Добірка наукової літератури з теми "Tasimelteon"

In January 2014, the US Food and Drug Administration approved tasimelteon (Hetlioz™), a melatonin-receptor agonist for the treatment of non-24-hour sleep–wake disorder. This article provides an overview of the mechanism of action, pharmacokinetic properties, as well as the clinical efficacy, safety, and tolerability of tasimelteon. Relevant information was identified through a comprehensive literature search of several databases using the key words tasimelteon, Non-24-hour Sleep–Wake disorder, Non-24, and melatonin. Further information was obtained from the tasimelteon package insert, fda.gov , clinicaltrials.gov , briefing materials provided by Vanda Pharmaceuticals, and posters from scientific meetings.

Abstract Introduction Smith-Magenis Syndrome (SMS) is a rare (1/15,000 - 25,000 births) neurodevelopmental disorder resulting from an interstitial deletion of chromosome 17p11.2, or from a point mutation in the RAI1 gene. Severe sleep disorder is almost universal in patients with SMS and poses a significant challenge to patients and their families. Tasimelteon improved sleep symptoms in a randomized, double-blind, two-period, crossover study; and here we show that this effect persists for up to four years in an open-label extension. To our knowledge, this is the largest interventional study of SMS patients to date. Methods Following the 4-week crossover study, all eligible participants had the option to enroll in an open-label extension. 31/39 (79.4%) of all individuals who participated in the efficacy study have continued on tasimelteon treatment. Participants in the open-label extension provided daily diary sleep quality (DDSQ), and daily diary total sleep time (DDTST) measures via parental post sleep questionnaire and characterized behavior using the Aberrant Behavior Checklist (ABC). Results In the open-label extension, tasimelteon continued to show improvement in the primary endpoints of 50% worst sleep quality (mean = 0.7, SD = 0.94) and 50% worst total nighttime sleep duration (mean = 53.3, SD = 59.01) when compared to baseline. Tasimelteon also improved overall sleep quality (mean=0.7, SD=0.83) and overall total nighttime sleep duration (mean = 51.9, SD=53.03). ABC scores also improved with tasimelteon (mean= -16.3, SD = 15.82). Conclusion Tasimelteon continues to demonstrate persistence in efficacy (longest approximately 4 years) with similar magnitudes observed in the 4-week crossover study for sleep quality and total sleep time. Interestingly, daytime behavior also demonstrates long-term improvement in patients with SMS treated with tasimelteon. These results further confirm tasimelteon as a novel therapy for the treatment of sleep disorders in patients with SMS and may provide benefit for behavioral symptoms. Support This work was supported by Vanda Pharmaceuticals Inc.

Melatonin agonists have become an area of interest in the treatment of sleep disorders. This article reviews the available data on this class of medications, with a focus on ramelteon and tasimelteon.

Gli Antibody-Drug Conjugates (ADC) sono tra i farmaci più promettenti per la terapia mirata antitumorale. Gli ADC sfruttano infatti la capacità degli anticorpi monoclonali di indirizzare il trasporto di molecole citotossiche in modo selettivo al sito del tumore, con un miglioramento dell’efficacia della sicurezza del farmaco citotossico. La porzione linker di collegamento tra l’anticorpo e il farmaco è una componente cruciale di ogni ADC: deve essere stabile in plasma ma instabile all’interno della cellula, permettendo il rilascio del farmaco citotossico solo nell’ambiente citoplasmatico ed evitando un rilascio prematuro nella circolazione sanguigna. In questo progetto di tesi sono stati esplorati numerosi aspetti degli ADC. Abbiamo sviluppato il primo ADC coniugato con un acido idrossamico, l’inibitore dell’enzima istone deacetilasi vorinostat, connesso attraverso un linker degradabile dal metabolismo cellulare. Inoltre, il farmaco è meno potente di quelli solitamente usati negli ADC con una ridotta tossicità sistemica. Per quanto riguarda i “self-immolative spacers”, abbiamo sviluppato un nuovo linker ramificato che permette la possibilità di una sintesi modulare dei vari componenti: tale linker è capace di rilasciare un modello di farmaco citotossico mediante la riduzione di un gruppo disolfuro. Inoltre, sono stati effettuati anche studi verso un approccio convergente alla sintesi dei linker. Oltre al lavoro con i bioconiugati, sono stati sintetizzate alcune impurezze della sintesi industriale dell’agonista dei recettori della melatonina Tasimelteon ed è stata sviluppata una nuova sintesi stereoselettiva dell’agonista dei recettori della sfingosina Ozanimod.
Antibody-Drug Conjugates (ADCs) are emerging as the next generation anticancer therapeutic agents. ADCs take advantage of the specificity of monoclonal antibody to target the delivery of drugs to the tumor site, with an expectation of improving the efficacy and safety of the cytotoxic payload. The linker plays a key role in the development of ADC derivatives and its blood stability as well as its possible degradation into the cell need to be carefully tuned. The synthesis of the linker offers many opportunities for organic chemistry. In this thesis we explored several different aspects of the ADC field. We developed the first ADC charged with a hydroxamic acid payload (the HDAC inhibitor vorinostat), connected through a metabolic sensitive linker. Moreover, the presence of a not highly cytotoxic drug leads to a lower systemic toxicity compared the one generally observed with traditional ADCs. With regard to self-immolative spacers, we designed a novel multifunctional branched linker that offers the opportunity of a modular synthesis of the various ADCs components. This linker is able to release a model of an amine payload from a disulfide trigger moiety. Furthermore, we present also studies towards a convergent approach to the synthesis of the linker. Besides the work on bioconjugates, we report the preparation of several synthetic impurities of the melatonin receptors agonist Tasimelteon and a new protecting group-free stereoselective synthesis of the sphingosine-1-phosphate receptor agonist Ozanimod.