Randomised, double-blinded, placebo-controlled trial assessing the efficacy of Mi-Gel® in the treatment of women with vulval pain / entry dyspareunia.

Start Date01 Nov 2024

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100 Clinical Results associated with Isoleucine menthyl esters

100 Translational Medicine associated with Isoleucine menthyl esters

100 Patents (Medical) associated with Isoleucine menthyl esters

Literatures (Medical) associated with Isoleucine menthyl esters

01 Nov 2024·Pharmacological Research

Revisiting the nature and pharmacodynamics of tacrolimus metabolites

Article

Author: Giraud, Nicolas ; Bertho, Gildas ; Marquet, Pierre ; de Sousa, Rodolphe Alves ; Campana, Mélanie ; Alves de Sousa, Rodolphe ; Pinault, Emilie ; Sauvage, François-Ludovic ; Di Meo, Florent ; Arnion, Hélène ; Lopez-Noriega, Adolfo ; Aouad, Hassan ; Mevizou, Rudy ; Bernard, Jean-Sébastien

The toxicity of tacrolimus metabolites and their potential pharmacodynamic (PD) interactions with tacrolimus might respectively explain the surprising combination of higher toxicity and lower efficacy of tacrolimus despite normal blood concentrations, described in extensive metabolizers. To evaluate such interactions, we produced tacrolimus metabolites in vitro and characterized them by high resolution mass spectrometry (HRMS, for all) and nuclear magnetic resonance (NMR, for the most abundant, M-I). We quantified tacrolimus metabolites and checked their structure in patient whole blood and peripheral blood mononuclear cells (PBMC). We explored the interactions of M-I with tacrolimus in silico, in vitro and ex vivo. In vitro metabolization produced isoforms of tacrolimus and of its metabolites M-I and M-III, whose HRMS fragmentation suggested an open-ring structure. M-I and M-III open-ring isomers were also observed in patient blood. By contrast, NMR could not detect these open-ring forms. Transplant patients expressing CYP3A5 exhibited higher M-I/TAC ratios in blood and PBMC than non-expressers. Molecular Dynamics simulations showed that: all possible tacrolimus metabolites and isomers bind FKPB12; and the hypothetical open-ring structures induce looser binding between FKBP12 and calcineurins, leading to lower CN inhibition. In vitro, tacrolimus bound FKPB12 with more affinity than purified M-I, and the pool of tacrolimus metabolites and purified M-I had only weak inhibitory activity on IL2 secretion and not at all on NFAT nuclear translocation. M-I showed no competitive effect with tacrolimus on either test. Finally, M-I or the metabolite pool did not significantly interact with tacrolimus MLR suppression, thus eliminating a pharmacodynamic interaction.

01 Aug 2024·Pharmacology Research & Perspectives

Phase 1 pharmacokinetic and safety study of soticlestat in participants with mild or moderate hepatic impairment or normal hepatic function

Article

Author: Lawitz, Eric J. ; Hui, Tom ; Asgharnejad, Mahnaz ; Rondon, Juan Carlos ; Yin, Wei ; Copalu, Veronique ; Khan, Yasir ; Mitra, Pranab ; Baratta, Mike ; Marbury, Thomas C. ; Lloyd, Valerie

AbstractThis phase 1, open‐label, three‐arm study (NCT05098054) compared the pharmacokinetics and safety of soticlestat (TAK‐935) in participants with hepatic impairment. Participants aged ≥18 to <75 years had moderate (Child‐Pugh B) or mild (Child‐Pugh A) hepatic impairment or normal hepatic function (matched to hepatic‐impaired participants by sex, age, and body mass index). Soticlestat was administered as a single oral 300 mg dose. Pharmacokinetic parameters of soticlestat and its metabolites TAK‐935‐G (M3) and M‐I were assessed and compared by group. The incidence of treatment‐emergent adverse events (TEAEs) and other safety parameters were also monitored. The pharmacokinetic analyses comprised 35 participants. Participants with moderate hepatic impairment had lower proportions of bound and higher proportions of unbound soticlestat than participants with mild hepatic impairment and normal hepatic function. Total plasma soticlestat pharmacokinetic parameters (maximum observed concentration [Cmax], area under the concentration‐time curve from time 0 to time of last quantifiable concentration [AUClast], and AUC from time 0 to infinity [AUC∞]) were approximately 115%, 216%, and 199% higher with moderate and approximately 45%, 35%, and 30% higher with mild hepatic impairment, respectively, than healthy matched participants. Moderate hepatic impairment decreased the liver's ability to metabolize soticlestat to M‐I; glucuronidation to M3 was also affected. Mild hepatic impairment resulted in a lower total plasma M‐I exposure, but glucuronidation was unaffected. TEAEs were similar across study arms, mild, and no new safety findings were observed. A soticlestat dose reduction is required for individuals with moderate but not mild hepatic impairment.

100 Deals associated with Isoleucine menthyl esters

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Preclinical	JP	Tokyo University of Science	08 May 2024
Obesity	Preclinical	JP	Tokyo University of Science	08 May 2024

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