-
American Journal of Cardiovascular... Sep 2022Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease of the cardiomyocyte with a diverse and heterogeneous clinical presentation and course. This... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease of the cardiomyocyte with a diverse and heterogeneous clinical presentation and course. This diversity and heterogeneity have added to the complexity of modeling the pathophysiological pathways that contribute to the disease burden. The development of novel therapeutic approaches targeting precise mechanisms within the underlying biology of HCM provides a tool to model and test these pathways. Here, we integrate the results of clinical observations with mavacamten, an allosteric, selective, and reversible inhibitor of cardiac myosin, the motor unit of the sarcomere, to develop an integrated pathophysiological pathway model of HCM, confirming the key role of excess sarcomeric activity. This model may serve as a foundation to understand the role of HCM pathophysiological pathways in the clinical presentation of the disease, and how a targeted therapeutic intervention capable of normalizing sarcomeric activity and repopulating low-energy utilization states may reduce the impact of these pathways in HCM and potentially related disease states.
Topics: Benzylamines; Cardiomyopathy, Hypertrophic; Humans; Sarcomeres; Uracil
PubMed: 35435607
DOI: 10.1007/s40256-022-00532-x -
Expert Opinion on Investigational Drugs May 2014Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. Non-dopaminergic... (Review)
Review
INTRODUCTION
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. Non-dopaminergic neurotransmitter systems are also involved in its pathomechanism. The aim of the treatment is to improve the dopamine-deficient state and to alleviate the motor and the non-motor symptoms. Safinamide is an α-aminoamide derivative with a combined, dopaminergic and non-dopaminergic mode of action. Phase III clinical trials with safinamide, as add-on therapy to a dopamine agonist (DAA) and to levodopa (LD) in early and advanced stage PD, respectively, demonstrated an improvement of the motor symptoms.
AREAS COVERED
The review discusses the pharmacokinetic and pharmacodynamic properties of safinamide and provides an overview of the clinical trials conducted with safinamide in PD. A literature search was made in PubMed for safinamide, safinamide pharmacokinetics, PD treatment and monoamine oxidase-B inhibitors, and in PubMed and on the ClinicalTrials.gov site for clinical trials with safinamide in PD.
EXPERT OPINION
The place of safinamide in the therapy of PD is yet to be determined. However, the authors believe that safinamide is a valuable drug in the treatment of PD treatment with favorable pharmacokinetic and side-effect profiles. Data so far suggest that it can be used beneficially as add-on therapy both to DAAs in early PD and to LD in the later stages of the disease.
Topics: Alanine; Animals; Benzylamines; Clinical Trials as Topic; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Treatment Outcome
PubMed: 24650154
DOI: 10.1517/13543784.2014.897694 -
International Journal of Molecular... Dec 2022In this research, the synthesis, photochemistry, and computational study of new - and -isomers of amino-thienostilbenes is performed to test the efficiency of their...
In this research, the synthesis, photochemistry, and computational study of new - and -isomers of amino-thienostilbenes is performed to test the efficiency of their production and acid resistance, and to investigate their electronic structure, photoreactivity, photophysical characteristics, and potential biological activity. The electronic structure and conformations of synthesized thienostilbene amines and their photocyclization products are examined computationally, along with molecular modeling of amines possessing two thiophene rings that showed inhibitory potential toward cholinesterases. New amino-styryl thiophenes, with favorable photophysical properties and proven acid resistance, represent model compounds for their water-soluble ammonium salts as potential styryl optical dyes. The comparison with organic dyes possessing a -aminostilbene subunit as the scaffold shows that the newly synthesized -aminostilbenes have very similar absorbance wavelengths. Furthermore, their functionalized -isomers and photocyclization products are good candidates for cholinesterase inhibitors because of the structural similarity of the molecular skeleton to some already proven bioactive derivatives.
Topics: Photochemistry; Thiophenes; Benzylamines; Models, Molecular; Coloring Agents
PubMed: 36614053
DOI: 10.3390/ijms24010610 -
Drug Design, Development and Therapy 2021Parkinson's therapeutic interventions are only symptomatic. An optimal treatment should therefore address the largest number of motor and non-motor symptoms, to manage... (Review)
Review
INTRODUCTION
Parkinson's therapeutic interventions are only symptomatic. An optimal treatment should therefore address the largest number of motor and non-motor symptoms, to manage patients at best. Safinamide is one of the most recent approved drugs for fluctuating patients, in add-on to levodopa, that remains the gold standard treatment. It has a unique mechanism of action, both dopaminergic (as MAO-B inhibitor) and glutamatergic (through Na channel blockade). Results from Phase III trials, post-hoc analyses and real-life experiences suggest a beneficial effect on motor (such as tremor, bradykinesia, rigidity and gait) and non-motor (pain, mood, sleep) symptoms.
AREAS COVERED
Here, the authors discuss clinical efficacy and safety of safinamide, identifying the patients' profiles that could benefit most. A search in PubMed was performed in September 2020, with no time limits. Publications' abstracts were reviewed.
CONCLUSION
Safinamide is peculiar due to its double mechanism of action. Its benefits in improving motor functions and fluctuations, and some non-motor symptoms, could have a valuable impact on patients' quality of life (QoL), together with its safety profile.
Topics: Alanine; Animals; Antiparkinson Agents; Benzylamines; Drug Therapy, Combination; Humans; Levodopa; Monoamine Oxidase Inhibitors; Parkinson Disease; Quality of Life; Treatment Outcome
PubMed: 34140766
DOI: 10.2147/DDDT.S302673 -
PloS One 2023Dysphagia is a potentially fatal symptom of Parkinson's disease (PD) and is characterized by frequent silent aspiration, a risk factor for aspiration pneumonia. The...
Dysphagia is a potentially fatal symptom of Parkinson's disease (PD) and is characterized by frequent silent aspiration, a risk factor for aspiration pneumonia. The transdermal dopamine agonist rotigotine alleviates dysphagia in patients with PD and is more effective than oral levodopa, suggesting the importance of continuous dopaminergic stimulation (CDS) in swallowing. Safinamide is a monoamine oxidase B (MAOB) inhibitor that facilitates CDS. In this retrospective open-label evaluator-blinded research, swallowing functions in nine patients with PD were examined using a video fluoroscopic swallowing study (VFSS) before and after treatment with 50 mg of oral safinamide. The VFSS results showed that safinamide significantly improved some swallowing measures during oral and pharyngeal phases, including oral transit time and pharyngeal transit time, without worsening of any measures. Notably, improvements in lip closure, an oral phase component, seemed to be most attributable to improvements in oral phase scores. In conclusion, a medicine for CDS may effectively improve swallowing functions in patients with PD. This is the first study to show that the MAOB inhibitor safinamide partly but significantly improves swallowing function in patients with PD.
Topics: Humans; Parkinson Disease; Deglutition Disorders; Retrospective Studies; Levodopa; Benzylamines; Alanine; Monoamine Oxidase Inhibitors; Antiparkinson Agents
PubMed: 37228084
DOI: 10.1371/journal.pone.0286066 -
Journal of Neural Transmission (Vienna,... Jul 2023Fatigue is a common non-motor symptom in Parkinson's disease (PD). Among other pathophysiological mechanisms, neuroinflammation, a pathological PD hallmark associated...
Fatigue is a common non-motor symptom in Parkinson's disease (PD). Among other pathophysiological mechanisms, neuroinflammation, a pathological PD hallmark associated with changes in glutamatergic transmission in basal ganglia, has been proposed as a crucial factor closely related to fatigue. To test the hypothesis that safinamide could represent an effective treatment of fatigue in PD patients, given its dual mechanism of action (it selectively and reversibly inhibits MAOB and modulates glutamate release), we administered the validated versions of fatigue severity scale (FSS) and Parkinson fatigue scale-16 (PFS-16) to 39 fluctuating PD patients with fatigue before and after a 24-week treatment period with safinamide as add-on therapy. An assessment of secondary variables such as depression, quality of life (QoL), and motor and non-motor symptoms (NMS) was conducted. After 24 weeks of treatment with safinamide, both FSS (p < 0.001) and PF-S16 (p = 0.02) scores were significantly lower than at baseline. Moreover, 46.2% and 41% of patients scored below the cut-off for the presence of fatigue according to FSS and PFS-16, respectively (responders). At follow-up, a significant difference emerged between responders and non-responders in mood, QoL, and NMS. Fatigue improved in fluctuating PD, and more than 40% of patients were "fatigue-free" after a 6 month treatment with safinamide. Patients without fatigue at follow-up displayed significantly better scores in QoL domains, such as mobility or activities of daily living, although disease severity remained stable, supporting the hypothesis that fatigue could considerably affect QoL. Drugs that interact with multiple neurotransmission systems, such as safinamide, could be useful in reducing this symptom.
Topics: Humans; Parkinson Disease; Antiparkinson Agents; Quality of Life; Activities of Daily Living; Benzylamines
PubMed: 37210459
DOI: 10.1007/s00702-023-02654-1 -
Journal of the American College of... Jun 2020
Topics: Benzylamines; Cardiomyopathy, Hypertrophic; Humans; Uracil
PubMed: 32466880
DOI: 10.1016/j.jacc.2020.04.017 -
Pharmacology & Therapeutics Jan 2020Products of lipid peroxidation include a number of reactive lipid aldehydes such as malondialdehyde, 4-hydroxy-nonenal, 4-oxo-nonenal, and isolevuglandins (IsoLGs).... (Review)
Review
Products of lipid peroxidation include a number of reactive lipid aldehydes such as malondialdehyde, 4-hydroxy-nonenal, 4-oxo-nonenal, and isolevuglandins (IsoLGs). Although these all contribute to disease processes, the most reactive are the IsoLGs, which rapidly adduct to lysine and other cellular primary amines, leading to changes in protein function, cross-linking and immunogenicity. Their rapid reactivity means that only IsoLG adducts, and not the unreacted aldehyde, can be readily measured. This high reactivity also makes it challenging for standard cellular defense mechanisms such as aldehyde reductases and oxidases to dispose of them before they react with proteins and other cellular amines. This led us to seek small molecule primary amines that might trap and inactivate IsoLGs before they could modify cellular proteins or other endogenous cellular amines such as phosphatidylethanolamines to cause disease. Our studies identified 2-aminomethylphenols including 2-hydroxybenzylamine as IsoLG scavengers. Subsequent studies showed that they also trap other lipid dicarbonyls that react with primary amines such as 4-oxo-nonenal and malondialdehyde, but not hydroxyalkenals like 4-hydroxy-nonenal that preferentially react with soft nucleophiles. This review describes the use of these 2-aminomethylphenols as dicarbonyl scavengers to assess the contribution of IsoLGs and other amine-reactive lipid dicarbonyls to disease and as therapeutic agents.
Topics: Aldehydes; Amines; Animals; Benzylamines; Drug Development; Humans; Lipid Peroxidation; Lipids; Proteins
PubMed: 31629006
DOI: 10.1016/j.pharmthera.2019.107418 -
Drug Design, Development and Therapy 2016Safinamide (SAF) is a new drug developed for the treatment of Parkinson's disease (PD). It is a benzylamino derivative with multiple mechanisms of action and... (Review)
Review
Safinamide (SAF) is a new drug developed for the treatment of Parkinson's disease (PD). It is a benzylamino derivative with multiple mechanisms of action and antiparkinsonian, anticonvulsant, and neuroprotective properties. SAF inhibits monoamine oxidase B and dopamine reuptake and glutamate release, blocks voltage-dependent sodium channels, and modulates calcium channels. Although the antiparkinsonian effect can be ascribed in part to the inhibition of the monoamine oxidase B, which is complete at 50 mg, the enhanced benefit seen at the 100 mg dose is probably due to nondopaminergic mechanisms. SAF will represent an important option for patients with both early and advanced PD. In early PD patients, the addition of SAF to dopamine agonists may be an effective treatment strategy to improve motor function, prolong the use of dopamine agonists, and/or delay the introduction of levodopa. In advanced parkinsonian patients, SAF has been demonstrated to significantly increase on time with no, or nontroublesome dyskinesias. All studies performed have demonstrated its efficacy in benefiting both short-term and long-term quality-of-life outcomes in both early and advanced PD patients. SAF has been investigated in long-term (24 months), double-blind, placebo-controlled studies, where it showed a very good safety profile. SAF has not been studied in de novo PD patients, and its potential positive effect on dyskinesia deserves further dedicated studies.
Topics: Adult; Aged; Alanine; Benzylamines; Double-Blind Method; Humans; Middle Aged; Monoamine Oxidase Inhibitors; Parkinson Disease; Randomized Controlled Trials as Topic
PubMed: 26917951
DOI: 10.2147/DDDT.S77749 -
Neurologia Sep 2020
Topics: Alanine; Antiparkinson Agents; Benzylamines; Sexuality
PubMed: 30551909
DOI: 10.1016/j.nrl.2018.07.004