A Randomized Phase 3 Study Comparing P2B001 to its Components (Low-Dose Extended-Release Rasagiline and Pramipexole) and to Optimized Doses of Marketed Extended-Release Pramipexole in Early Parkinson's Disease.

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.

Longitudinal course of neurofilament light chain levels in amyotrophic lateral sclerosis-insights from a completed randomized controlled trial with rasagiline.

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.

In-depth analysis of data from the RAS-ALS study reveals new insights in rasagiline treatment for amyotrophic lateral sclerosis.

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.

Efficient application of Pyrosin B for nano-gram level assay of antiparkinsonian medication, rasagiline: Evaluation of tablets and content uniformity.

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.

Trace level quantification of N-nitrosorasagiline in rasagiline tablets by LC-TQ-MS/MS.

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.

Effects of rasagiline combined with levodopa and benserazide hydrochloride on motor function and homocysteine and IGF-1 levels in elderly patients with Parkinson's disease.

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.

Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline.

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.

Diffusion Magnetic Resonance Imaging Detects Progression in Parkinson's Disease: A Placebo-Controlled Trial of Rasagiline.

BACKGROUND: Rasagiline has received attention as a potential disease-modifying therapy for Parkinson's disease (PD). Whether rasagiline is disease modifying remains in question. OBJECTIVE: The main objective of this study was to determine whether rasagiline has disease-modifying effects in PD over 1 year. Secondarily we evaluated two diffusion magnetic resonance imaging pulse sequences to determine the best sequence to measure disease progression. METHODS: This prospective, randomized, double-blind, placebo-controlled trial assessed the effects of rasagiline administered at 1 mg/day over 12 months in early-stage PD. The primary outcome was 1-year change in free-water accumulation in posterior substantia nigra (pSN) measured using two diffusion magnetic resonance imaging pulse sequences, one with a repetition time (TR) of 2500 ms (short TR; n = 90) and one with a TR of 6400 ms (long TR; n = 75). Secondary clinical outcomes also were assessed. RESULTS: Absolute change in pSN free-water accumulation was not significantly different between groups (short TR: P = 0.346; long TR: P = 0.228). No significant differences were found in any secondary clinical outcomes between groups. Long TR, but not short TR, data show pSN free-water increased significantly over 1 year (P = 0.025). Movement Disorder Society Unified Parkinson's Disease Rating Scale testing of motor function, Part III increased significantly over 1 year (P = 0.009), and baseline free-water in the pSN correlated with the 1-year change in Movement Disorder Society Unified Parkinson's Disease Rating Scale testing of motor function, Part III (P = 0.004) and 1-year change in bradykinesia score (P = 0.044). CONCLUSIONS: We found no evidence that 1 mg/day rasagiline has a disease-modifying effect in PD over 1 year. We found pSN free-water increased over 1 year, and baseline free-water relates to clinical motor progression, demonstrating the importance of diffusion imaging parameters for detecting and predicting PD progression. © 2021 International Parkinson and Movement Disorder Society.

A critical appraisal of MAO-B inhibitors in the treatment of Parkinson's disease.

Since the 1980s, the MAO-B inhibitors have gained considerable status in the therapy of the Parkinson's disease. In addition to the symptomatic effect in mono- and combination therapies, a neuroprotective effect has repeatedly been a matter of some discussion, which has unfortunately led to a good many misunderstandings. Due to potential interactions, selegiline has declined in significance in the field. For the MAO-B inhibitor safinamide, recently introduced to the market, an additional inhibition of pathological release of glutamate has been postulated. At present, rasagiline and selegiline are being administered in early therapy as well as in combination with levodopa. Safinamide has been approved only for combination therapy with levodopa when motor fluctuations have occurred. MAO-B inhibitors are a significant therapeutic option for Parkinson's disease, an option which is too often not appreciated properly.

The evaluation of N-propargylamine-2-aminotetralin as an inhibitor of monoamine oxidase.

Monoamine oxidase B (MAO-B) inhibitors are established therapy for Parkinson's disease and act, in part, by blocking the MAO-catalysed metabolism of dopamine in the brain. Two propargylamine-containing MAO-B inhibitors, selegiline [(R)-deprenyl] and rasagiline, are currently used in the clinic for this purpose. These compounds are mechanism-based inactivators and, after oxidative activation, form covalent adducts with the FAD co-factor. An important consideration is that selegiline and rasagiline display specificity for MAO-B over the MAO-A isoform thus reducing the risk of tyramine-induced changes in blood-pressure. In the interest of discovering new propargylamine MAO inhibitors, the present study synthesises racemic N-propargylamine-2-aminotetralin (2-PAT), a compound that may be considered as both a six-membered ring analogue of rasagiline and a semi-rigid N-desmethyl ring-closed analogue of selegiline. The in vitro human MAO inhibition properties of this compound were measured and the results showed that 2-PAT is a 20-fold more potent inhibitor of MAO-A (IC50 = 0.721 µM) compared to MAO-B (IC50 = 14.6 µM). Interestingly, dialysis studies found that 2-PAT is a reversible MAO-A inhibitor, while acting as an inactivator of MAO-B. Since reversible MAO-A inhibitors are much less liable to potentiate tyramine-induced side effects than MAO-A inactivators, it is reasonable to suggest that 2-PAT could be a useful and safe therapeutic agent for disorders such as Parkinson's disease and depression.

A new approach to sepsis treatment by rasagiline: a molecular, biochemical and histopathological study.

AIM: We aimed to investigate the effects of rasagiline on acute lung injury that develops in the sepsis model induced with the cecal ligation and puncture in rats. MAIN METHODS: The rats were separated into the following six groups, Group 1: Sham, Group 2: Sham + Rasagiline 4 mg/kg, Group 3: Sepsis, Group 4: Sepsis + Rasagiline 1 mg/kg, Group 5: Sepsis + Rasagiline 2 mg/kg, Group 6: Sepsis + Rasagiline 4 mg/kg. A total of four holes were opened with a 16-gauge needle through the cecum distal to the point of ligation. KEY FINDINGS: Rasagiline treatment increased glutathione level and superoxide dismutase activity while decreased the malondialdehyde level after the sepsis. There was a statistically significant improvement in the doses of 2 mg/kg and 4 mg/kg. Rasagiline also increased Tnf-α, IL1ß, IL6, NF-κßand HMGB1 gene expressions in dose-dependent at 2 mg/kg and 4 mg/kg doses. In increased doses, rasagiline prevent the development of edema, the formation of inflammation, and hemorrhage. SIGNIFICANCE: Rasagiline exerts both antioxidant and anti-inflammatory effects on the cecal ligation and puncture induced acute lung injury in rats.

The risk of melanoma with rasagiline compared with other antiparkinsonian medications: A retrospective cohort study in the United States medicare database.

PURPOSE: Compare the risk of melanoma between initiators of rasagiline or other antiparkinsonian drugs (APDs) in a Parkinson's disease (PD) population. METHODS: A retrospective cohort study was conducted in the US Medicare claims research database (2006-2015) in adults aged ≥65 years with PD claims. Other APD initiators were randomly matched (4:1) to rasagiline initiators on age, sex, and cohort entry year. Cutaneous melanoma events were identified by a validated claims algorithm. Incidence rates (IRs), incidence rate ratios (IRRs), and Cox-adjusted hazard ratios (HRs) for melanoma comparing rasagiline with other APD initiators were calculated and analyzed by duration of study medication use and cumulative dose of rasagiline. Potential indicators of surveillance bias were explored. RESULTS: Among 23 708 rasagiline initiators and 96 552 matched APD initiators, the crude IR of melanoma/100 000 person-years was 334.3 (95% confidence interval [CI], 291.5-381.6) and 208.2 (95% CI, 190.1-227.5), respectively (crude IRR 1.61; 95% CI, 1.36-1.89). The adjusted HR was 1.37 (95% CI, 1.14-1.65) and increased with longer rasagiline exposure and higher cumulative rasagiline doses. Rasagiline initiators more frequently had dermatologist visits or skin biopsies before cohort entry than APD initiators and had a higher incidence of nonmelanoma skin cancer during follow-up (crude IRR, 1.44; 95% CI, 1.35-1.54). CONCLUSIONS: A small increased incidence of melanoma with exposure to rasagiline compared with other APDs was observed. Although the pattern with dose and duration is consistent with a hypothesized biologic effect, the increased skin cancer surveillance among rasagiline users suggests surveillance bias as a contributing explanation for the observed results.

Differences in CSF Biomarkers Profile of Patients with Parkinson's Disease Treated with MAO-B Inhibitors in Add-On.

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- ß -42, amyloid- ß -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.

Neuroprotective Function of Rasagiline and Selegiline, Inhibitors of Type B Monoamine Oxidase, and Role of Monoamine Oxidases in Synucleinopathies.

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.

Possible neuroprotective effects of rasagiline in Alzheimer's disease: a SPECT study.

BACKGROUND: The current lack of effective treatments for Alzheimer's disease (AD) and the rapidly increasing burden of the disease highlight the urgent need to find new treatments. Despite accumulating evidence of the beneficial effects of rasagiline in neurodegenerative diseases such as Parkinson's disease, the effects of rasagiline on the brains of patients with AD have not been elucidated. PURPOSE: To examine the effects of rasagiline on regional cerebral flow (rCBF) in patients with AD using single photon emission computed tomography (SPECT). MATERIAL AND METHODS: Among 22 patients with AD, 11 patients received adjunctive rasagiline at 1 mg/day in conjunction with acetylcholinesterase inhibitors (AChEI); 11 patients were only treated with AChEI for about 1.6 years. All patients underwent brain technetium-99m hexamethylpropylene amine oxime SPECT scans and clinical assessments at baseline and follow-up visits. Annual percent changes in rCBF were compared between the groups in a voxel-wise manner. RESULTS: SPECT analysis revealed that the rasagiline-treated group showed more increased rCBF in the cingulate gyrus, inferior frontal gyrus, putamen, and thalamus compared to the comparison group (P < 0.005). CONCLUSION: We demonstrated that adjunctive rasagiline treatment may have beneficial effects on brain perfusion in patients with AD, suggesting potential neuroprotective effects.

Influence of chitosan thioglycolic acid conjugate in improving bioavailability of an antiparkinson drug; Rasagiline Mesylate from transdermal patch.

OBJECTIVE: Parkinson disease (PD) is a chronic disorder of central nervous system mainly affecting the motor systems. The drug of choice to treat PD is Rasagiline Mesylate (RM) and it belongs to BCS class III drug. The objective of the present study was the preparation of transdermal drug delivery system for RM. Several permeation enhancers were screened to be included in the formulation. To achieve desired flux a new strategy was developed by including in-house prepared CTC to enhance the permeation of RM. METHODS: The CTC was prepared by reaction between chitosan and thioglycolicacid, characterized by determining physical properties and applying analytical tools. Seven permeation enhancers with different mechanisms were screened. The transdermal patches were prepared with chitosan along with permeation enhancer IPM, various proportions of CTC and evaluated for physical and permeation studies. The optimized transdermal patch was obtained by two factors and three responses to obtain the design space and further evaluated for pharmacokinetic studies. RESULTS: The results of the present study confirmed the formation of CTC, IPM was best permeation enhancer among all. The presence of CTC in the formulations significantly improved the permeation of RM to achieve desired steady-state flux. The relative bioavailability of optimized transdermal patch was determined and it was observed that improved bioavailability as compared to marketed conventional tablets. CONCLUSION: The study was concluded that CTC has significant influence on permeation enhancing ability of IPM.

Rasagiline combined with levodopa therapy versus levodopa monotherapy for patients with Parkinson's disease: a systematic review.

OBJECTIVE: The aim of this report was to systematically evaluate the efficacy and safety of rasagiline (R) plus levodopa (L) (R + L) for the treatment of Parkinson's disease (PD) compared with that of L monotherapy, in order to provide a reference resource for rational drug use. METHODS: Randomized controlled trials (RCTs) of R + L for PD published up to September 2018 were searched. Sensitivity analyses were also performed. RESULTS: Fourteen RCTs with 2531 participants were included. Compared with L monotherapy, the pooled effects of R + L combination therapy on unified Parkinson's disease rating scale (UPDRS) score were (SMD - 0.50, 95% CI - 0.70 to - 0.30, P < 0.00001) for UPDRS motor score, (SMD - 0.59, 95% CI - 0.79 to - 0.39, P < 0.00001) for UPDRS activities of daily living (ADL) score, (SMD - 0.65, 95% CI - 0.81 to - 0.49, P < 0.00001) for UPDRS total score. R + L combination therapy was better than L monotherapy in reducing daily off-time (SMD - 1.15, 95% CI - 2.13 to - 0.17, P = 0.02), but there was a statistically nonsignificant result in daily on-time increase (SMD 1.39, 95% CI - 0.69 to 3.48, P = 0.19). There were no statistical differences in number of adverse events (OR 1.33, 95% CI 0.97 to 1.82, P = 0.07) and number of dropout (OR 0.88, 95% CI 0.65 to 1.19, P = 0.39) between R + L combination therapy and L monotherapy. CONCLUSIONS: R + L combination therapy was superior to L monotherapy for improvement of UPDRS scores and off-time in PD patients. Moreover, R + L combination therapy and L monotherapy were similar in terms of safety and tolerability.

First Synthesis of Racemic Trans Propargylamino-Donepezil, a Pleiotrope Agent Able to Both Inhibit AChE and MAO-B, with Potential Interest against Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC50 = 0.4 µM) and (h)MAO-B (IC50 = 6.4 µM).

Rasagiline for amyotrophic lateral sclerosis: A randomized, controlled trial.

INTRODUCTION: Rasagiline is a monoamine oxidase B (MAO-B) inhibitor with possible neuroprotective effects in patients with amyotrophic lateral sclerosis (ALS). METHODS: 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. RESULTS: 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. DISCUSSION: Rasagiline did not alter disease progression compared with controls over 12 months of treatment. Muscle Nerve 59:201-207, 2019.

Long-term safety and efficacy of adjunctive rasagiline in levodopa-treated Japanese patients with Parkinson's disease.

Rasagiline is a monoamine oxidase type-B inhibitor in development in Japan for Parkinson's disease (PD). This open-label study evaluated the long-term safety and efficacy of rasagiline in Japanese patients with PD receiving levodopa. Patients were aged 30-79 years and had wearing-off or weakened effect. Patients received rasagiline 1 mg/day for 52 weeks. The primary objective was to evaluate safety. Secondary endpoints included MDS-UPDRS Part II and Part III total scores (ON-state) and change from baseline in mean daily OFF-time. An additional endpoint was the Parkinson's Disease Questionnaire-39 (PDQ-39) Summary Index (SI) score. In total, 222 patients were enrolled; 52.3% had wearing-off phenomena. Treatment-emergent adverse events (TEAEs) were mostly mild or moderate and occurred in 83.3% of patients; 63.1% had drug-related TEAEs; and 21.2% had TEAEs resulting in discontinuation. Fall (16.7%), nasopharyngitis (14.0%), and dyskinesia (10.8%) were the most frequent TEAEs. Serious TEAEs were reported in 17.6% of patients, and led to discontinuation in 9.5%. At week 52 (last-observation-carried forward), the mean change from baseline in MDS-UPDRS Part III total score (ON-state) was - 7.6; the mean change from baseline in daily OFF-time was - 0.89 h in patients with wearing-off phenomena at the start of the run-in period. The mean change from baseline in PDQ-39 SI was - 0.64. No major safety issues were observed during this 52-week trial of rasagiline as an adjunct to levodopa in Japanese patients. Mean changes in MDS-UPDRS scores and daily OFF-time suggested that adjunctive rasagiline treatment with levodopa was efficacious, with efficacy maintained for at least 52 weeks.