Bruno Fonseca-Santos, Marlus Chorilli, International Journal of Pharmaceutics, 2020, 119832, doi:10.1016/j.ijpharm.2020.119832.
Due to the insolubility of this compound; the use of nanotechnology-based systems has been proposed for the incorporation of RES and RES-loaded nanocarriers have been designed for intranasal administration, oral or parenteral routes to deliver it to the brain. In general, these nanosystems have shown to be effective in many studies, pharmacological and pharmacokinetic assays, as well as some cell studies. The outcomes show that RES has been reported in human clinical trials for some neurological diseases, although no studies were performed in humans using nanocarriers, animal and/or cellular models have been reported to show good results regarding therapeutics on neurological diseases. Thus, the use of this nutraceutical has shown true for neurological diseases and its loading into nanocarriers displaying good results on the stability, delivery and targeting to the brain.
Wednesday, September 2, 2020
Tuesday, September 1, 2020
An Optimally Weighted User- and Item-based Collaborative Filtering Approach to Predicting Baseline Data for Friedreich’s Ataxia Patients
Wenbin Yue, Zidong Wang, Weibo Liu, Bo Tian, Stanislao Lauria, Xiaohui Liu, Neurocomputing, 2020, doi:10.1016/j.neucom.2020.08.031.
In this paper, a modified collaborative filtering (MCF) algorithm with improved performance is developed for recommendation systems with application in predicting baseline data of Friedreich’s Ataxia (FRDA) patients. The proposed MCF algorithm combines the individual merits of both the user-based collaborative filtering (UBCF) method and the item-based collaborative filtering (IBCF) method, where both the positively and negatively correlated neighbors are taken into account. The weighting parameters are introduced to quantify the degrees of utilizations of the UBCF and IBCF methods in the rating prediction, and the particle swarm optimization algorithm is applied to optimize the weighting parameters in order to achieve an adequate tradeoff between the positively and negatively correlated neighbors in terms of predicting the rating values. To demonstrate the prediction performance of the proposed MCF algorithm, the developed MCF algorithm is employed to assist with the baseline data collection for the FRDA patients. The effectiveness of the proposed MCF algorithm is confirmed by extensive experiments and, furthermore, it is shown that our algorithm outperforms some conventional approaches.
In this paper, a modified collaborative filtering (MCF) algorithm with improved performance is developed for recommendation systems with application in predicting baseline data of Friedreich’s Ataxia (FRDA) patients. The proposed MCF algorithm combines the individual merits of both the user-based collaborative filtering (UBCF) method and the item-based collaborative filtering (IBCF) method, where both the positively and negatively correlated neighbors are taken into account. The weighting parameters are introduced to quantify the degrees of utilizations of the UBCF and IBCF methods in the rating prediction, and the particle swarm optimization algorithm is applied to optimize the weighting parameters in order to achieve an adequate tradeoff between the positively and negatively correlated neighbors in terms of predicting the rating values. To demonstrate the prediction performance of the proposed MCF algorithm, the developed MCF algorithm is employed to assist with the baseline data collection for the FRDA patients. The effectiveness of the proposed MCF algorithm is confirmed by extensive experiments and, furthermore, it is shown that our algorithm outperforms some conventional approaches.
Monday, August 31, 2020
Plasma and red blood cell membrane accretion and pharmacokinetics of RT001 (bis-allylic 11,11-D2-linoleic acid ethyl ester) during long term dosing in patients
J. Thomas Brenna, Genevieve James, Mark Midei, Frederic Heerinckx, Paldeep Atwal, Peter Milner, Karsten Schmidt, Lex van der Ploeg, Robert Fielding, Mikhail S. Shchepinov, Journal of Pharmaceutical Sciences, 2020, doi:10.1016/j.xphs.2020.08.019.
RT001 is the di-deutero isotopologue of linoleic acid ethyl ester (D2-LA). Resistance to oxidative damage at the carbon-deuterium bond depends upon the concentration of D2-LA as a percentage of total LA. We report here on the plasma and red cell (RBC) pharmacokinetics (PK) of D2-LA, and its metabolite 13,13-D2-arachidonic acid (D2-AA), in patients with multiple neurodegenerative diseases (total of 59 participants). In Friedreich’s ataxia patients, D2-LA was absorbed and transported similarly to dietary LA, peaking at about 6 h after oral dosing. Plasma D2-LA concentrations approached steady state after 28 days of dosing. After 6 months of daily dosing in subjects with other disorders, D2-LA and D2-AA levels were at or above the 20% of total (D2-LA/ total LA, or D2-AA/ total AA) therapeutic targets for most subjects. We conclude that chronic dosing of RT001 and associated dietary guidance can be maintained over many months to achieve target plasma and RBC levels, forming a basis for therapeutic dosing across a broad range of conditions. RT001 has been safe and well-tolerated in 59 different participants treated across 10 different neurodegenerative diseases in multiple clinical trials for up to 36 months with no significant drug related adverse events limiting use.
RT001 is the di-deutero isotopologue of linoleic acid ethyl ester (D2-LA). Resistance to oxidative damage at the carbon-deuterium bond depends upon the concentration of D2-LA as a percentage of total LA. We report here on the plasma and red cell (RBC) pharmacokinetics (PK) of D2-LA, and its metabolite 13,13-D2-arachidonic acid (D2-AA), in patients with multiple neurodegenerative diseases (total of 59 participants). In Friedreich’s ataxia patients, D2-LA was absorbed and transported similarly to dietary LA, peaking at about 6 h after oral dosing. Plasma D2-LA concentrations approached steady state after 28 days of dosing. After 6 months of daily dosing in subjects with other disorders, D2-LA and D2-AA levels were at or above the 20% of total (D2-LA/ total LA, or D2-AA/ total AA) therapeutic targets for most subjects. We conclude that chronic dosing of RT001 and associated dietary guidance can be maintained over many months to achieve target plasma and RBC levels, forming a basis for therapeutic dosing across a broad range of conditions. RT001 has been safe and well-tolerated in 59 different participants treated across 10 different neurodegenerative diseases in multiple clinical trials for up to 36 months with no significant drug related adverse events limiting use.
Monday, August 24, 2020
Friedreich Ataxia: current state-of-the-art, and future prospects for mitochondrial-focused therapies
Federico V. Pallardó, Giovanni Pagano, Laura R. RodrÃguez, Pilar Gonzalez-Cabo, Alex Lyakhovich, Marco Trifuoggi; Translational Research,
2020, doi:10.1016/j.trsl.2020.08.009.
The present mini review is aimed at evaluating the basic and clinical reports on the roles and the use of a set of iron chelators, antioxidants and some cofactors involved in the key mitochondrial functions. Extensive literature has focused on the protective roles of iron chelators, coenzyme Q10 and analogs, and vitamin E, altogether with varying outcomes in clinical studies. Other studies have suggested mitoprotective roles for other mitochondrial cofactors, involved in Krebs cycle, such as alpha-lipoic acid and carnitine, involved in acyl transport across the mitochondrial membrane.
2020, doi:10.1016/j.trsl.2020.08.009.
The present mini review is aimed at evaluating the basic and clinical reports on the roles and the use of a set of iron chelators, antioxidants and some cofactors involved in the key mitochondrial functions. Extensive literature has focused on the protective roles of iron chelators, coenzyme Q10 and analogs, and vitamin E, altogether with varying outcomes in clinical studies. Other studies have suggested mitoprotective roles for other mitochondrial cofactors, involved in Krebs cycle, such as alpha-lipoic acid and carnitine, involved in acyl transport across the mitochondrial membrane.
Sunday, August 23, 2020
Frataxin gene editing rescues Friedreich’s ataxia pathology in dorsal root ganglia organoid-derived sensory neurons
Pietro Giuseppe Mazzara, Sharon Muggeo, Mirko Luoni, Luca Massimino, Mattia Zaghi, Parisa Tajalli-Tehrani Valverde, Simone Brusco, Matteo Jacopo Marzi, Cecilia Palma, Gaia Colasante, Angelo Iannielli, Marianna Paulis, Chiara Cordiglieri, Serena Gea Giannelli, Paola Podini, Cinzia Gellera, Franco Taroni, Francesco Nicassio, Marco Rasponi & Vania Broccoli; Nat Commun 11, 4178 (2020). doi:10.1038/s41467-020-17954-3
These results strongly suggest that removal of the repressed chromatin flanking the GAA tract might contribute to rescue FXN total expression and fully revert the pathological hallmarks of FRDA DRG neurons.
These results strongly suggest that removal of the repressed chromatin flanking the GAA tract might contribute to rescue FXN total expression and fully revert the pathological hallmarks of FRDA DRG neurons.
Saturday, August 22, 2020
Atypical structures of GAA/TTC trinucleotide repeats underlying Friedreich’s ataxia: DNA triplexes and RNA/DNA hybrids
Jiahui Zhang, Ashkan Fakharzadeh, Feng Pan, Christopher Roland, Celeste Sagui; Nucleic Acids Research, gkaa665, doi:10.1093/nar/gkaa665
The authors intended the study to provide a ‘rationale for the discovery and characterization of the non-B DNA regulatory structures involved in the formation of the RNA:DNA interactome’. However, experimental data with molecular resolution for these non-B DNA structures is noticeably scarce. We believe that structural studies such as ours can meaningfully contribute in the creation of such a roadmap.
The authors intended the study to provide a ‘rationale for the discovery and characterization of the non-B DNA regulatory structures involved in the formation of the RNA:DNA interactome’. However, experimental data with molecular resolution for these non-B DNA structures is noticeably scarce. We believe that structural studies such as ours can meaningfully contribute in the creation of such a roadmap.
Friday, August 21, 2020
Clinical presentation and survival of childhood hypertrophic cardiomyopathy: a retrospective study in United Kingdom
Gabrielle Norrish, Ella Field, Karen Mcleod, Maria Ilina, Graham Stuart, Vinay Bhole, Orhan Uzun, Elspeth Brown, Piers E F Daubeney, Amrit Lota, Katie Linter, Sujeev Mathur, Tara Bharucha, Khoon Li Kok, Satish Adwani, Caroline B Jones, Zdenka Reinhardt, Juan Pablo Kaski; European Heart Journal, Volume 40, Issue 12, 21 March 2019, Pages 986–993, doi:10.1093/eurheartj/ehy798
This study describes the clinical characteristics and outcomes of childhood HCM over four decades in a well-characterized United Kingdom cohort.
Aetiology was: non-syndromic (n = 433, 63%), RASopathy (n = 126, 18.3%), Friedreich’s ataxia (n = 59, 8.6%) or inborn errors of metabolism (IEM) (n = 64, 9%). In infants (n = 159, 23%) underlying aetiology was more commonly a RASopathy (42% vs. 11.2%, P < 0.0001) or IEM (18.9% vs. 6.4% P < 0.0001)
This study describes the clinical characteristics and outcomes of childhood HCM over four decades in a well-characterized United Kingdom cohort.
Aetiology was: non-syndromic (n = 433, 63%), RASopathy (n = 126, 18.3%), Friedreich’s ataxia (n = 59, 8.6%) or inborn errors of metabolism (IEM) (n = 64, 9%). In infants (n = 159, 23%) underlying aetiology was more commonly a RASopathy (42% vs. 11.2%, P < 0.0001) or IEM (18.9% vs. 6.4% P < 0.0001)
Thursday, August 20, 2020
Multiple Ascending Dose Study of CTI-1601 Versus Placebo in Subjects With Friedreich's Ataxia
ClinicalTrials.gov Identifier: NCT04519567 Responsible Party: Larimar Therapeutics, Inc. First Posted: August 19, 2020
A Phase 1 Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous CTI-1601 Versus Placebo in Subjects With Friedreich's Ataxia
Actual Study Start Date: July 31, 2020
Estimated Primary Completion Date: June 30, 2021
Estimated Study Completion Date: June 30, 2021
A Phase 1 Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous CTI-1601 Versus Placebo in Subjects With Friedreich's Ataxia
Actual Study Start Date: July 31, 2020
Estimated Primary Completion Date: June 30, 2021
Estimated Study Completion Date: June 30, 2021
Tuesday, August 18, 2020
Validation of low-cost system for gait assessment in children with ataxia
S. Summa, G. Tartarisco, M. Favetta, A. Buzachis, A. Romano, G.M. Bernava, A. Sancesario, G. Vasco, G. Pioggia, M. Petrarca, E. Castelli, E. Bertini, T. Schirinzi; Computer Methods and Programs in Biomedicine, 2020, 105705, Doi:10.1016/j.cmpb.2020.105705.
This study aims to test the usability of the Kinect system for assessing ataxia severity, exploring the potentiality of clustering algorithms and validating this system with a standard motion capture system.
The spatio-temporal parameters measured by Kinect cannot be used interchangeably with those parameters acquired with standard motion capture system in clinical practice but can still provide fundamental information. Specifically, these results might bring to the development of a novel system to perform easy and quick evaluation of gait in young patients with ataxia, useful for patients stratification in terms of clinical severity and diagnosis.
This study aims to test the usability of the Kinect system for assessing ataxia severity, exploring the potentiality of clustering algorithms and validating this system with a standard motion capture system.
The spatio-temporal parameters measured by Kinect cannot be used interchangeably with those parameters acquired with standard motion capture system in clinical practice but can still provide fundamental information. Specifically, these results might bring to the development of a novel system to perform easy and quick evaluation of gait in young patients with ataxia, useful for patients stratification in terms of clinical severity and diagnosis.
Monday, August 17, 2020
LARIMAR THERAPEUTICS : Management's Discussion and Analysis of Financial Condition and Results of Operations (form 10-Q) share with twitter share with LinkedIn share with facebook
MarketScreener; 08/14/2020.
CTI-1601 is currently being evaluated in Phase 1 clinical trials in patients with Friedreich's Ataxia. We have received orphan drug status, fast track designation and rare pediatric disease designation, from the U.S. Food and Drug Administration (the "FDA"), for CTI1601. In addition, the European Medicines Agency ("EMA") Committee for Orphan Medicinal Products ("COMP") issued a positive opinion on the Company's application for orphan drug designation for CTI-1601. The receipt of such designations or positive opinions may not result in a faster development process, review or approval compared to products considered for approval under conventional FDA or EMA procedures and does not assure ultimate approval by the FDA or EMA.
CTI-1601 is currently being evaluated in Phase 1 clinical trials in patients with Friedreich's Ataxia. We have received orphan drug status, fast track designation and rare pediatric disease designation, from the U.S. Food and Drug Administration (the "FDA"), for CTI1601. In addition, the European Medicines Agency ("EMA") Committee for Orphan Medicinal Products ("COMP") issued a positive opinion on the Company's application for orphan drug designation for CTI-1601. The receipt of such designations or positive opinions may not result in a faster development process, review or approval compared to products considered for approval under conventional FDA or EMA procedures and does not assure ultimate approval by the FDA or EMA.
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