys were given fruits in the morning and food pellets 3.5 hours after
the afternoon L-DOPA dose to optimize gastrointestinal absorption. The results
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showed that 80% of the animals developed stable parkinsonism, and 0.5 mg/kg
treatment with nicotine attenuated the dyskinesias at the maximum dose
throughout the day for 8 weeks [34].
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The mechanisms related to the activation of nicotinic receptors and as

these may affect the expression of LIDs remains unclear [2]. Pharmacological
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studies with nicotinic receptor agonist and antagonist ligands demonstrated to

reduce LIDs in PD animal models. In addition, nicotine also demonstrated to
providing neuroprotection [35].
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In another document, the company Neurosearch A/S through the

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invention WO 2009156380 A1, the rats were lesioned with 6-OHDA in MFB and
treated with L-DOPA and L-DOPA combined a 5-HT1A and 5-HT1B receptor
agonist Eltoprazine 0.1 mg/kg or L-DOPA plus Eltoprazine 0.3 mg/kg,
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respectively. The results showed that Eltoprazine decreased approximately

50% of the dyskinetic motions at the dose 0.1 mg/kg compared to the group
treated with L-DOPA alone, as well as attenuated the LIDs in relation to the
dose of 0.3 mg/kg, noting that in the last dose few orolingual movements were
observed [36].
In 2010, the number document WO2010097092 A1, evaluated
antidyskinetic effect by compound (4aR, 10aR)-1-n-propyl-
1,2,3,4,4a,5,7,8,9,10,10a-octahydro-benzo[g]quinoline-6,7-diol [herein referred

Information Classification: General

 to as Compound 10] (0.1 and 50 mg/ day; administered subcutaneously). The
rats with unilateral 6-OHDA lesions received L-DOPA/Benserazide (6mg/kg and
15 mg/kg; administered subcutaneously, respectively) for 14 consecutive days
for inducing LIDs. Following this experiment, all rats were given subcutaneous
injections of compound 10 and after 8 days of treatment in hemiparkinsonian
rats was a significant decrease in the LIDs, in addition to an increase in the
locomotor activity of the animals [37].
In another document (WO 2010147938 A2) also in 2010, evaluated the

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effect of compound (R)-5-((E)-2-pyrrolidin-3-yivinyl)pyrimidine [herein referred to
as PD1] in biological testing as a promising compound for treating LIDs. The

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rats were lesioned with 6-OHDA and 2 weeks after initiation of drug treatment,
the animals were administered injections of L-DOPA (6-8 mg/kg) plus

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benserazide (15 mg/kg; administered subcutaneously) daily for dyskinesias
inducing. Treatment with compound PD1 was systemically infused via osmotic
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minipumps in doses of (0.1 and 0.3 mg/kg) for 6 weeks. The results showed
that administration of PD1 at doses (0.1 and 0.3 mg/kg) a significant reduction
of AIMs, total or in any subtype (axial, oral and/or limb). The results presented
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demonstrate that compound PD1 appears to be a promising compound for

reducing L-DOPA-induced AIMs without aggravating parkinsonism at any of the
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doses tested throughout the experiment [38].

In 2011, Merck Serono SA, through a randomized study of 36 patients,
found that daily doses greater than 200 mg Safinamide or Safinamide
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Methanesulfonate are effective in the treatment of dyskinesias (chorea and

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dystonia), particularly in patients in advanced stages of PD with treatment by L-

DOPA [39].
In 2012, University of Medicine and Dentistry of New Jersey under
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WO2012149113 A1, it was aimed to verify the efficacy, safety, and dosage of
Nalbuphine in the treatment of LIDs. Macaque monkeys (Macaca FascicuJaris)
are used in these studies, to which MPTP [0.5-0.8 mg/kg; administered
intravenously (iv)] until a stable Parkinsonian state of moderate to severe
degree develops. Induction of the LIDs occurred by oral administration of
levodopa/carbidopa (25 mg/Kg and 100 mg/kg, respectively) twice daily. The
study was divided into A (Nalbuphine 0.1 mg/kg plus L-DOPA 75 mg/kg or
Nalbuphine 0.2 mg/kg plus L-DOPA 75 mg/kg) and B (L-DOPA 75 mg/kg, L-

Information Classification: General

 DOPA 75 mg/kg plus Nalbuphine 0.25 mg/kg or L-DOPA 75 mg/kg plus
Nalbuphine 0.5 mg/kg). The results demonstrated that at time A was found a
decrease in severity and duration of dyskinesias occurs. At the time B, the
animals receiving the highest Nalbuphine dose had a better reduction of the
LIDs in relation to the lower dose, suggesting a dose-response effect [40].
The invention of the company Melior Discovery, INC. patented WO
2014145126 A2 evaluated the effect of Sydnocarb at doses (10 and 30 mg/kg,
i.p) and L-DOPA/benserazide (12 ml/kg, ip). Rats were lesioned with 6-OHDA.

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Two weeks later were treated with L-DOPA at 12 mg/kg and Sydnocarb at (10-
30 mg/kg, i.p) for 12 days. The treatment with this dose of L-DOPA produced an

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increase in AIMS compared vehicle. The results with the compound Sydnocarb
for 12 days demonstrate that the compound had a number of 20-fold lower

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dyskinetic scores when treatment was compared to L-DOPA vehicle [41].
In 2018, Northwestern University associated with WO 2018013951 A1
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evaluated the A2aR adenosine receptor (Tozadenant) attenuates the induction
of LID. Mice were lesioned with 6-OHDA. Three weeks after surgery, mice
underwent treatment with L-DOPA at the dose of (3 mg/kg) was given daily for
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15 days for dyskinesias inducing. The treatment with Tozadenant (30 mg/kg)
was given 5-6 hours after L-DOPA doses. The results showed that the systemic
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administration of Tozadenant 5 hours after the dose of L-DOPA reduces the

behavioral changes related to the LIDs [42].
In 2019, WO2019050775 A1 evaluated the potential antidyskinetic effect
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of Pridopidine in an acute experiment using the non-human primate model of

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parkinsonism induced by 0.2 mg/kg MPTP. The invention was performed with
the induction of L-DOPA (25 mg/kg) alone or in combination with doses of
pridopidine (7, 15, 20 and 30 mg/kg). The inventors assume that low doses (7
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and 15 mg/kg), the effect of pridopidine is mainly mediated by the sigma-1

receptor (SIR), while in the higher doses (20 and 30 mg/kg), pridopidine
connects to SIR. Pridopidine at the dose of 20 mg/kg significantly reduced the
effect of dyskinesias over the two-hour period with a moderate effect and at the
third hour the dose of 30 mg/kg showed a mild to moderate effect. It is
suggested that the motor activity of pridopidine can be mediated mainly by its
moderate affinity targets, including antagonistic activity at the dopamine D2
receptor [43].

Information Classification: General

 4. Expert opinion
The LIDs represent a medical problem due to limited dopamine
replacement, consisting of involuntary motor disorders, dystonia, athetosis and
chorea [9]. The treatments for LIDs are based on NMDA receptors, where a
single drug, amantadine, has been gold standard with antidyskinetic effect,
however, in the long run, it exhibits significant side effects [24]. Studies in vivo
models (rodents and non-human primates) have been widely used in the tests
to expand the understanding of the LID-related pathophysiology and thus to

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study new therapeutic targets [44].
The compounds were positive in experimental animal models but failed

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in clinical trials except for the amantadine retarded release formulations. The
reasons are rather simple, i.e. the uniform expression of dyskinesia in models

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but the complex causes and interactions between dopamine substituting drugs
pharmacokinetic and pharmacodynamic properties in PD patients [45].
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The compounds analyzed no demonstrated side effects in all studies.
However, further research is needed to improve treatment options and the
action of the possible mechanism involved in pathogenesis in LID.
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In analysing the depositary countries, it was noted that the United States
(USA) stands out with a total of nine patents, Australia and Germany being tied
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with two each country, followed by Italy, the United Kingdom and Canada all
with only one patent each. Brazil had no registered patent deposit (Figure 3).
According to Figure 4, were found 16 patents registered from 2002 to
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2019. There has been a reduction in the number of patents between 2002 and
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2004, resulting in an interruption between the years 2005 to 2007. From 2008
the rate of deposits was positive, with subsequent linearity, these changes in
deposit profile of patents could be due to the confidentiality of time requests.
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In assessing the profile of patent depositors related to the treatment of L-

DOPA-induced dyskinesias, it can be observed that pharmaceutical companies
(62%) exhibits highest amount of patent deposited for the LID treatment. A
small portion was disclosed by universities (25%) and individuals (13%),
respectively (Figure 5).
From patents analyzed, 85.7% (n = 14) demonstrated that the
compounds tested for the treatment of LIDs were evaluated through preclinical
studies, an already expected analysis, since tests of efficacy and safety in the

Information Classification: General

 use of new compounds. The protocols for inducing dyskinesias in vivo models
with rodents and nonhuman primates provide an exceptional tool for studying
dyskinesias, since when administered chronically, L-DOPA develops AIMs like
the dyskinesias observed in patients with PD (LUNDBLAND et al. 2002).

Author contributions
The authors S da Silva Barroso and LE Sena Lopes contributed to
conceptualization; investigation and validation phases; S da Silva Barroso, K

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Silva Santos, and M Zanardo Gomes designed the study, supervised the work,
analysis of the data, drafted the paper and contributed to critical reading of the

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manuscript.

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Funding
This paper was not funded.
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Declaration of interest
The authors have no relevant affiliations or financial involvement with any
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organization or entity with a financial interest in or financial conflict with the

subject matter or materials discussed in the manuscript. This includes
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employment, consultancies, honoraria, stock ownership or options, expert

testimony, grants or patents received or pending, or royalties.
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Reviewer disclosures
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Peer reviewers on this manuscript have no relevant financial or other

relationships to disclose.
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Suppplemental material:
m Ch
hemical strructures of the compo
ounds foundd in the paatents

publiished in thee last 18 yeaars and usedd in the treattment of LID

Ds.

Moleecular structture and loccal destiny uused for co

onstruction of
o the suppllementary

figurre:

Informattion Classifica
ation: Genera
al
 (1) Flibaserin (Patent AU2002310813 B2); (2) Buspirone; (3) Quetiapine; (4) Riluzole;
(8) UFP -112; (9) RO65-6570; (10) Nicotine; (14) Safinamide
https://www.guidetopharmacology.org; (5) Kynurenine https://www.sigmaaldrich.com;
(6) RO61 -8048 https://www.invivochem.com/ro-61-8048; (7) Carbamide; (16)
Sydnocarb; (17) Tozadenant http://www.chemspider.com; (11) Eltoprazine (Patent WO
2009156380 A1); (12) (4aR, 10aR)-1-n-propyl-1,2,3,4,4a, 5,7,8,9,10,10a-octahydro-
benzo[g]quinoline-6,7-diol (Patente WO2010097092 A1); (13) PD1 (Patent WO
2010147938 A2); (15) Nalbuphine (Patent WO2012149113 A1); (18) Pridopine Site:
https://www.medchemexpress.com/Pridopidine.html

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