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Rasagiline (RAS) is a medication for Parkinson's disease that increases dopamine levels in the brain by inhibiting monoamine oxidase, helping to alleviate symptoms. The proposed study aims to develop an efficient, feasible, and sensitive method for RAS assay, utilizing Pyrosin B dye, a convenient fluorescent ligand. Combining the RAS analyte with Pyrosin B ligand in a mildly acidic buffered solution rapidly quenches the native fluorescence of the ligand. This quenching results from the formation of a specific ion‐dipole association complex between the lone pair‐bearing atoms of the ligand and the protonated amine moiety of RAS, highlighting their interactive chemistry under these conditions. The degree of this interaction demonstrated superior sensitivity compared with reported alternatives, exhibiting a linear range of 50.0 to 1000.0 ng/mL. The method is characterized by a limit of detection (LOD) of 16.0 ng/mL and a limit of quantification (LOQ) of 48.0 ng/mL. By optimizing the RAS‐Pyrosin B system, the variable parameters were finely tuned, ensuring the assay method's reliability. The method's accuracy, precision, selectivity, and robustness were validated according to International Council for Harmonization (ICH) guidelines, enabling precise and efficient analysis of RAS in the nanogram range. This method streamlines the analysis procedure and reduces environmental impact, making it a promising approach for the quality control of ParkintreatR tablets (1 mg) and other analytical applications. [ABSTRACT FROM AUTHOR]

Rasagiline (Azilect®) is a selective monoamine oxidase B (MAO-B) inhibitor that provides symptomatic benefits in Parkinson's disease (PD) treatment and has been found to exert preclinical neuroprotective effects. Here, we investigated the neuroprotective signaling pathways of acute rasagiline treatment for 22 h in PC12 neuronal cultures exposed to oxygen–glucose deprivation (OGD) for 4 h, followed by 18 h of reoxygenation (R), causing 40% aponecrotic cell death. In this study, 3–10 µM rasagiline induced dose-dependent neuroprotection of 20–80%, reduced the production of the neurotoxic reactive oxygen species by 15%, and reduced the nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by 75–90%. In addition, 10 µM rasagiline increased protein kinase B (Akt) phosphorylation by 50% and decreased the protein expression of the ischemia-induced α-synuclein protein by 50% in correlation with the neuroprotective effect. Treatment with 1–5 µM rasagiline induced nuclear shuttling of transcription factor Nrf2 by 40–90% and increased the mRNA levels of the antioxidant enzymes heme oxygenase-1, (NAD (P) H- quinone dehydrogenase, and catalase by 1.8–2.0-fold compared to OGD/R insult. These results indicate that rasagiline provides neuroprotection to the ischemic neuronal cultures through the inhibition of α-synuclein and GAPDH-mediated aponecrotic cell death, as well as via mitochondrial protection, by increasing mitochondria-specific antioxidant enzymes through a mechanism involving the Akt/Nrf2 redox-signaling pathway. These findings may be exploited for neuroprotective drug development in PD and stroke therapy. [ABSTRACT FROM AUTHOR]

Background and purpose: In 2016, we concluded a randomized controlled trial testing 1 mg rasagiline per day add‐on to standard therapy in 252 amyotrophic lateral sclerosis (ALS) patients. This article aims at better characterizing ALS patients who could possibly benefit from rasagiline by reporting new subgroup analysis and genetic data. Methods: We performed further exploratory in‐depth analyses of the study population and investigated the relevance of single nucleotide polymorphisms (SNPs) related to the dopaminergic system. Results: Placebo‐treated patients with very slow disease progression (loss of Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised [ALSFRS‐R] per month before randomization of ≤0.328 points) showed a per se survival probability after 24 months of 0.85 (95% confidence interval = 0.65–0.94). The large group of intermediate to fast progressing ALS patients showed a prolonged survival in the rasagiline group compared to placebo after 6 and 12 months (p = 0.02, p = 0.04), and a reduced decline of ALSFRS‐R after 18 months (p = 0.049). SNP genotypes in the MAOB gene and DRD2 gene did not show clear associations with rasagiline treatment effects. Conclusions: These results underline the need to consider individual disease progression at baseline in future ALS studies. Very slow disease progressors compromise the statistical power of studies with treatment durations of 12–18 months using clinical endpoints. Analysis of MAOB and DRD2 SNPs revealed no clear relationship to any outcome parameter. More insights are expected from future studies elucidating whether patients with DRD2CC genotype (Rs2283265) show a pronounced benefit from treatment with rasagiline, pointing to the opportunities precision medicine could open up for ALS patients in the future. [ABSTRACT FROM AUTHOR]

Background and purpose: Rasagiline might be disease modifying in patients with amyotrophic lateral sclerosis (ALS). The aim was to evaluate the effect of rasagiline 2 mg/day on neurofilament light chain (NfL), a prognostic biomarker in ALS. Methods: In 65 patients with ALS randomized in a 3:1 ratio to rasagiline 2 mg/day (n = 48) or placebo (n = 17) in a completed randomized controlled multicentre trial, NfL levels in plasma were measured at baseline, month 6 and month 12. Longitudinal changes in NfL levels were evaluated regarding treatment and clinical parameters. Results: Baseline NfL levels did not differ between the study arms and correlated with disease progression rates both pre‐baseline (r = 0.64, p < 0.001) and during the study (r = 0.61, p < 0.001). NfL measured at months 6 and 12 did not change significantly from baseline in both arms, with a median individual NfL change of +1.4 pg/mL (interquartile range [IQR] −5.6, 14.2) across all follow‐up time points. However, a significant difference in NfL change at month 12 was observed between patients with high and low NfL baseline levels treated with rasagiline (high [n = 13], −6.9 pg/mL, IQR −20.4, 6.0; low [n = 18], +5.9 pg/mL, IQR −1.4, 19.7; p = 0.025). Additionally, generally higher longitudinal NfL variability was observed in patients with high baseline levels, whereas disease progression rates and disease duration at baseline had no impact on the longitudinal NfL course. Conclusion: Post hoc NfL measurements in completed clinical trials are helpful in interpreting NfL data from ongoing and future interventional trials and could provide hypothesis‐generating complementary insights. Further studies are warranted to ultimately differentiate NfL response to treatment from other factors. [ABSTRACT FROM AUTHOR]

Background: There remains uncertainty as to the optimal way to initiate therapy for Parkinson's disease (PD) to maximize benefit and minimize adversity. Objectives: The objective was to determine if P2B001 (a fixed, low‐dose, extended‐release [ER] combination of pramipexole 0.6 mg and rasagiline 0.75 mg) is superior to each of its components and compare its safety and efficacy to optimized treatment with marketed doses of pramipexole‐ER. Methods: This was a 12‐week, double‐blind study (NCT03329508). Total of 544 untreated patients with PD were randomized (2:2:2:1) to treatment with P2B001, its individual components (pramipexole‐ER 0.6 mg or rasagiline‐ER 0.75 mg), or commercial doses of pramipexole‐ER titrated to optimal dose (1.5–4.5 mg). The primary endpoint was change from baseline to week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III. The key secondary endpoint was the change from baseline in the Epworth Sleepiness Scale (ESS) for P2B001 versus the titrated dose of pramipexole‐ER. Results: P2B001 provided superior efficacy compared to each of its components; mean (95% CI) treatment differences in UPDRS II + III scores were −2.66 (95% CI, −4.33 to −1.00) versus pramipexole‐ER 0.6 mg (P = 0.0018) and − 3.30 (95% CI, −4.96 to −1.63) versus rasagiline‐ER 0.75 mg (P < 0.0001). P2B001 had comparable efficacy with the titrated dose of pramipexole‐ER (mean, 3.2 mg), but significantly less worsening in daytime‐sleepiness (ESS treatment difference: −2.66 [95% CI, −3.50 to −1.81]; P < 0.0001). P2B001 was well‐tolerated with fewer sleep‐related and dopaminergic adverse events than titrated doses of pramipexole‐ER including somnolence, orthostatic hypotension, and neuropsychiatric side effects. Conclusions: P2B001 had superior efficacy to its individual components and was comparable with commercially used doses of pramipexole‐ER with less worsening of sleepiness and fewer dopaminergic adverse events. These findings support considering once‐daily P2B001 as initial therapy for patients with early PD. © 2023 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Abstract Background During the course of their illness, people with Parkinson’s disease may see changes in their insulin-like growth factor (IGF-1) and serum homocysteine (Hcy) indices. In this study, patients with intermediate to severe Parkinson’s disease were examined for how Resagiline and levodopa and benserazide hydrochloride affected their motor performance, serum levels of homocysteine (Hcy), and insulin-like growth factor (IGF-1). Methods From June 2020 to December 2021, a total of 100+ cases of Parkinson’s patients over 60 years old in the middle and late stages of Parkinson’s were seen in the outpatient and inpatient departments of the Third People’s Hospital of Chengdu City and had a detailed observation record, and according to the inclusion criteria, the patients who met the criteria were randomly grouped into a clinical observation group and a control group. The subjects in the control group received only levodopa and benserazide hydrochloride treatment, while the observation group was treated with Resagiline in combination with the clinical control group. The total treatment observation period was 1 year for both groups, and the motor function and serum Hcy and IGF-1 indexes of both groups were compared after the end of treatment. Results We randomly and evenly grouped 64 patients who met the requirements of the inclusion criteria into a clinical observation group and a control group, each with 32 patients, from among 168 patients over 60 years of age with detailed observation records in the middle and late stages of Parkinson’s. After the 1-year observation period, we found that the total effective rate after treatment in the clinical observation group (93.75%) and significantly higher than that in the control group (68.75%) (P

Dysphagia, a potentially fatal symptom of Parkinson's disease, is characterized by frequent silent aspiration, a risk factor for aspiration pneumonia. The transdermal dopamine agonist rotigotine alleviates dysphagia in patients with Parkinson's disease and is more effective than oral levodopa, suggesting the importance of continuous dopaminergic stimulation during swallowing. Rasagiline is a monoamine oxidase B (MAOB) inhibitor that facilitates continuous dopaminergic stimulation. We hypothesized that MAOB inhibition by rasagiline would be effective in improving swallowing function in patients with early- and mid-to late-stage Parkinson's disease. To this end, we performed an analytical observational study to determine the effects of rasagiline (1 mg/day) on swallowing function using videofluoroscopic swallowing study. This open-label, evaluator-blinded study enrolled 32 patients with Parkinson's disease, among whom 19 were drug-naïve and 13 were receiving add-on therapy. Our results showed that rasagiline significantly improved all swallowing measures during the oral and pharyngeal phases, including oral transit time and pharyngeal transit time, in all enrolled patients. Similar results were found in drug-naïve and mid-to late-stage patients, with no intergroup differences. In conclusion, drugs capable of continuous dopaminergic stimulation may effectively improve swallowing function in patients with Parkinson's disease, with similar effects in early- and mid-to late-stage Parkinson's disease. This study has been the first to show that rasagiline significantly improves swallowing function in mid-to late-stage patients receiving add-on therapy.

Background: During the course of their illness, people with Parkinson's disease may see changes in their insulin-like growth factor (IGF-1) and serum homocysteine (Hcy) indices. In this study, patients with intermediate to severe Parkinson's disease were examined for how Resagiline and levodopa and benserazide hydrochloride affected their motor performance, serum levels of homocysteine (Hcy), and insulin-like growth factor (IGF-1). Methods: From June 2020 to December 2021, a total of 100+ cases of Parkinson's patients over 60 years old in the middle and late stages of Parkinson's were seen in the outpatient and inpatient departments of the Third People's Hospital of Chengdu City and had a detailed observation record, and according to the inclusion criteria, the patients who met the criteria were randomly grouped into a clinical observation group and a control group. The subjects in the control group received only levodopa and benserazide hydrochloride treatment, while the observation group was treated with Resagiline in combination with the clinical control group. The total treatment observation period was 1 year for both groups, and the motor function and serum Hcy and IGF-1 indexes of both groups were compared after the end of treatment. Results: We randomly and evenly grouped 64 patients who met the requirements of the inclusion criteria into a clinical observation group and a control group, each with 32 patients, from among 168 patients over 60 years of age with detailed observation records in the middle and late stages of Parkinson's. After the 1-year observation period, we found that the total effective rate after treatment in the clinical observation group (93.75%) and significantly higher than that in the control group (68.75%) (P < 0.05); after 1 year of treatment, the UPDRS score decreased in both groups, and the observation group was significantly lower than the control group (P < 0.05); after treatment, serum Hcy decreased and IGF-1 increased in both groups, and the observation group was higher than the control group mean values (P < 0.05). Conclusions: In patients with Parkinson's disease who are in the middle and late stages of the disease, the administration of Resagiline combined with levodopa and benserazide hydrochloride can significantly lower the body's serum Hcy level, significantly raise IGF-1 levels, and significantly improve motor function in patients with Parkinson's disease. It can also have significant therapeutic effects. [ABSTRACT FROM AUTHOR]

Selegiline and rasagiline are two selective monoamine oxidase B (MAO-B) inhibitors used in the treatment of Parkinson's disease. In their clinical application, however, differences in L-dopa-sparing potencies have been observed. The aim of this study was to find neurochemical and behavioral explanations for the antiparkinsonian effects of these drugs. We found that selegiline possesses a dopaminergic enhancer effect: it stimulated the electrically induced [3H]dopamine release without influencing the resting [3H]dopamine release from rat striatal slices in 10−10–10−9 mol/L concentrations. Rasagiline added in 10−13 to 10−5 mol/L concentrations did not alter the resting or electrically stimulated [3H]dopamine release. Rasagiline (10−9 mol/L), however, suspended the stimulatory effect of selegiline on the electrically induced [3H]dopamine release. The trace amine-associated receptor 1 (TAAR1) antagonist EPPTB (10−8–10−7 mol/L) also inhibited the stimulatory effect of selegiline on [3H]dopamine release. The effect of selegiline in its enhancer dose (5.33 nmol/kg) against tetrabenazine-induced learning deficit measured in a shuttle box apparatus was abolished by a 5.84 nmol/kg dose of rasagiline. The selegiline metabolite (−)methamphetamine (10−9 mol/L) also exhibited enhancer activity on [3H]dopamine release. We have concluded that selegiline acts as an MAO-B inhibitor and a dopaminergic enhancer drug, and the latter relates to an agonist effect on TAAR1. In contrast, rasagiline is devoid of enhancer activity but may act as an antagonist on TAAR1. [ABSTRACT FROM AUTHOR]

BackgroundA Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a monoamine oxidase B (MAO-B) inhibitor approved for Parkinson disease, in mild to moderate Alzheimer's disease (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluorodeoxyglucose-positron emission tomography [FDG-PET]) compared to placebo. Secondary objectives included measurement of effects on tau PET and evaluation of directional consistency of clinical end points.MethodsThis was a double-blind, parallel group, placebo-controlled, community-based, three-site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG-PET was analyzed for the presence of an AD-like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest and voxel-based analyses. Tau PET was evaluated at baseline and longitudinally. Clinical outcomes were analyzed using an intention-to-treat (ITT) model.ResultsFifty patients were randomized and 43 completed treatment. The study met its primary end point, demonstrating favorable change in FDG-PET differences in rasagiline versus placebo in middle frontal (P

Objective(s): Parkinson’s disease (PD) is one of the most incurable, chronic, and progressive neurodegenerative disorders Worldwide. Curcumin, a natural polyphenolic antioxidant compound, has a long history in traditional medicine. We investigate the effect of curcumin on brain oxidative stress, DNA fragmentation, and motor changes in rotenone-induced PD in mice. The possible modulation of the anti-parkinsonian action of drugs L-dopa and rasagiline by curcumin was also studied.Materials and Methods: Mice received rotenone 1.5 mg/kg and were treated with curcumin (150 mg/kg), L-dopa (25 mg/kg), rasagiline (1 mg/kg), L-dopa+curcumin, or rasagiline+curcumin. Striatal malondialdehyde, reduced glutathione, nitric oxide, tyrosine hydroxylase, and brain DNA fragmentations were measured. Histopathological examination of brain tissues was done. Motor coordination and behavioral tests such as wire-hanging, stair, and wood-waking tests were included.Results: Rotenone caused elevation in brain malondialdehyde and nitric oxide contents, depletion of reduced glutathione accompanied by a reduction in rearing behavior, and impairment of motor activity in wire-hanging, stair, and wood-waking tests. Also, severe DNA fragmentation in the striatum, marked decrease of substantia nigra pigmented neurons, neuronal degeneration in the cerebral cortex and hippocampus, decreased glial fibrillary acidic protein reaction (GFAP) and glial cell size in the cerebral cortex were caused by rotenone. In rotenone-treated mice, brain oxidative stress was decreased by curcumin, L-dopa, rasagiline, curcumin+L-dopa, and curcumin+rasagiline. These treatments also prevented DNA fragmentation and markedly improved the motor and behavioral impairment caused by rotenone. Rotenone-induced histopathological changes were ameliorated by curcumin which had an additive effect to that of l-dopa or rasagiline.Conclusion: These data indicate that curcumin showed additive neuroprotective effects to L-dopa or rasagiline and ameliorated neurodegeneration, DNA fragmentation, and motor defects caused by rotenone in mice.

Background: Effects of dopaminergic medications used to treat Parkinson's disease (PD) may be compared with each other by using conversion factors, calculated as Levodopa equivalent dose (LED). However, current LED proposals on MAO‐B inhibitors (iMAO‐B) safinamide and rasagiline are still based on empirical approaches. Objectives: To estimate LED of safinamide 50 and 100 mg. Methods: In this multicenter, longitudinal, case–control study, we retrospectively reviewed clinical charts of 500 consecutive PD patients with motor complications and treated with (i) safinamide 100 mg (N = 130), safinamide 50 mg (N = 144), or rasagiline 1 mg (N = 97) for 9 ± 3 months and a control group of patients never treated with any iMAO‐B (N = 129). Results: Major baseline features (age, sex, disease duration and stage, severity of motor signs and motor complications) were similar among the groups. Patients on rasagiline had lower UPDRS‐II scores and Levodopa dose than control subjects. After a mean follow‐up of 8.8‐to‐10.1 months, patients on Safinamide 50 mg and 100 mg had lower UPDRS‐III and OFF‐related UPDRS‐IV scores than control subjects, who in turn had larger increase in total LED than the three iMAO‐B groups. After adjusting for age, disease duration, duration of follow‐up, baseline values and taking change in UPDRS‐III scores into account (sensitivity analysis), safinamide 100 mg corresponded to 125 mg LED, whereas safinamide 50 mg and rasagiline 1 mg equally corresponded to 100 mg LED. Conclusions: We used a rigorous approach to calculate LED of safinamide 50 and 100 mg. Large prospective pragmatic trials are needed to replicate our findings. [ABSTRACT FROM AUTHOR]

Rasagiline has a certain potential in neuroprotection and delaying the progression of Parkinson's disease (PD). However, the poor pharmacokinetics (PK) characteristics of conventional oral tablets and poor medication compliance limit the optimal efficacy of rasagiline. Based on this, we designed and optimized a sustained-release rasagiline in situ gel based on in vitro release and in vivo PK results. Among them, we found for the first time that aluminum hydroxide can effectively shorten the lag phase and promote early and late release, making the daily release more uniform. After subcutaneous administration of the optimized gel formulation at a monthly dose, the Cmax (64 ng/ml) was lower than that of free rasagiline (494 ng/ml) administered subcutaneously at a daily dose and comparable to that of oral administration of Azilect® (59.1 ng/ml) at a daily dose. In the meantime, the plasma concentration of rasagiline was mainly maintained at 5–10 ng/ml for about 1 month, and the active metabolite 1-aminoindane in plasma was also able to maintain a steady state. The rasagiline in situ gel has suitable viscosity and injectability, good repeatability of subcutaneous injection, and controllable impurities and can achieve sustained release in vivo with small burst release, which may have the clinical application advantages of maximizing the disease-modifying effect of rasagiline and improving medication compliance. The rasagiline in situ gel was optimized through the feedback of in vitro release and in vivo pharmacokinetics (PK), in which the addition of aluminum hydroxide had a modulating effect on uniform release. The gel has low burst release and maintains steady-state blood drug concentration for about 1 month. [ABSTRACT FROM AUTHOR]

Rasagiline is a monoamine oxidase B (MAO-B) inhibitor with possible neuroprotective effects in patients with amyotrophic lateral sclerosis (ALS). We performed a randomized, double-blind, placebo-controlled trial of 80 ALS participants with enrichment of the placebo group with historical controls (n = 177) at 10 centers in the United States. Participants were randomized in a 3:1 ratio to 2 mg/day rasagiline or placebo. The primary outcome was average slope of decline on the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary measures included slow vital capacity, survival, mitochondrial and molecular biomarkers, and adverse-event reporting. There was no difference in the average 12-month ALSFRS-R slope between rasagiline and the mixed placebo and historical control cohorts. Rasagiline did not show signs of drug-target engagement in urine and blood biomarkers. Rasagiline was well tolerated with no serious adverse events. Rasagiline did not alter disease progression compared with controls over 12 months of treatment. Muscle Nerve 59:201-207, 2019.

Parkinson's disease (PD) is a complex disease, and the treatment is focused on the patient's clinical symptoms. Levodopa continues to be the most effective drug for symptomatic PD treatment. However, chronic levodopa treatment is associated with the development of motor complications in most patients. Add-on therapeutic drugs, such as dopamine agonists and monoamine oxidase B (MAO-B) inhibitors, for example, safinamide and rasagiline, may be a desirable addition to continuously increase the levodopa dose for the optimization of motor control in PD. The scientific literature shows that safinamide significantly alleviated motor fluctuations with no increase in troublesome dyskinesia, thanks to its unique double mechanism, providing further benefits to fluctuating PD patients when compared to a placebo or other drugs. Switching from rasagiline to safinamide has been shown to improve the wearing-off phenomena, which is defined as the recurrent, predictable worsening of symptoms of parkinsonism at the end of the levodopa dose until the next dose reaches a clinical effect. In this situation, safinamide may be helpful for reducing the total daily dose of levodopa, improving the OFF time and ON time without troublesome dyskinesias, and being more effective than other MAO-B inhibitors. In this narrative review, we explore the switch from rasagiline to safinamide in patients with motor complications as a feasible and effective alternative to optimize antiparkinsonian treatment. [ABSTRACT FROM AUTHOR]

Objective(s): Parkinson's disease (PD) is one of the most incurable, chronic, and progressive neurodegenerative disorders Worldwide. Curcumin, a natural polyphenolic anti-oxidant compound, has a long history in traditional medicine. We investigate the effect of curcumin on brain oxidative stress, DNA fragmentation, and motor changes in rotenone-induced PD in mice. The possible modulation of the anti-parkinsonian action of drugs L-dopa and rasagiline by curcumin was also studied. Materials and Methods: Mice received rotenone 1.5 mg/kg and were treated with curcumin (150 mg/kg), L-dopa (25 mg/kg), rasagiline (1 mg/kg), L-dopa+curcumin, or rasagiline+curcumin. Striatal malondialdehyde, reduced glutathione, nitric oxide, tyrosine hydroxylase, and brain DNA fragmentations were measured. Histopathological examination of brain tissues was done. Motor coordination and behavioral tests such as wire-hanging, stair, and wood-waking tests were included. Results: Rotenone caused elevation in brain malondialdehyde and nitric oxide contents, depletion of reduced glutathione accompanied by a reduction in rearing behavior, and impairment of motor activity in wire-hanging, stair, and wood-waking tests. Also, severe DNA fragmentation in the striatum, marked decrease of substantia nigra pigmented neurons, neuronal degeneration in the cerebral cortex and hippocampus, decreased glial fibrillary acidic protein reaction (GFAP) and glial cell size in the cerebral cortex were caused by rotenone. In rotenone-treated mice, brain oxidative stress was decreased by curcumin, L-dopa, rasagiline, curcumin+L-dopa, and curcumin+rasagiline. These treatments also prevented DNA fragmentation and markedly improved the motor and behavioral impairment caused by rotenone. Rotenone-induced histopathological changes were ameliorated by curcumin which had an additive effect to that of l-dopa or rasagiline. Conclusion: These data indicate that curcumin showed additive neuroprotective effects to L-dopa or rasagiline and ameliorated neurodegeneration, DNA fragmentation, and motor defects caused by rotenone in mice. [ABSTRACT FROM AUTHOR]

A set of new rasagiline derivatives is presented. They were designed to be antioxidant compounds with the potential to be used for treating neurodegenerative disorders. They are expected to be multifunctional molecules that can help reduce oxidative stress, which is thought to contribute to neurodegenerative disorders. The CADMA‐Chem computational protocol was used to produce rasagiline derivatives and to evaluate their likeliness as oral drugs and antioxidants. Three of them were identified as the most promising ones. They are proposed to be better free radical scavengers than rasagiline. In addition, they are expected to keep the parent's molecule neuroprotective capability. Hopefully, the results presented here would promote further experimental and theoretical investigations on these compounds. [ABSTRACT FROM AUTHOR]

Background: Monoamine oxidase type B inhibitors (iMAO-Bs) are a class of largely-used antiparkinsonian agents that, based on experimental evidence, are supposed to exert different degrees of neuroprotection in Parkinson's disease (PD). However, clinical proofs on this regard are very scarce. Since cerebrospinal fluid (CSF) reflects pathological changes occurring at brain level, we examined the neurodegeneration-related CSF biomarkers profile of PD patients under chronic treatment with different iMAO-Bs to identify biochemical signatures suggestive for differential neurobiological effects. Methods: Thirty-five PD patients under chronic treatment with different iMAO-Bs in add-on to levodopa were enrolled and grouped in rasagiline (n = 13), selegiline (n = 9), safinamide (n = 13). Respective standard clinical scores for motor and non-motor disturbances, together with CSF biomarkers of neurodegeneration levels (amyloid-β-42, amyloid-β-40, total and 181-phosphorylated tau, and lactate) were collected and compared among the three iMAO-B groups. Results: No significant clinical differences emerged among the iMAO-B groups. CSF levels of tau proteins and lactate were instead different, resulting higher in patients under selegiline than in those under rasagiline and safinamide. Conclusions: Although preliminary and limited, this study indicates that patients under different iMAO-Bs may present distinct profiles of CSF neurodegeneration-related biomarkers, probably because of the differential neurobiological effects of the drugs. Larger studies are now needed to confirm and extend these initial observations. [ABSTRACT FROM AUTHOR]

Sleep problems commonly occur in Parkinson's disease (PD) and significantly affect patients' quality of life. A possible effect on subjective sleep disturbances of monoamine oxidase-B inhibitors (MAOB-Is) has been described. This prospective, observational, single-centre study involved 45 fluctuating PD patients complaining sleep problems as documented by the PD Sleep Scale -2nd version (PDSS-2 ≥18) starting rasagiline 1 mg/daily or safinamide 100 mg/daily, according to common clinical practice, and maintaining antiparkinsonian therapy unchanged. Polysomnography (PSG), sleep questionnaires (PDSS-2, Epworth Sleepiness Scale - ESS), and motor function were evaluated at baseline (T0) and after 4 months of treatment (T1). Safinamide was prescribed in thirty patients and rasagiline in fifteen patients. Both drugs induced a significant improvement in Movement Disorder Society Unified PD Rating Scale III scores. Patients treated with rasagiline showed a significant increase in stage 1 (N1) Non-REM sleep compared to T0, with no significant effects on sleep scales. Patients treated with safinamide showed a significant increase in stage 3 of Non-REM sleep and sleep efficiency and a reduction in the rate of periodic limb movements, matching a significant reduction in PDSS-2 and ESS scales compared to T0. This study showed that safinamide, in addition to having a significant effect on PD motor symptoms, like the other MAOB-Is, may exert a specific beneficial effect on subjective and objective sleep, probably driven by its dual mechanism of action, which involves both dopaminergic and glutamatergic neurotransmission. • Sleep problems commonly occur in fluctuating patients with Parkinson's disease. • The study evaluates the impact of rasagiline and safinamide on PD sleep problems. • Safinamide improved sleep efficiency and reduced periodic limb movements. • Safinamide showed a marked positive effect on sleep compared to rasagiline. • The beneficial action of safinamide might be due to its dual mechanism of action. [ABSTRACT FROM AUTHOR]

Abstract Background Caffeine is a natural alkaloid present in a variety of highly consumed popular drinks such as coffee, tea and soft drinks as well as chocolate. Its consumption elicits beneficiary psychostimulant that has been linked to a reduced risk of developing Parkinson’s disease (PD). The aim of the present study is to investigate the possible synergistic neuroprotective effects of co-administration of caffeine (CAF) or coffee (COF) with rasagiline (R) or l-dopa against paraquat (PQ)-induced neurochemical and motor behavior impairments in mice. Results In behavioral tests, R + COF increased the locomotor activity in rotarod test compared to l-dopa + COF. l-Dopa combinations decreased the immobility time in FST compared to rasagiline combinations; l-dopa + CAF provided a similar increase in locomotor activity compared to R + CAF. Combination of CAF or COF with l-dopa or rasagiline resulted in a substantial improvement in brain neurotransmitter and antioxidant levels as they significantly increased dopamine and super oxide dismutase but significantly decreased nitric oxide levels as compared to l-dopa or rasagiline, respectively. Furthermore, they also exerted a protective effect against the neurodegenerative histopathological changes induced by PQ. Conclusions Our findings demonstrated co-administration of COF or CAF, adenosine 2A receptor antagonists, along with l-dopa or rasagiline possesses a new therapeutic strategy for the management of PD neurochemical disturbances and motor behavior impairments through preservation of the brain dopamine and serotonin content, antioxidants level and histological features.

Rasagiline is a selective and irreversible inhibitor of monoamine oxidase type B with neuroprotective effect, indicated for the management of Parkinson's disease. The aim of this work was to evaluate the impact of seven CYP1A2 alleles and of 120 additional variants located in other CYP enzymes (e.g., CYP2C19), UGT enzymes (e.g., UGT1A1) or other enzymes (e.g., NAT2), and transporters (e.g., SLCO1B1) on the pharmacokinetic variability and safety of rasagiline. A total of 118 healthy volunteers enrolled in four bioequivalence clinical trials consented to participate in this pharmacogenetic study. CYP1A2 alleles were not associated with the pharmacokinetic variability of rasagiline. Patients with ABCB1 rs1045642 G/A+A/A genotypes presented higher area under the curve adjusted by dose per weight (AUC0-∞/DW) than those with the G/G genotype (p = 0.012) and lower volume of distribution (Vd/F) and clearance (Cl/F) (p = 0.001 and p = 0.012, respectively). Subjects with the ABCC2 rs2273697 A/A genotype presented lower tmax (i.e., the time to reach the maximum concentration, Cmax) compared to those with G/G+G/A genotypes (p = 0.001). Volunteers with the SLC22A1 *1/*5 genotype exhibited lower Cmax/DW and higher tmax (p = 0.003 and p = 0.018, respectively) than subjects with the *1/*1 diplotype. Only one adverse drug reaction was reported: headache. Our results suggest the genetic polymorphism of drug transporters, rather than metabolizing enzymes, conditions the pharmacokinetics of rasagiline. [ABSTRACT FROM AUTHOR]

Synucleinopathies are a group of neurodegenerative disorders caused by the accumulation of toxic species of α-synuclein. The common clinical features are chronic progressive decline of motor, cognitive, behavioral, and autonomic functions. They include Parkinson's disease, dementia with Lewy body, and multiple system atrophy. Their etiology has not been clarified and multiple pathogenic factors include oxidative stress, mitochondrial dysfunction, impaired protein degradation systems, and neuroinflammation. Current available therapy cannot prevent progressive neurodegeneration and "disease-modifying or neuroprotective" therapy has been proposed. This paper presents the molecular mechanisms of neuroprotection by the inhibitors of type B monoamine oxidase, rasagiline and selegiline. They prevent mitochondrial apoptosis, induce anti-apoptotic Bcl-2 protein family, and pro-survival brain- and glial cell line-derived neurotrophic factors. They also prevent toxic oligomerization and aggregation of α-synuclein. Monoamine oxidase is involved in neurodegeneration and neuroprotection, independently of the catalytic activity. Type A monoamine oxidases mediates rasagiline-activated signaling pathways to induce neuroprotective genes in neuronal cells. Multi-targeting propargylamine derivatives have been developed for therapy in various neurodegenerative diseases. Preclinical studies have presented neuroprotection of rasagiline and selegiline, but beneficial effects have been scarcely presented. Strategy to improve clinical trials is discussed to achieve disease-modification in synucleinopathies. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to evaluate the effects and safety of monoamine oxidase-B inhibitors (MAO-B inhibitors) for early Parkinson's disease (PD)., Methods: All studies that assessed the efficacy of MAO-B inhibitors in patients with early PD were searched. Publications were screened, and data were extracted according to predefined criteria. Rev Man 5.4 and Stata 14.0 software were used for statistical analysis. Outcomes assessed included change of Unified Parkinson's Disease Rating Scale (UPDRS) total score, UPDRS part II score, UPDRS part III score, and the incidence of adverse events., Results: Thirty trials were identified and included in this meta-analysis. Compared with placebo, rasagiline, selegiline, safinamide, and zonisamide were significantly more effective, with a standardized mean difference (SMD) of -0.41 (95% confidence interval (CI) = -0.64 to -0.18), SMD = -0.38 (95% CI = -0.51 to -0.24), SMD = -0.37 (95% CI = -0.54 to -0.21), and SMD = -0.31 (95% CI = -0.57 to -0.05) on the UPDRS III score change, respectively. The surface under the cumulative ranking results showed that rasagiline ranked first in improving UPDRS II and UPDRS III, respectively. For safety outcomes, safinamide combination with dopaminergic treatment had lower risk of incurring any adverse events (risk ratio = 0.1, 95% CI = 0.01-0.2), and no statistical difference in incidence of adverse events was observed among other MAO-B inhibitor regimes and placebo., Conclusion: Rasagiline, selegiline, safinamide, and zonisamide were effective compared to placebo in the treatment of early PD, but rasagiline was the most effective drug. As for safety, safinamide combination with dopaminergic treatment had lower risk of incurring any adverse events., (© 2024 S. Karger AG, Basel.)

Parkinson's disease is a chronic, progressive neurological disease that currently affects about more than 10 million population worldwide. Rasagiline is a selective, irreversible monoamine oxidase type B inhibitor used as monotherapy in early Parkinson's disease. Rasagiline tablets have been recalled from market due to the presence of unacceptable levels of nitrosamine impurity. European Medical Agency has set up very stringent limit 100ng/day of N-nitrosorasagiline (NSRG) in drug product based on its mutagenicity. The analytical methods need to be sufficiently sensitive in order to adequately detect and quantify trace levels of NSRG. A highly sensitive LC-MS/MS method for determination of NSRG in rasagiline tablet formulation was developed by effectively separating on zorbax eclipse XDB C18 column using 0.1% formic acid in mixture of water and acetonitrile (35:65 v/v) in an isocratic mode at 0.5mL/min flow rate. The measurement of NSRG was performed using triple quadrupole mass detection accompanied by electrospray ionization in the multiple reaction monitoring mode. The validation of the method was comprehensive, demonstrating strong linearity across the concentration spectrum of 2 to 200ng/mL for NSRG. The obtained correlation coefficient exceeded 0.998, signifying a robust relationship. Recoveries spanning from 80.0% to 120.0% for NSRG were deemed satisfactory. The developed method was able to detect and quantitate NSRG at a concentration level of 1 to 2ng/mL respectively (1 to 2ppm with respect to 1mg/mL of rasagiline tablet sample concentration). The developed and validated method can be employed for routine quality control testing of rasagiline tablets., (Copyright © 2024 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)