Efficacy Of Levodopa Research Articles

Bacteriophages targeting Enterococcus faecalis enhance the therapeutic efficacy of levodopa in an MPTP-induced Parkinson’s disease mouse model with E. faecalis gut colonization

Despite the intensive research on gut microbiome-associated diseases over the past 20 years, pharmacological methods for effectively eliminating pathobionts remain unsatisfactory. This study investigated the therapeutic potential of bacteriophages against Enterococcus faecalis, in which bacterial tyrosine decarboxylase (TDC) converts orally administered levodopa (L-DOPA) to dopamine, in an MPTP mouse model of Parkinson’s disease (PD). E. faecalis bacteriophages PBEF62, PBEF66, and PBEF67 (4 × 1010 PFU total/200 µl/day), and E. faecalis cells (2 × 109 CFU/200 µl/day) were orally administered at 2-h intervals before every MPTP (i.p.) and/or L-DOPA (p.o.) treatments for 13 days. The relative abundances of E. faecalis cells and bacteriophages in the feces peaked at 4 and 12 h after administration and gradually decreased by 12 and 48 h, respectively. While the administration of E. faecalis cells eliminated the beneficial effect of L-DOPA on MPTP-induced behavioral deficits, as assessed by cylinder and rotarod tests, the co-administration of bacteriophages with bacterial cells restored this effect. The modulating effects of L-DOPA, E. faecalis, and bacteriophages on PD behavior were closely associated with choline acetyltransferase expression levels in the striatum but not with tyrosine hydroxylase in the substantia nigra of each group. Recurrence and extinction of PD behaviors following treatment with E. faecalis and/or bacteriophages were also coincident with the dopamine levels in the blood and brain tissues of PD mice. The effectiveness of L-DOPA was restored after the three types of E. faecalis bacteriophages selectively eliminated E. faecalis cells, along with the TDC gene copies and transcripts responsible for converting L-DOPA to dopamine in the gastrointestinal tract. In conclusion, a combination of bacteriophages PBEF62, PBEF66, and PBEF67 targeting E. faecalis demonstrates potential as a valuable supplement to L-DOPA therapy for PD.

Motor Efficacy of Subcutaneous DIZ102, Intravenous DIZ101 or Intestinal Levodopa/Carbidopa Infusion.

It has been suggested that carbidopa at high blood concentrations may counter the therapeutic effect of levodopa in Parkinson's disease by entering the brain and blocking central levodopa conversion to dopamine. We previously demonstrated equivalent plasma levodopa concentration in patients with Parkinson's disease during 16 h of (1) intravenous carbidopa/levodopa (DIZ101) infusion, (2) subcutaneous carbidopa/levodopa (DIZ102) infusion or (3) intestinal carbidopa/levodopa gel infusion. Plasma levels of carbidopa were however approximately four times higher with DIZ101 and DIZ102 than with LCIG, and higher than those usually observed with oral levodopa/carbidopa. To investigate if high carbidopa blood concentrations obtained with parenteral levodopa/carbidopa (ratio 8:1) counter the effect of levodopa on motor symptoms. Eighteen patients with advanced Parkinson's disease were administered DIZ101, DIZ102, and intestinal levodopa/carbidopa gel for 16 h on different days in randomized order. Video recordings of a subset of the motor examination in the Unified Parkinson's Disease Rating Scale (UPDRS) were evaluated by raters blinded for treatment and time. Motor function was also measured using a wrist-worn device monitoring bradykinesia, dyskinesia, and tremor (Parkinson KinetiGraph). There was no tendency for poorer levodopa effect with DIZ101 or DIZ102 as compared to LCIG. Although DIZ101 or DIZ102 causes approximately four times higher plasma carbidopa levels than LCIG, patients responded equally well to all treatments. The results do not indicate that high plasma carbidopa levels hamper the motor efficacy of levodopa.

Unlocking the potential: T1-weighed MRI as a powerful predictor of levodopa response in Parkinson’s disease

BackgroundThe efficacy of levodopa, the most crucial metric for Parkinson’s disease diagnosis and treatment, is traditionally gauged through the levodopa challenge test, which lacks a predictive model. This study aims to probe the predictive power of T1-weighted MRI, the most accessible modality for levodopa response.MethodsThis retrospective study used two datasets: from the Parkinson’s Progression Markers Initiative (219 records) and the external clinical dataset from Ruijin Hospital (217 records). A novel feature extraction method using MedicalNet, a pre-trained deep learning network, along with three previous approaches was applied. Three machine learning models were trained and tested on the PPMI dataset and included clinical features, imaging features, and their union set, using the area under the curve (AUC) as the metric. The most significant brain regions were visualized. The external clinical dataset was further evaluated using trained models. A paired one-tailed t-test was performed between the two sets; statistical significance was set at p < 0.001.ResultsFor 46 test set records (mean age, 62 ± 9 years, 28 men), MedicalNet-extracted features demonstrated a consistent improvement in all three machine learning models (SVM 0.83 ± 0.01 versus 0.73 ± 0.01, XgBoost 0.80 ± 0.04 versus 0.74 ± 0.02, MLP 0.80 ± 0.03 versus 0.70 ± 0.07, p < 0.001). Both feature sets were validated on the clinical dataset using SVM, where MedicalNet features alone achieved an AUC of 0.64 ± 0.03. Key responsible brain regions were visualized.ConclusionThe T1-weighed MRI features were more robust and generalizable than the clinical features in prediction; their combination provided the best results. T1-weighed MRI provided insights on specific regions responsible for levodopa response prediction.Critical relevance statementThis study demonstrated that T1w MRI features extracted by a deep learning model have the potential to predict the levodopa response of PD patients and are more robust than widely used clinical information, which might help in determining treatment strategy.Key PointsThis study investigated the predictive value of T1w features for levodopa response.MedicalNet extractor outperformed all other previously published methods with key region visualization.T1w features are more effective than clinical information in levodopa response prediction.Graphical

Efficacy of antiparkinsonian therapy in tremor correction according to tremorography

Objective: to evaluate the efficacy of antiparkinsonian drugs of different groups considering the frequency-amplitude characteristics in the correction of tremulous hyperkinesis in Parkinson's disease (PD) using tremorography. Material and methods. 172 patients with a confirmed diagnosis of PD were observed. Taking into account age and contraindications, patients were divided into four groups receiving one of four drugs in monotherapy: dopamine receptor agonists (ADR; pramipexole), levodopa (Tidomet forte), anticholinergics (biperiden), amantadines (amantadine sulfate). Before starting treatment and after completion of the selected therapy, patients underwent tremorography to analyse the frequency, amplitude and duration of tremor over time in four standard tests. Results. All antiparkinsonian drugs reduced rest tremor, and the efficacy of pramipexole in treating tremor was comparable to that of levodopa in the early stages of the disease. As the severity of the disease increased, the efficacy of ADRs decreased, whereas levodopa became more important. Amantadine sulfate showed the lowest efficacy in rest tremor. The efficacy of anticholinergics against tremor is high but inconsistent. Conclusion. We demonstrated feasibility of using tremorography in the selection of an individualised treatment programme for patients with shaking hyperkinesis in PD , and the high efficacy of levodopa in shaking hyperkinesis was confirmed.

Levodopa And Pramipexole Combination Therapy Efficacy In Vietnamese Patients With Parkinson’s Disease: A Randomized Controlled Trial

Early diagnosis and appropriate treatment of Parkinson's disease to minimize the adverse effects of the disease and drug side effects on the patient. Using levodopa combined with pramipexole is an effective therapy for treating Parkinson's disease. Objectives — This study aims to evaluate the treatment outcome of combination therapy with levodopa and pramipexole compared to levodopa monotherapy in Vietnamese Parkinson's patients. Material and Methods — A randomized controlled clinical trial with a 1:1 randomized ratio of 80 individuals with Parkinson's disease. The intervention group received a combination therapy with levodopa/benserazide and pramipexole, and the control group received a monotherapy with levodopa/benserazide. Motor symptoms, non-motor symptoms, The Unified Parkinson's Disease Rating (UPDRS), and The Parkinson's Disease Questionnaire (PDQ-39) scores were assessed before, after, and a follow-up period of 1 and 4 weeks after discharge to evaluate the treatment outcome. Results — Combining therapy with levodopa and pramipexole led to statistically significant improvements in UPDRS and PDQ-39 scores (p&lt;0.05). The mean difference in UPDRS parts I, II, and III after 4 weeks of discharge was -0.5 (p=0.014), -1.68 (p=0.005), and -2.52 (p=0.010) respectively. The quality of life was also enhanced by combining therapy due to a better reduction of PDQ-39 score: 26.0±6.3 versus 32.7±6.4 (p&lt;0.001). The most common side effects were headache, nausea/vomiting, and somnolence. Conclusions — Treatment with levodopa combined with pramipexole improves clinical symptoms and quality of life in patients with Parkinson's, as evidenced by improvements in UPDRS and PDQ-39 scores.

The effects of Nardosinone on levodopa intervention in the treatment of Parkinson's disease

BackgroundThe roots and rhizomes of Nardostachys jatamansi DC. are reported to be useful for the treatment of Parkinson's disease (PD). Previous research has also shown that Nardosinone, the main active component isolated from Nardostachys jatamansi DC., exhibits the potential to treat PD. Aim of the studyTo investigate how the effects of Nardosinone could assist levodopa in the treatment of PD, how this process changes the intestinal flora, and to explore the effective forms of Nardosinone in the intestinal flora. Material and methodsWe used behavioral experiments, and hematoxylin-eosin staining and immunohistochemical staining, to investigate the effects of a combination of Nardosinone and levodopa on rotenone-induced PD rats. In addition, we used LC/MS-MS to determine the levels of levodopa, 5-hydroxytryptamine, dopamine and its metabolite 3, 4-dihydroxyphenylacetic acid, and homovanillic acid, to investigate the effect of the intestinal flora on co-administration in the treatment of PD. LC/MS-MS was also used to detect the metabolites of Nardosinone on the gastrointestinal tract and intestinal flora. ResultsThe behavioral disorders and neuronal damage associated with PD were significantly improved following the co-administration. Analysis also revealed that the co-administration increased the levels of five neurotransmitters in the striatum, plasma and feces. In vitro experiments further demonstrated that the levels of dopamine and levodopa were increased in the intestinal flora. In total, five metabolites of Nardosinone were identified. ConclusionOur findings indicate that Nardosinone and its metabolites might act as a potential adjutant to enhance the efficacy of levodopa via the intestinal flora, thus expanding the therapeutic potential of the combination of Chinese and Western medicine as a treatment method for PD.

Synchronous Dosing of Levodopa with Quercetin Enhances Therapeutic Efficacy and Mitigates Apoptotic Events in Experimental Parkinsonism

Parkinson’s disease (PD) affects millions of people annually across the globe and is primarily managed through dopamine replacement therapy employing levodopa (L-DOPA), which is still the preferred gold standard. Prolonged use of L-DOPA leads to severe adverse effects, including motor complications such as L-DOPA-induced dyskinesia, which considerably compromise treatment outcomes and patients’ quality of life. Potentiating L-DOPA with natural or synthetic compounds with less toxicity and neuroprotective activity is an area of emerging significance, and many studies in this area have gained widespread research attention. Phytochemicals, essentially compounds with antioxidant and neuroprotective activity, may be potent candidates to potentiate L-DOPA, and in this context, we explored the potential of combining quercetin with L-DOPA to mitigate rotenone-induced PD using human neuroblastoma cells. The optimal nontoxic concentrations of L-DOPA and quercetin were determined via the MTT [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide] assay. The combination treatment notably increased cell viability to 95% at a concentration of 6.25 μg/ml, whereas the viability of the rotenone-treated group was 46.8%. Lactate dehydrogenase leakage assays further confirmed that membrane integrity was significantly preserved in the combination-treated groups compared with those treated with L-DOPA or quercetin alone. Morphological improvements were evident under microscopic observation. Compared with the individual treatments, the combination treatment also resulted in increased inhibition of acetylcholinesterase activity. Additionally, apoptosis induction was significantly reduced in the combination group, as shown by EtBr/acridine orange fluorescence staining. Cellular calcium levels, which were elevated by rotenone exposure, were effectively normalized by the combination treatment. Moreover, the combination therapy promoted neurite outgrowth more effectively than L-DOPA or quercetin alone. These findings suggest that coadministration of quercetin with L-DOPA could be a promising strategy to increase the efficacy of L-DOPA while potentially reducing its dosage, leveraging the benefits of natural phytochemicals in PD management.

Stalevo® : A pioneering treatment for OFF periods in Parkinsons disease.

Enzymatic metabolism is the key determinant of the overall bioavailability, brain penetration, and efficacy of levodopa in the treatment of Parkinsons disease (PD). Enzyme inhibitors in the form of peripheral dopa-decarboxylase inhibitors and monoamine oxidase type-B inhibitors have been successfully employed to maximize the utility of levodopa in both early- and late-stage PD. However, another major pathway of the peripheral metabolism of levodopa through catechol-O-methyltransferase (COMT) remains unchecked by those measures. Consequently, this becomes a major factor in determining the extent of delivery to the brain. The introduction of tolcapone as a potent and effective peripheral and central COMT inhibitor was frustrated by the emergence of hepatic toxicity. Only with the subsequent introduction of entacapone as an effective inhibitor of peripheral COMT activity has it become possible to fully control the peripheral metabolism of levodopa and to optimize its delivery to the brain. At a single-dose level of 200 mg, the efficacy of entacapone in reducing OFF time and increasing ON time has led to its widespread use for the treatment of "wearing off". To maximize the efficacy of entacapone and to time-lock its pharmacokinetic profile to that of levodopa, a triple combination of levodopa, carbidopa, and entacapone in the form of Stalevo® that allowed for flexibility in levodopa dosing was introduced early in the 21st century. This pioneering development has been successfully used worldwide for the past 20 years. This review considers the role of all three classes of enzyme inhibitors in PD medicine.

Perioperative Use of Intravenous Levodopa as an Anti-Parkinsonian Drug: A Propensity Score Analysis.

Perioperative discontinuation of oral anti-parkinsonian medication can negatively impact the prognosis of abdominal surgery in patients with Parkinson's disease. Although intravenous levodopa may be an alternative, its efficacy has not yet been investigated. To determine the efficacy of intravenous levodopa as an alternative to oral anti-Parkinsonian drugs during gastric or colorectal cancer surgery. We identified patients with Parkinson's disease who underwent surgery for gastric or colorectal cancer between April 2010 and March 2020, using the Diagnosis Procedure Combination database, a nationwide inpatient database in Japan. Patients were divided into two groups: those who received intravenous levodopa during the perioperative period and those who did not. We compared in-hospital mortalities, major complications, and postoperative length of stay between the groups after adjusting for background characteristics with overlap weights based on propensity scores. We identified 648 patients who received intravenous levodopa and 1207 who did not receive levodopa during the perioperative period. In the adjusted cohort, the mean postoperative length of stay was 24.7 and 29.0 days (percent difference, -7.7%; 95% confidence interval, -13.1 to -1.5); in-hospital death was 3.2% and 3.3% (adjusted odds ratio, 0.95; 95% CI: 0.54-1.67); and incidence of major complications were 21.4% and 19.3% (adjusted odds ratio, 0.89; 95% confidence interval, 0.70-1.13) in those with and without intravenous levodopa, respectively. Intravenous levodopa was associated with a shorter postoperative length of stay, but not with mortality or morbidity. Intravenous levodopa may improve perioperative care in patients with Parkinson's disease.

Piperine improves levodopa availability in the 6-OHDA-lesioned rat model of Parkinson's disease by suppressing gut bacterial tyrosine decarboxylase.

Tyrosine decarboxylase (TDC) presented in the gut-associated strain Enterococcus faecalis can convert levodopa (L-dopa) into dopamine (DA), and its increased abundance would potentially minimize the availability and efficacy of L-dopa. However, the known human decarboxylase inhibitors are ineffective in this bacteria-mediated conversion. This study aims to investigate the inhibition of piperine (PIP) on L-dopa bacterial metabolism and evaluates the synergistic effect of PIP combined with L-dopa on Parkinson's disease (PD). Metagenomics sequencing was adopted to determine the regulation of PIP on rat intestinal microbiota structure, especially on the relative abundance of E. faecalis. Then, the inhibitory effects of PIP on L-dopa conversion and TDC expression of E. faecalis were tested in vitro. We examined the synergetic effect of the combination of L-dopa and PIP on 6-hydroxydopamine (6-OHDA)-lesioned rats and tested the regulations of L-dopa bioavailability and brain DA level by pharmacokinetics study and MALDI-MS imaging. Finally, we evaluated the microbiota-dependent improvement effect of PIP on L-dopa availability using pseudo-germ-free and E. faecalis-transplanted rats. We found that PIP combined with L-dopa could better ameliorate the move disorders of 6-OHDA-lesioned rats by remarkably improving L-dopa availability and brain DA level than L-dopa alone, which was associated with the effect of PIP on suppressing the bacterial decarboxylation of L-dopa via effectively downregulating the abnormal high abundances of E. faecalis and TDC in 6-OHDA-lesioned rats. Oral administration of L-dopa combined with PIP can improve L-dopa availability and brain DA level in 6-OHDA-lesioned rats by suppressing intestinal bacterial TDC.

5-Hydroxytryptophan Reduces Levodopa-Induced Dyskinesia via Regulating AKT/mTOR/S6K and CREB/ΔFosB Signals in a Mouse Model of Parkinson's Disease.

Long-term administration of levodopa (L-DOPA) to patients with Parkinson's disease (PD) commonly results in involuntary dyskinetic movements, as is known for L-DOPA-induced dyskinesia (LID). 5-Hydroxytryptophan (5-HTP) has recently been shown to alleviate LID; however, no biochemical alterations to aberrant excitatory conditions have been revealed yet. In the present study, we aimed to confirm its anti-dyskinetic effect and to discover the unknown molecular mechanisms of action of 5-HTP in LID. We made an LID-induced mouse model through chronic L-DOPA treatment to 6-hydroxydopamine-induced hemi-parkinsonian mice and then administered 5-HTP 60 mg/kg for 15 days orally to LID-induced mice. In addition, we performed behavioral tests and analyzed the histological alterations in the lesioned part of the striatum (ST). Our results showed that 5-HTP significantly suppressed all types of dyskinetic movements (axial, limb, orolingual and locomotive) and its effects were similar to those of amantadine, the only approved drug by Food and Drug Administration. Moreover, 5-HTP did not affect the efficacy of L-DOPA on PD motor manifestations. From a molecular perspective, 5-HTP treatment significantly decreased phosphorylated CREB and ΔFosB expression, commonly known as downstream factors, increased in LID conditions. Furthermore, we found that the effects of 5-HTP were not mediated by dopamine1 receptor (D1)/DARPP32/ERK signaling, but regulated by AKT/mTOR/S6K signaling, which showed different mechanisms with amantadine in the denervated ST. Taken together, 5-HTP alleviates LID by regulating the hyperactivated striatal AKT/mTOR/S6K and CREB/ΔFosB signaling.

Results confirming the efficacy of oral L-dopa on cortisol secretion in patients being evaluated for suspected growth hormone deficiency

Objective: Adrenal insufficiency is a life-threatening disease and therefore, accurate diagnosis and prompt treatment are life-saving. The main purpose of this study was to retrospectively evaluate the serum cortisol levels measured during the L-dopa test in cases suspected GH deficiency and to compare the effect of L-dopa on cortisol secretion with the results of previous studies. Method: Between January 2019 and January 2021, patients who underwent the L-dopa test for the evaluation of GH deficiency in our Pediatric Endocrinology Clinic and whose basal cortisol levels were measured at the baseline and at the 120th minutes of the test were included. The clinical, anthropometric, and laboratory data of the patients were obtained from the medical records. Results: Eighty-five patients (38 girls, 47 boys) were included in the study. The mean age of the patients was 10.3 ± 3.5 years (range, 4.1 - 14.9 years). The mean serum cortisol level was 11.1 ± 3.6 µg/dL at baseline and 20.9 ± 3.8 µg/dL at 120th minutes (the mean cortisol increase was 9.8 ± 4.1 µg/dL). Cortisol response was adequate (&gt; 18 µg / dL) in 76 cases (89.4%). Nausea/vomiting was observed in 53 (62.4%) of the patients during the L-dopa test. Peak cortisol responses of the cases with and without side effects were similar (20.9 ± 3.8; 20.8 ± 3.7; p = 0.945). Conclusion: In conclusion, the L-dopa test is easy to apply, effective, and safe and can be performed to evaluate cortisol adequacy at least in patients being evaluated for suspected GH deficiency.

Parkinson's Disease: Technological Approaches for Optimized Therapeutic Efficacy of Levodopa

Parkinson's Disease: Technological Approaches for Optimized Therapeutic Efficacy of Levodopa

Characterizing the relationship between L-DOPA-induced-dyskinesia and psychosis-like behaviors in a bilateral rat model of Parkinson's disease

Parkinson's disease associated psychosis (PDAP) is a prevalent non-motor symptom (NMS) that significantly erodes patients' and caregivers' quality of life yet remains vastly understudied. One potential source of PDAP in late-stage Parkinson's disease (PD) is the common dopamine (DA) replacement therapy for motor symptoms, Levodopa (L-DOPA). Given the high incidence of L-DOPA-induced dyskinesia (LID) in later phases of PD, this study sought to characterize the relationship between PDAP and LID in a bilateral medial forebrain bundle 6-hydroxydopamine hydrobromide (6-OHDA) lesion rat model. To assess PDAP in this model, prepulse inhibition (PPI), a well-validated assay of sensorimotor gating, was employed. First, we tested whether a bilateral lesion alone or after chronic L-DOPA treatment was sufficient to induce PPI dysfunction. Rats were also monitored for LID development, using the abnormal involuntary movements (AIMs) test, to examine PPI and LID associations. In experiment 2, Vilazodone (VZD), a serotonin transporter (SERT) blocker and 1A receptor (5-HT1A) partial agonist was administered to test its potential efficacy in reducing LID and PPI dysfunction. Once testing was complete, tissue was collected for high performance liquid chromatography (HPLC) to examine the monoamine levels in motor and non-motor circuits. Results indicate that bilateral DA lesions produced motor deficits and that chronic L-DOPA induced moderate AIMs; importantly, rats that developed more severe AIMs were more likely to display sensorimotor gating dysfunction. In addition, VZD treatment dose-dependently reduced L-DOPA-induced AIMs without impairing L-DOPA efficacy, although VZD's effects on PPI were limited. Altogether, this project established the bilateral 6-OHDA lesion model accurately portrayed LID and PDAP-like behaviors, uncovered their potential relationship, and finally, demonstrated the utility of VZD for reducing LID.

S1548 GI Dysmotility Symptoms Are Not Associated With Increased L-Dopa Requirements in Parkinson’s Disease Patients

Introduction: Gastrointestinal (GI) motility disorders like gastroparesis or small bowel bacterial overgrowth are thought to impair efficacy of L-dopa, which is absorbed in the proximal small intestine, resulting in motor fluctuations among Parkinson’s Disease (PD) patients that prompt dosage increases. While symptoms of dysmotility are frequently reported in PD, results are mixed concerning their effect, if any, on L-dopa pharmacokinetics. In this study, we compare L-dopa equivalent daily dose (LEDD) and motor function among patient with 5 upper GI symptoms to study the possible relationship between dysmotility symptoms and increased L-dopa requirement. Methods: Two hundred PD patients evaluated by outpatient neurology at Mass General Brigham Healthcare between 2018-2019 were included. History of 5 upper GI symptoms (dysphagia, nausea, vomiting, epigastric pain, and bloating), as well as LEDD were obtained from the medical record. Unified PD Rating Scale (UDPRS) part III motor exam scores off medication were extracted from clinical notes. Differences between LEDD and UDPRS motor scores among patients with and without a history of each of the 5 GI symptoms were calculated via Student t-tests. Results: Dysphagia was significantly associated with increased LEDD (230mg, P=0.0067) as well as increased motor severity (4.6 UDPRS, P=0.036). In contrast, nausea was associated with decreased LEDD (-187 mg, P=0.030) despite similar motor severity (1.1 UDPRS, P=0.63) to those without nausea (Table). There were no differences in LEDD and UDPRS scores among patients with and without vomiting, epigastric pain, and bloating. Conclusion: Except dysphagia, we found that GI dysmotility symptoms were not associated with increased LEDD nor increased motor severity. This suggests that symptomatic GI dysmotility may not be directly related to poor L-dopa absorption, a common clinical question for PD patients referred to GI. While dysphagia was linked with higher LEDD, this may have stemmed from higher UDPRS scores in this population. Interestingly, those with nausea required lower LEDD despite comparable motor severity. Nausea, a frequent symptom of delayed intestinal transit, may extend absorption time leading to better motor outcomes on less L-dopa. However, further studies are needed to discern any underlying mechanism. Our results nonetheless indicate that clinical management of dysmotility may not reduce motor fluctuations and the need for increased L-dopa as previously presumed. Table 1. - Changes in L-dopa Requirements and Motor Severity in the Presence of Dysmotility Symptoms GI Symptom ΔLEDD, mg (SD) P value ΔUDPRS III (SD) P value Nausea -187 (86) 0.03 1 (2) 0.633 Vomiting 11 (95) 0.91 -2 (2) 0.343 Dysphagia 230 (84) 0.007 5 (2) 0.036 Epigastric pain 101 (104) 0.33 0 (3) 0.881 Bloating 62 (99) 0.533 1 (2) 0.764 LEDD—L-dopa equivalent daily dose UDPRS—Unified Parkinson's Disease Rating Scale.

Carbidopa suppresses estrogen receptor-positive breast cancer via AhR-mediated proteasomal degradation of ERα.

Estrogen receptor-α (ERα) promotes breast cancer, and ER-positive cancer accounts for ~ 80% of breast cancers. This subtype responds positively to hormone/endocrine therapies involving either inhibition of estrogen synthesis or blockade of estrogen action. Carbidopa, a drug used to potentiate the therapeutic efficacy of L-DOPA in Parkinson's disease, is an agonist for aryl hydrocarbon receptor (AhR). Pharmacotherapy in Parkinson's disease decreases the risk for cancers, including breast cancer. The effects of carbidopa on ER-positive breast cancer were evaluated in cell culture and in mouse xenografts. The assays included cell proliferation, apoptosis, cell migration/invasion, subcellular localization of AhR, proteasomal degradation, and tumor growth in xenografts. Carbidopa decreased proliferation and migration of ER-positive human breast cancer cells in vitro with no significant effect on ER-negative breast cancer cells. Treatment of ER-positive cells with carbidopa promoted nuclear localization of AhR and expression of AhR target genes; it also decreased cellular levels of ERα via proteasomal degradation in an AhR-dependent manner. In vivo, carbidopa suppressed the growth of ER-positive breast cancer cells in mouse xenografts; this was associated with increased apoptosis and decreased cell proliferation. Carbidopa has therapeutic potential for ER-positive breast cancer either as a single agent or in combination with other standard chemotherapies.

Association Between Microbial Tyrosine Decarboxylase Gene and Levodopa Responsiveness in Patients With Parkinson Disease.

Interindividual variability in levodopa efficacy is a challenge for the personalized treatment of Parkinson disease (PD). Gut microbiota might represent a new approach for personalized medicine. Recently, a novel microbial levodopa metabolism pathway was identified, which is mediated by tyrosine decarboxylase mainly encoded by tyrosine decarboxylase gene (tyrDC) in Enterococcus faecalis. In this study, we aimed to identify whether the abundance of microbial tyrDC gene and E faecalis is associated with levodopa responsiveness and could predict the drug response. This cross-sectional study enrolled patients with PD between December 2019 and January 2022 and evaluated levodopa responsiveness using a levodopa challenge test. Patients were stratified into moderate and good responders based on levodopa responsiveness. The tyrDC gene and E. faecalis abundance in fecal samples were measured using quantitative real-time PCR. Plasma levodopa concentrations were measured using liquid chromatography-tandem mass spectrometry analysis. The predictive models for levodopa responsiveness were constructed and verified through cross-validation and external validation. A total of 101 patients with PD were enrolled in the primary cohort and 43 were enrolled in the external validation cohort. Moderate responders had higher abundances of the tyrDC gene (3.6 [3.1-4.3] vs 2.6 [2.1-2.9], p < 0.001) and E faecalis (3.2 [2.5-4.4] vs 2.6 [2.1-3.6], p = 0.010) than good responders. The tyrDC gene abundance was independently associated with levodopa responsiveness (OR: 5.848; 95% CI: 2.664-12.838; p < 0.001). Notably, tyrDC gene abundance showed certain discriminative power for levodopa responsiveness in primary cohort (sensitivity: 80.0%; specificity: 84.3%; area under the curve [AUC]: 0.85; 95% CI: 0.77-0.93; p < 0.001) and external validation cohort (sensitivity: 85.0%; specificity: 95.7%; AUC: 0.95; 95% CI: 0.89-1.02; p < 0.001). The prediction of levodopa responsiveness based on tyrDC gene abundance had good calibration and discrimination in cross-validation (C-index in training and test sets: 0.856 and 0.851, respectively) and external validation (C-index: 0.952). The microbial tyrDC gene abundance could serve as a potential biomarker of levodopa responsiveness. Novel strategies targeting the tyrDC gene may provide new approaches for personalized levodopa treatment.

Efficacy of L-dopa in Treatment of Aggression, Frontal Lobe Cognitive Functioning and Task Switching Deficits in Parkinson’s Disease Patients

Objectives: To assess efficacy of L-dopa treatment on aggression, frontal lobe and task switching deficits in patients with Parkinson’s disease (PD).&#x0D; Study Design: Prospective comparative study.&#x0D; Place and Duration of Study: Bahawal Victoria Hospital and Civil Hospital Bahawalpur, Pakistan, from Apr 2016 to Oct 2017.&#x0D; Methodology: Seventy-five healthy individuals and seventy-five PD patients participated in the study. This study was completed in two testing sessions. Healthy participants had single testing session whereas patients were tested twice (pre and post L-dopa treatment). Participants completed Frontal Assessment Battery, part B TMT, and Buss-Perry Aggression Questionnaire.&#x0D; Results: PD patients (6.13 ± 0.81) showed deficient frontal lobe functioning F (1,48)=14489.66, p&lt;0.001, ηp2=0.99 than healthy individuals (17.93 ± 0.25). Patients (283.05 ± 6.02) had inferior task switching abilities F (1, 48) = 65397.85, p&lt;0.001, ηp2=0.99 than healthy individuals (78.37 ± 3.43). The level of aggression was higher F (1,48)=2369.24, p&lt;0.001, ηp2=0.94 in patients (131.12 ± 12.57) compared with healthy individuals (43.33 ± 9.26). Post L-dopa treatment testing session showed significant improvement in frontal lobe functioning (6.13 ± 0.81 vs. 13.46 ± 1.45), task switching abilities (216.80 ± 13.74 vs. 283.05 ± 6.02) in patients. In addition, aggression was reduced in patients (106.06 ± 1.07 vs. 131.12 ± 12.57).&#x0D; Conclusion: L-dopa was found beneficial to reduce aggression, frontal lobe cognitive and task switching deficits in patients with PD.

The multimodal serotonin compound Vilazodone alone, but not combined with the glutamate antagonist Amantadine, reduces l-DOPA-induced dyskinesia in hemiparkinsonian rats

Parkinson's disease (PD) is a progressive, neurodegenerative movement disorder caused by loss of nigrostriatal dopamine (DA) neurons. DA replacement therapy using L-3,4-dihydroxyphenylalanine (l-DOPA) improves motor function but often results in l-DOPA-induced dyskinesia (LID) typified by abnormal involuntary movements (AIMs). In states of DA depletion, striatal serotonin (5-HT) hyperinnervation and glutamate overactivity are implicated in LID. To target these co-mechanisms, this study investigated the potential anti-dyskinetic effects of FDA-approved Vilazodone (VZD), a 5-HT transport blocker and partial 5-HT1A agonist, and Amantadine (AMAT), a purported NMDA glutamate antagonist, in 6-hydroxydopamine-lesioned hemiparkinsonian Sprague-Dawley rats. Dose-response curves for each drug against l-DOPA-induced AIMs were determined to identify effective threshold doses. A second cohort of rats was tested using the threshold doses of VZD (1, 2.5 mg/kg, s.c.) and/or AMAT (40 mg/kg, s.c.) to examine their combined, acute effects on LID. In a third cohort, VZD and/or AMAT were administered daily with l-DOPA for 14 days to determine prophylactic effects on LID development. In a final cohort, rats with established LID received VZD and/or AMAT injections for 2 weeks to examine their interventional properties. Throughout experiments, AIMs were rated for dyskinesia severity and forepaw adjusting steps (FAS) were monitored l-DOPA motor efficacy. Results revealed that acute and chronic VZD + l-DOPA treatment significantly decreased AIMs and maintained FAS compared to l-DOPA alone. AMAT + l-DOPA co-administration did not exert any significant effects on AIMs or FAS, while the co-administration of VZD and AMAT with l-DOPA demonstrated intermediate effects. These results suggest that co-administration of low-dose VZD and AMAT with l-DOPA does not synergistically reduce LID in hemiparkinsonian rats. Importantly, low doses of VZD (2.5, 5 mg/kg) did reduce the development and expression of LID while maintaining l-DOPA efficacy, supporting its potential therapeutic utility for PD patients.

Pharmacological actions of a novel and highly selective D3 dopamine receptor agonist, ML417, in a rodent model of Parkinson’s disease

Since its first use in treating Parkinson’s disease (PD), L‐DOPA has remained the gold standard of therapy for this disorder, defined by the progressive degeneration of dopaminergic neurons in the CNS leading to profound bradykinesia and tremor. The efficacy of L‐DOPA wanes over time and is associated with increasing side effects, including motor fluctuations and dyskinesias. Several dopaminergic agonists have also been introduced to treat PD, including pramipexole and ropinirole, which exhibit fewer motor side effects but are associated with impulse control disorders such as excessive gambling and hypersexuality. Notably, the dopamine receptor subtype(s) mediating the therapeutic actions and/or side effects in PD therapy remain unknown. However, the preference of pramipexole and ropinirole for the D3 dopamine receptor (D3R) suggests the involvement of this subtype, although these drugs also activate the D2R at therapeutic doses. Importantly, no drug currently employed to treat PD alters the course of the disease and the discovery of neuroprotective agents remain an unmet need in PD therapeutics. Recently, we discovered a novel, potent and highly selective agonist for the D3R, ML417, that is brain penetrant and was found to protect against 6‐OHDA‐induced neurodegeneration of dopaminergic neurons (Moritz et al., J. Med. Chem. 63: 5526, 2020). In the current study, we used ML417 to probe the role of the D3R in a rat model of PD. We initially sought to investigate the role of the D3R in ameliorating bradykinesia in a hemi‐parkinsonian rat model induced by 6‐OHDA infusion into the medial forebrain bundle. Using a validated cylindrical treadmill test of locomotion, doses of ML417 up to 20 mg/kg had no effect on improving impairments in walking as assessed by step counts in the hemi‐parkinsonian rats. In contrast, administration of L‐DOPA (6 mg/kg) significantly improves locomotion in the same model. Further, pretreatment with a D3R‐selective antagonist, SB277011A (30 mg/kg), did not attenuate the effects of L‐DOPA in reducing bradykinesia. These results suggest that the D3R does not mediate the anti‐bradykinetic effects of current PD therapeutics. However, we hypothesize that D3R stimulation may be beneficial for the treatment of L‐DOPA‐induced dyskinesias (LIDs) in PD. To test this, we used a chronic L‐DOPA administration paradigm (12 mg/kg/day for 7 days) to induce dyskinesias in the hemi‐parkinsonian rats. Subsequently, the effects of ML417 and SB277011A were assessed in these animals using an abnormal involuntary movement (AIMs) scoring method. Pretreatment with a single dose of ML417 (20 mg/kg) significantly reduced the intensity and duration of dyskinesias promoted with a single dose of L‐DOPA (6 mg/kg). Further, co‐administration of SB277011A (30 mg/kg) with ML417 attenuated the anti‐dyskinetic effects of ML417, suggesting that the benefit is D3R‐mediated. Overall, this study implies that D3R stimulation has no therapeutic effect on bradykinesia in PD, however, it may be beneficial in treating dyskinesias arising from L‐DOPA therapy.