Higher Levodopa Dose Research Articles

Analysis of factors associated with brittle response in patients with Parkinson's disease.

IntroductionThe brittle response (BR) in patients with Parkinson’s disease (PD) refers to a special type of levodopa‐induced dyskinesia (LID). This study aimed to describe the clinical characteristics of BR patients and to analyze the associated risk factors.MethodsA retrospective study was conducted to analyze the data of 97 patients with PD. Patients were divided into a BR group and a non‐brittle response (NBR) group. Demographic and clinical data, motor symptoms, and non‐motor symptoms of the two groups were assessed.ResultsAmong 97 PD patients, 11 were in the BR group and 86 were in the NBR group. The proportion of female patients was 72.7% and 38.3%, respectively, in the BR and NBR groups (P < 0.05). Compared to NBR patients, BR patients had relatively low body weight, low BMI, long disease duration, high levodopa equivalent daily dosage (LEDD), and high levodopa dose per weight (P < 0.05). The BR group had significantly higher scores of UPDRS (II, III, and IV) (P < 0.05). But no difference was found in the UPDRS I, emotional state, cognitive status, and accompanied by REM sleep behavior disorder (RBD) (P> 0.05). Multivariate logistic regression analysis showed that BR patients had lower body weight and higher levodopa dose per weight.ConclusionBR is associated with being female, low body weight, low BMI, long disease duration, high LEDD, and high levodopa dose per weight. Body weight and levodopa dose per body weight are independent risk factors for BR.

Freezing of Gait in People with Parkinson's Disease: Nature, Occurrence, and Risk Factors.

Freezing of gait (FOG) is a common symptom of Parkinson's disease (PD) which can result in falls and fall related injuries, poor quality of life and reduced functional independence. It is a heterogeneous phenomenon that is difficult to quantify and eludes a unified pathophysiological framework. Our aim was to document the occurrence and nature of freezing, cognitive stops and stumbles in people with PD during walks with varying cognitive loads and conditions designed to elicit FOG. 130 people with PD walked under four conditions (normal walking, walking plus easy and hard dual-tasks, and a FOG elicitation condition. Video and accelerometry recordings were examined to document freezes and other gait disruptions. Participants experienced 391 freezes, 97 cognitive stops and 73 stumbles in the trial walks; with total gait disruptions increasing with task complexity. Most freezes in the FOG elicitation condition occurred during turning and approach destination. People who experienced freezing during the walks were more likely to have Postural Instability and Gait Difficulty (PIGD) subtype, longer disease duration and more severe UPDRS part II and part III sub-scores than people who did not freeze. They also took higher doses of levodopa, reported freezing in the past month, more prior falls, had poorer executive function, poorer proprioception, slower reaction time, poorer standing and leaning balance, more depressive symptoms, lower quality of life and greater fear of falling. PD disease duration, reduced controlled leaning balance and poor proprioception were identified as independent and significant determinants of freezing in logistic regression analysis. The multiple motor and cognitive factors identified as being associated with freezing, including poor proprioception and impaired controlled leaning balance provide new insights into this debilitating PD symptom and may contribute to potential new targets for rehabilitation.

Striatal Nurr1 Facilitates the Dyskinetic State and Exacerbates Levodopa-Induced Dyskinesia in a Rat Model of Parkinson's Disease.

The transcription factor Nurr1 has been identified to be ectopically induced in the striatum of rodents expressing l-DOPA-induced dyskinesia (LID). In the present study, we sought to characterize Nurr1 as a causative factor in LID expression. We used rAAV2/5 to overexpress Nurr1 or GFP in the parkinsonian striatum of LID-resistant Lewis or LID-prone Fischer-344 (F344) male rats. In a second cohort, rats received the Nurr1 agonist amodiaquine (AQ) together with l-DOPA or ropinirole. All rats received a chronic DA agonist and were evaluated for LID severity. Finally, we performed single-unit recordings and dendritic spine analyses on striatal medium spiny neurons (MSNs) in drug-naïve rAAV-injected male parkinsonian rats. rAAV-GFP injected LID-resistant hemi-parkinsonian Lewis rats displayed mild LID and no induction of striatal Nurr1 despite receiving a high dose of l-DOPA. However, Lewis rats overexpressing Nurr1 developed severe LID. Nurr1 agonism with AQ exacerbated LID in F344 rats. We additionally determined that in l-DOPA-naïve rats striatal rAAV-Nurr1 overexpression (1) increased cortically-evoked firing in a subpopulation of identified striatonigral MSNs, and (2) altered spine density and thin-spine morphology on striatal MSNs; both phenomena mimicking changes seen in dyskinetic rats. Finally, we provide postmortem evidence of Nurr1 expression in striatal neurons of l-DOPA-treated PD patients. Our data demonstrate that ectopic induction of striatal Nurr1 is capable of inducing LID behavior and associated neuropathology, even in resistant subjects. These data support a direct role of Nurr1 in aberrant neuronal plasticity and LID induction, providing a potential novel target for therapeutic development.SIGNIFICANCE STATEMENT The transcription factor Nurr1 is ectopically induced in striatal neurons of rats exhibiting levodopa-induced dyskinesia [LID; a side-effect to dopamine replacement strategies in Parkinson's disease (PD)]. Here we asked whether Nurr1 is causing LID. Indeed, rAAV-mediated expression of Nurr1 in striatal neurons was sufficient to overcome LID-resistance, and Nurr1 agonism exacerbated LID severity in dyskinetic rats. Moreover, we found that expression of Nurr1 in l-DOPA naïve hemi-parkinsonian rats resulted in the formation of morphologic and electrophysiological signatures of maladaptive neuronal plasticity; a phenomenon associated with LID. Finally, we determined that ectopic Nurr1 expression can be found in the putamen of l-DOPA-treated PD patients. These data suggest that striatal Nurr1 is an important mediator of the formation of LID.

Safety of Levodopa-Carbidopa Intestinal Gel Treatment in Patients with Advanced Parkinson's Disease Receiving ≥2000 mg Daily Dose of Levodopa.

Background Levodopa-carbidopa intestinal gel (LCIG) provides continuous levodopa administration and clinical benefits to patients with advanced Parkinson's disease (PD). This report evaluates long-term safety and efficacy of high-dose LCIG in PD patients. Methods Data were collected from several prospective, phase III clinical studies and an observational registry. The phase III program (N = 412) included four multicenter studies: a 12-week, randomized, double-blind study and three open-label studies extending ≥12 months. GLORIA (N = 412) included four multicenter studies: a 12-week, randomized, double-blind study and three open-label studies extending ≥12 months. GLORIA (Results A total of 72 of 412 (17.5%) patients required dosages ≥2000 mg/day LCIG in the phase III program and 47 of 375 (12.5%) patients in GLORIA. Baseline demographics and disease severity were similar between dosage groups with more men in the high-dosage group. Compared with the <2000 mg/day dosage group, patients requiring ≥2000 mg/day LCIG had higher rates of AEs/ADRs including polyneuropathy; improvements in “Off” time and discontinuations due to AEs were similar between dosage groups and lower for discontinuations due to ADRs reported in GLORIA. Conclusions Patients who require ≥2000 mg/day LCIG exhibited a safety profile comparable to the established safety/tolerability of LCIG with similar clinical improvements. Higher AEs were noted but within what is accepted for LCIG. Continuous administration of LCIG is beneficial to advanced PD patients who require very high doses of levodopa.

Plasma tau protein and Aβ42 level as markers of cognitive impairment in patients with Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder with a characteristic clinical picture. Apart from classical movement disorders, a significant role is also played by non-motor symptoms, in particular cognitive impairments, which have a significant impact on the quality of life of the patients. Tau protein and amyloid beta are well-known non-specific biomarkers in Alzheimer's disease (AD). The study assessed the practical value of determining tau protein and amyloid beta (Aβ42) in the blood serum of patients with PD and their relationship with cognitive impairments, radiographic image and the used dose of L-DOPA. The neuropsychological assessment was carried for 64 patients with PD. The levels of amyloid beta 1-42 (Aβ42) and tau proteins in serum were also measured. The Aβ42 level in the serum was statistically higher in patients with longer duration of the disease (p < 0.05) and those who were taking a higher dose of L-DOPA (p < 0.05). The average level of tau protein in the serum was slightly lower in the study groups than in the control group and showed no statistical significance. No correlation was found between the levels of tau protein and Aβ42 and the results of neuropsychological tests. Tau protein correlated with hippocampal atrophy (p < 0.05). Serum levels of Aβ42 and tau protein in PD may be a useful marker for the assessment of cognitive impairments. The role of L-DOPA in the process of dementia in PD remains unclear.

NYX-458 Improves Cognitive Performance in a Primate Parkinson's Disease Model.

NYX-458 is a N-methyl-d-aspartate receptor (NMDAR) modulator that enhances synaptic plasticity. Dopaminergic cell loss in Parkinson's disease (PD) leads to NMDAR dysregulation in the cortico-striato-pallidal-thalmo-cortical network and altered plasticity in brain regions important to cognitive function. We hypothesize that targeting the NMDAR may be an efficacious approach to treating cognitive impairment in PD. NYX-458 was evaluated in 2 nonhuman primate models of PD. The first, a chronic low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-administration model, was used to assess the effects of NYX-458 on cognitive domains impacted early in PD including attention, working memory, executive function, and visuospatial learning. The second, a high-dose MPTP-administration model, was used to assess potential for NYX-458 induced change in motor symptoms. NYX-458 was evaluated in the chronic low-dose MPTP model using the variable delayed response measure to assess attention and working memory and simple discrimination reversal to assess executive function. NYX-458 was also assessed in the high-dose MPTP model as a monotherapy and in combination with low-dose or high-dose levodopa to assess potential impact on motor symptoms. NYX-458 administration resulted in rapid and long-lasting improvement in cognitive function across the domains of attention, working memory, and executive function. Dose levels effective in improving cognitive performance had no effect on PD motor symptoms, the antiparkinsonian benefit of levodopa, or dyskinesia. NYX-458 provides benefit in specific domains known to be impaired in PD in a dopamine depletion model of PD-like cognitive impairment. These data support the continued evaluation of NYX-458 as a potential therapeutic for cognitive decline in PD. © 2020 International Parkinson and Movement Disorder Society.

Dynamics of impulsive-compulsive behaviors in early Parkinson's disease: a prospective study.

Impulsive compulsive behaviors (ICBs) in Parkinson's disease (PD) are debilitating disorders of repetitive, excessive, and compulsive nature affecting up to one third of PD patients. Objectives are to address clinical, psychiatric, and cognitive characteristics of ICBs and to define risk factors in PD patients in the initial motor stage, followed up for 5years. We analyzed 106 consecutive PD outpatients at Hoehn and Yahr disease stage 1 and 125 healthy controls. The participants were assessed for the presence of any ICB using the current clinical criteria and underwent comprehensive clinical, psychiatric, and neuropsychological evaluations. The patients completed the same protocol at Years 1, 2, 3, and 5. ICBs were present in 21 (19.8%) PD patients and 13 (10.4%) healthy controls at baseline. Prevalence of ICBs increased to 29.2% at Year 5, significantly after Year 2. Multiple ICBs were present in 4,7% and 61.9% of PD-ICBs at the baseline and Year 5, respectively. ICBs resolved in 30% of cases (most often compulsive eating). Dopamine agonist treatment at the baseline carried five times higher risk of having or developing ICB(s) anytime during follow-up. We identified risk factors for compulsive eating (dopamine agonist treatment at baseline), hypersexuality (males), compulsive buying (depression and younger age), and punding (younger age and higher levodopa dose at baseline). Significant interaction of rate of motor progression and ICB diagnosis was shown. PD patients showed increasing frequency of most ICBs during the 5-year follow-up. Specific risk factors were identified for different types of ICBs.

From OFF to ON—Treating OFF Episodes in Parkinson’s Disease

In Parkinson’s disease (PD), OFF episodes continue to present a serious burden for patients, and their effective management remains a substantial unmet clinical need. Understanding of the pathophysiology of OFF episodes has advanced in recent years, providing valuable insights for improved treatments. OFF episodes generally appear 3–5 years after starting levodopa treatment, but can begin much earlier. They are characterized by motor symptoms (including tremor, rigidity, slowness, incoordination, and weakness) and are almost always associated with some non-motor symptoms (including psychological symptoms, pain, urinary problems, swallowing difficulties, and shortness of breath). In PD, higher doses of levodopa are associated with increased risk of motor and non-motor complications, which are notable limitations for longterm therapy. Their occurrence is associated with intermittent levodopa delivery and consequent fluctuating plasma levels. These issues can be offset using lower levodopa doses where possible, incremental dose increases, and combinations of levodopa with other pharmacological agents. OFF episodes in PD can be caused by gastroparesis and/or by Helicobacter pylori infection, which delays delivery of levodopa. These issues can be addressed using new formulations for continuous intrajejunal administration. In addition, pen injector, intranasal, and inhaled dosing systems have been studied and may provide relief via non-intestinal routes. Other approaches include deep-brain stimulation, which is effective but is restricted by costs and potential adverse events. This report presents the highlights of a satellite symposium held at the 14th International Conference on Alzheimer’s &amp; Parkinson’s Diseases (AD/PD™ 2019), Lisbon, Portugal, which discussed the nature of OFF episodes in PD, associated risk factors and the potential of current and future treatments to effectively manage them and increase ON time.

Risk Factors and Metabolism of Different Brain Regions by Positron Emission Tomography in Parkinson Disease with Disabling Dyskinesia

Dyskinesia is the most common motor complication in advanced Parkinson's Disease (PD) and has a severe impact on daily life. But the mechanism of dyskinesia is still poorly understood. This study aims to explore risk factors for disabling dyskinesia in PD and further analyze the Vesicular Monoamine Transporter 2 (VMAT2) distribution (labeled with 18F-AV133) in the corpus striatum and the 18F-fluorodeoxyglucose (18F-FDG) metabolism of different brain regions by PET-CT. This is a cross-sectional study involving 135 PD patients. They were divided into disabling dyskinesia group (DD group, N=22) and non-dyskinesia group (ND group, N=113). All the patients were agreed to undergo PET-CT scans. Clinical data were analyzed between two groups by using multivariate logistic regression analysis, and risk factors for disabling dyskinesia were then determined. The standard uptake value ratios (SUVr) of 18F-AV133 in the corpus striatum and the 18F-FDG metabolism of different brain regions were identified and calculated by the software. 16.3% patients have disabling dyskinesia. DD group were more likely to have longer Disease Duration, higher Hoehn-Yahr degree, more severe clinic symptoms, more frequent sleep behavior disorder, and higher levodopa dose equivalency than ND group (P < 0.05). After adjusting confounding factors by multivariate logistic regression, DD group had longer PD duration and high levodopa dose equivalency compared with ND group (P < 0.05). There is no significant difference between the VMAT2 distribution (labeled with 18F- AV133) in the putamen and caudate between two groups. And the 18F-FDG metabolic changes in cortical and subcortical regions did not show a significant difference between the two groups either (P > 0.05). Long PD duration and high levodopa dose equivalency were two independent risk factors for disabling dyskinesia in PD patients. Compared to non-dyskinesia PD patients, there was no significant dopamine decline of the nigrostriatal system in disabling dyskinesia PD patients. Activities of different brain regions were not different between the two groups by 18F-FDG PETCT.

Apomorphine induced immune hemolytic anemia

Drug‐induced immune hemolytic anemia (DIIHA) is not a frequent complication yet has threatening consequences. Managing patients with parkinsonism, L-Dopa was first described as a drug which directly cause DIHA. Very few confirmed cases have been reported for the same adverse effect of other dopaminergic drugs such as apomorphine and cabergoline. Hereby, We Describe a patient with severe parkinsonism for whom Apomorphine was started as the last choice since he was resistant to high dose L-Dopa. He developed pallor and jaundice and further work up revealed DIHA at very early stages of administration of the drug at Intensive Care Unit. The drug was withdrawn for the prevention of serious adverse effects. Strong clinical suspicion is required to detect this rare complication. proper immunohematological test and prompt management is warranted

Large-Fiber Neuropathy in Parkinson's Disease: Clinical, Biological, and Electroneurographic Assessment of a Romanian Cohort.

(1) Background: Increased attention has lately been given to polyneuropathy in Parkinson’s Disease (PD). Several papers postulated that large-fiber neuropathy (PNP) in PD is related to vitamin B12 deficiency and L-Dopa exposure. (2) Methods: Using a cross-sectional, observational study, we evaluated 73 PD patients without a previously known cause of PNP using clinical scores (UPDRS II and III and Toronto Clinical Scoring System), biological evaluation of vitamin B12 and folic acid, and nerve conduction studies to assess the prevalence and features of PNP. (3) Results: The prevalence of PNP was 49.3% in the study group. In the L-Dopa group, the frequency of PNP was 67.3% as compared to PNP in the non-L-Dopa group, where one subject had PNP (χ2 = 23.41, p < 0.01). PNP was predominantly sensory with mild to moderate axonal loss. Cyanocobalamin correlated with L-Dopa daily dose (r = −0.287, p < 0.05) and L-Dopa duration of administration (r = −0.316, p < 0.05). L-Dopa daily dose correlated with the amplitudes of sensory nerve action potentials of the superficial peroneal and radial nerves (r = −0.312, p < 0.05) (r = −0.336, p < 0.05), respectively. (4) Conclusions: PNP is more frequent in L-Dopa-treated patients than in L-Dopa-naïve patients. The results imply that longer exposure to high doses of L-Dopa may cause vitamin B12 and folate imbalance and PNP, secondarily.

Risk thresholds of levodopa dose for dyskinesia in Chinese patients with Parkinson's disease: a pilot study.

Levodopa is widely used to treat Parkinson's disease (PD), and its long-term therapy may induce dyskinesia in a dose-dependent manner. However, the threshold dose with a relatively low risk for dyskinesia has not been determined. Demographic, clinical profiles and detailed information of dopaminergic drugs were recorded for 403 PD patients in treatment with levodopa. Variables were compared between dyskinesia and non-dyskinesia groups. Logistic regression analysis was used to assess the association between levodopa dose-related variables and dyskinesia. Receiver operating characteristic curve and decision tree classification model were used to investigate the cut-off value of levodopa dose to best separate the dyskinesia group from the non-dyskinesia group. Patients with dyskinesia tended to have a lower weight and age at onset, higher percentage of female and wearing-off, longer duration of disease and levodopa treatment, higher H-Y stage and MDS-UPDRS Part III score, and higher levodopa dose and levodopa equivalent dose than those without dyskinesia. After adjusted for demographical and clinical variables, levodopa dose-related factors (daily dose, cumulative dose, and weight-adjusted dose) were still associated with dyskinesia. Both the receiver operating characteristic and decision tree classification analysis indicated that patients who have taken levodopa dose ≤ 400mg per day may be associated with a reduced risk for dyskinesia. In conclusion, we evaluated the thresholds of levodopa treatment with a relatively low risk for dyskinesia. These data should be considered for prevention and management of dyskinesia in patients with PD.

Genetic silencing of striatal CaV1.3 prevents and ameliorates levodopa dyskinesia.

BackgroundLevodopa‐induced dyskinesias are an often debilitating side effect of levodopa therapy in Parkinson's disease. Although up to 90% of individuals with PD develop this side effect, uniformly effective and well‐tolerated antidyskinetic treatment remains a significant unmet need. The pathognomonic loss of striatal dopamine in PD results in dysregulation and disinhibition of striatal CaV1.3 calcium channels, leading to synaptopathology that appears to be involved in levodopa‐induced dyskinesias. Although there are clinically available drugs that can inhibit CaV1.3 channels, they are not adequately potent and have only partial and transient impact on levodopa‐induced dyskinesias.MethodsTo provide unequivocal target validation, free of pharmacological limitations, we developed a CaV1.3 shRNA to provide high‐potency, target‐selective, mRNA‐level silencing of striatal CaV1.3 channels and examined its ability to impact levodopa‐induced dyskinesias in severely parkinsonian rats.ResultsWe demonstrate that vector‐mediated silencing of striatal CaV1.3 expression in severely parkinsonian rats prior to the introduction of levodopa can uniformly and completely prevent induction of levodopa‐induced dyskinesias, and this antidyskinetic benefit persists long term and with high‐dose levodopa. In addition, this approach is capable of ameliorating preexisting severe levodopa‐induced dyskinesias. Importantly, motoric responses to low‐dose levodopa remained intact in the presence of striatal CaV1.3 silencing, indicating preservation of levodopa benefit without dyskinesia liability.DiscussionThe current data provide some of the most profound antidyskinetic benefit reported to date and suggest that genetic silencing of striatal CaV1.3 channels has the potential to transform treatment of individuals with PD by allowing maintenance of motor benefit of levodopa in the absence of the debilitating levodopa‐induced dyskinesia side effect. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Baicalein enhances the effect of low dose Levodopa on the gait deficits and protects dopaminergic neurons in experimental Parkinsonism

Parkinson’s Disease (PD) is the second most common neurodegenerative disease with the clinical characteristics of gait deficits. The classical symptomatic treatment for PD is Levodopa (L-DOPA) which brings a plethora of side effects and dosage problems in a prolonged drug regimen. Baicalein is a flavonoid extracted from Scutellaria baicalensis Georgi with the properties of neuroprotection. In this study, we investigated the ameliorative effect of baicalein with low dose L-DOPA (25 mg/kg) on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinsonism. The gait variability was assessed by a computer-assisted gait analysis system Catwalk. The results showed that MPTP challenged mice had significant gait deficits on dynamic paw function and posture stability. L-DOPA reversed the MPTP induced gait deficits and the effect was positively dose-dependent. The combined treatment of baicalein and under threshold dose of L-DOPA significantly improved gait functions, compared with exclusive low dose L-DOPA treatment, and the effect was comparable with high dose L-DOPA treatment. The histological assessment demonstrated that the Tyrosine hydroxylase expression increased in all the baicalein stratified groups, which suggest baicalein might have the neuroprotective effect to retain the dopaminergic neurons or enhance the dopaminergic neuron regeneration after MPTP injection. This neuroprotection probably depended on altering the inflammatory response and resisting the apoptosis through the underlying mechanism investigation. Our study provides experimental evidence that the combination of L-DOPA and baicalein might be a potential treatment for Parkinson's disease. The synergistic interaction of baicalein and L-dopa treatment might reduce the side-effect of the normal to high dose L-DOPA used today.

Frailty in Patients with Parkinson's Disease: Associations with Disability and Timed Up and Go.

Introduction:Aim of this study was identify the prevalence of frailty in patients with idiopathic Parkinson’s disease (PD), to describe the relationship between severity of the disease and frailty, and to evaluate if timed up and go (TUG) is an eligible test for determination of frailty in idiopathic PD patients.Methods:We conducted a cross-sectional study which included 66 patients, aged 60 and over in a tertiary hospital. Frailty was assessed by the Fried Frailty Index (FFI). Severity of the idiopathic PD was detected by the Hoehn and Yahr (H&Y) scale. Mobility was measured by the TUG test. Demographic characteristics and comprehensive geriatric assessments were evaluated. Descriptive statistics and logistic regression were used in analyses. Receiver operating characteristic (ROC) curves were used to identify the discriminative effect of TUG test on frailty.Results:The numbers of frail, prefrail, and robust subjects were 34 (51.5%), 24 (36.4%), and 8 (12.1%), respectively. Dependency in instrumental activities of daily living (IADL) was significantly associated with frailty (Odds ratio (OR): 36.00, Confidence interval (CI): 8.43–153.80). Multivariate logistic regression analysis results yielded, depression (OR: 10.37, CI: 2.82–38.12) and higher levodopa doses (OR: 6.28, CI: 1.77–22.24) were independently associated with frailty. TUG test performance was strongly associated with frailty with high sensitivity (0.806) and specificity (0.826) (Area under the curve (AUC): 0.831).Conclusions:Frailty is highly prevalent in idiopathic PD and is strongly associated with disabilities as well as specific risk factors of the disease. The TUG may be a reliable test for prediction of frailty in patients with idiopathic PD.

The influence of SLC6A3 and DRD2 polymorphisms on levodopa-therapy in patients with sporadic Parkinson's disease.

The aim of this study was to evaluate a possible relationship between DRD2/ANKK1 (rs1800497) and SLC6A3/DAT1 (rs28363170) gene polymorphisms with the response to levodopa (L-DOPA)-therapy in patients with Parkinson's disease (PD). One hundred and ninety-five patients with idiopathic PD were investigated. Patients were genotyped for rs1800497 and rs28363170 polymorphisms using PCR-RFLP. Logistic regression was performed to assess the association of polymorphisms with the occurrence of the chronic complications of L-DOPA therapy. Our results showed association between the occurrence of dyskinesia with an increased greater disease severity (P=0.007), higher L-DOPA dose (P=0.007) and use of dopamine agonist (P=0.020). Moreover, there were significant protective effects for age (P=0.004) and male subjects (P=0.006). Clinical and demographic characteristics of Brazilian PD patients and differences in DRD2 and DAT1 genes may to determine individual variations in the therapeutic response to L-DOPA in the Brazilian PD patients.

Use of anti-Parkinson medication during pregnancy: a case series.

Experience about the use and safety of anti-Parkinson (anti-PD) medication during pregnancy is scarce. We have retrospectively evaluated the course and outcome of pregnancy in PD patients who used anti-PD medication during their pregnancy. 14 PD patients who used anti-PD medication during part or whole of their pregnancy were included. Dopamine agonists were used in 13 patients, levodopa/benserazide in 4, levodopa/carbidopa/entacapone in 1, rasagiline in 7, amantadine in 4, and biperiden in 1 patient. Nine patients were on combination treatment at the time of their pregnancy. During their whole pregnancy, dopamine agonists had been used in six patients, levodopa in four, and rasagiline in one. Four patients experienced adverse outcomes: one had spontaneous abortion while receiving pramipexole, one elderly mother gave birth to a child with Down syndrome, while receiving pramipexole and rasagiline, in one case, there was fetal distress under levodopa/benserazide, piribedil, and rasagiline which resolved spontaneously, in one case, one of the twins did not survive after the birth while the mother was receiving pramipexole and rasagiline. In none of these cases an association with the use of anti-PD medication and adverse outcomes was clearly established. In one patient, motor symptoms worsened despite high dose levodopa, four others experienced transient worsening upon dose reduction. Results in our case series suggest that levodopa, rasagiline, pramipexole, and ropinirole alone or in combination with each other may be considered relatively safe during pregnancy. Expected benefits and risks should be considered when prescribing anti-PD medication in pregnant women.

MAO-B and COMT Genetic Variations Associated With Levodopa Treatment Response in Patients With Parkinson's Disease.

The most commonly used Parkinson's disease (PD) treatment is the replacement of dopamine by its levodopa precursor (l-dopa). Monoamine oxidase-B (MAO-B) and catechol-o-methyl transferase (COMT) are enzymes involved in the metabolism and regulation of dopamine availability. In our study we investigated the possible relation among selected single-nucleotide polymorphisms (SNPs) in the MAO-B (rs1799836) and COMT (rs4680) genes and the therapeutic response to levodopa (l-dopa). A total of 162 Brazilian patients from the Pro-Parkinson service of Clinics Hospital of Pernambuco diagnosed with sporadic PD and treated with levodopa were enrolled. PD patients were stratified into 2 groups according to the daily levodopa dose. MAO-B and COMT SNP genotyping was conducted by polymerase chain reaction-restriction fragment length polymorphism. After multivariate analysis, we observed a significant difference between PD groups for the following variables: sex (P=.02), longer duration of disease (P=.02), longer levodopa therapy duration (P=.01), younger onset of PD (P = .01), and use of COMT inhibitor (P=.02). We observed that patients carrying MAO-B (rs1799836) A and AA genotypes and COMT (rs4680) LL genotype suffered more frequently from levodopa-induced-dyskinesia. In addition, we found an increased risk of 2.84-fold for male individuals carrying the MAO-B G allele to be treated with higher doses of levodopa (P=.04). We concluded that before beginning PD pharmacological treatment, it is important to consider the genetic variants of the MAO-B and COMT genes and the sex, reinforcing the evidence that sexual dimorphism in the genes related to dopamine metabolism might affect PD treatment.

DPI-289, a novel mixed delta opioid agonist / mu opioid antagonist (DAMA), has L-DOPA-sparing potential in Parkinson's disease.

L-DOPA-induced dyskinesia (LID) remains a significant problem in the management of Parkinson's disease (PD). In rodent and macaque models of PD, delta opioid receptor agonists have anti-parkinsonian actions while mu opioid antagonists can reduce the expression of LID. DPI-289 is a novel molecule with a unique combination of opioid receptor DAMA actions: delta agonist (Ki: 0.73 nM); mu antagonist (Ki: 12 nM). We demonstrated that DPI-289 has oral bioavailability and established its pharmacokinetic profile in both rat and primate. We hypothesised that these combined DAMA actions would provide an enhancement of L-DOPA effect without an associated increase in dyskinesia. In parkinsonian 6-OHDA lesioned rats and MPTP-lesioned macaques, DPI-289 provided anti-parkinsonian actions as monotherapy and an enhancement of L-DOPA benefit. Thus, acute administration of DPI-289 (3 mg/kg, p.o.) to 6-OHDA-lesioned rats produced a significant reduction in forelimb asymmetry (by 48%) that was maintained throughout the fifteen-day repeat-treatment period. Importantly, and in contrast to L-DOPA administration (6 mg/kg, i.p.), these benefits were not compromised by the development of abnormal involuntary movements. In the macaque, as monotherapy, DPI-289 (10 and 20 mg/kg) had significant, though incomplete, anti-parkinsonian actions lasting approximately 4 h. These benefits were not associated with dyskinesia. In fact, over the 6 h period of observation, DPI-289 (20 mg/kg) decreased parkinsonism by 19% and increased activity by 67% compared to vehicle treatment. By contrast, while high-dose L-DOPA (LDh) alone alleviated parkinsonism (for 3 h) this benefit was accompanied by significant dyskinesia that was disabling in nature. LDh provided a 50% reduction in parkinsonism over 6 h and 151% increase in activity. The combination of DPI-289 (20 mg/kg) and a low-dose of L-DOPA (LDl) provided anti-parkinsonian benefits greater than LDl alone without eliciting any significant dyskinesia. Treatment with LDl alone provided only transient statistically significant anti-parkinsonian benefit. However, the combination of LDl and DPI-289 reduced parkinsonism for 6 h (duration of monitoring), with parkinsonism being reduced by 35% and activity increased by 90% but with no increase in dyskinesia over that observed with LDl alone. Thus, DPI-289 has potential to improve the benefits of dopaminergic therapy in Parkinson's disease.

Effects of a combination treatment of KD5040 and L-dopa in a mouse model of Parkinson\u2019s disease

BackgroundAlthough the dopamine precursor L-3, 4-dihydroxyphenylalanine (l-dopa) remains the gold standard pharmacological therapy for patients with Parkinson’s disease (PD), long-term treatment with this drug has been known to result in several adverse effects, including l-dopa-induced dyskinesia (LID). Recently, our group reported that KD5040, a modified herbal remedy, had neuroprotective effects in both in vitro and in vivo models of PD. Thus, the present study investigated whether KD5040 would have synergistic effects with l-dopa and antidyskinetic effects caused by l-dopa as well.MethodsThe effects of KD5040 and l-dopa on motor function, expression levels of substance P (SP) and enkephalin (ENK) in the basal ganglia, and glutamate content in the motor cortex were assessed using behavioral assays, immunohistochemistry, Western blot analyses, and liquid chromatography tandem mass spectrometry in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In addition, the antidyskinetic effects of KD5040 on pathological movements triggered by l-dopa were investigated by testing abnormal involuntary movements (AIMs) and measuring the activations of FosB, cAMP-dependent phosphor protein of 32 kDa (DARPP-32), extracellular signal-regulated kinases (ERK), and cAMP response element-binding (CREB) protein in the striatum.ResultsKD5040 synergistically improved the motor function when low-dose l-dopa (LL) was co-administered. In addition, it significantly reversed MPTP-induced lowering of SP, improved ENK levels in the basal ganglia, and ameliorated abnormal reduction in glutamate content in the motor cortex. Furthermore, KD5040 significantly lowered AIMs and controlled abnormal levels of striatal FosB, pDARPP-32, pERK, and pCREB induced by high-dose l-dopa.ConclusionsKD5040 lowered the effective dose of l-dopa and alleviated LID. These findings suggest that KD5040 may be used as an adjunct therapy to enhance the efficacy of l-dopa and alleviate its adverse effects in patients with PD.