Endocannabinoid Modulation Using Monoacylglycerol Lipase Inhibition in Tourette Syndrome: A Phase 1 Randomized, Placebo-Controlled Study.

INTRODUCTION: Tourette syndrome (TS) is a complex neurodevelopmental disorder characterized by chronic motor and vocal tics. While consistently effective treatment is lacking, evidence indicates that the modulation of endocannabinoid system is potentially beneficial. Lu AG06466 (previously ABX-1431) is a highly selective inhibitor of monoacylglycerol lipase, the primary enzyme responsible for the degradation of the endocannabinoid ligand 2-arachidonoylglycerol. This exploratory study aimed to determine the effect of Lu AG06466 versus placebo on tics and other symptoms in patients with TS. METHODS: In this phase 1b cross-over study, 20 adult patients with TS on standard-of-care medications were randomized to a single fasted dose of Lu AG06466 (40 mg) or placebo in period 1, followed by the other treatment in period 2. The effects on tics, premonitory urges, and psychiatric comorbidities were evaluated using a variety of scaled approaches at different time points before and after treatment. RESULTS: All scales showed an overall trend of tic reduction, with two out of three tic scales (including the Total Tic Score of the Yale Global Tic Severity Score) showing a significant effect of a single dose of Lu AG06466 versus placebo at various timepoints. Treatment with Lu AG06466 resulted in a significant reduction in premonitory urges versus placebo. Single doses of Lu AG06466 were generally well-tolerated, and the most common adverse events were headache, somnolence, and fatigue. CONCLUSION: In this exploratory trial, a single dose of Lu AG06466 showed statistically significant positive effects on key measures of TS symptoms.

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors.

Fatty acid ethanolamides (FAEs) and endocannabinoids (ECs) have been shown to alleviate pain and inflammation, regulate motility and appetite, and produce anticancer, anxiolytic, and neuroprotective efficacies via cannabinoid receptor type 1 (CB1) or type 2 (CB2) or via peroxisome proliferator-activated receptor α (PPAR-α) stimulation. FAEs and ECs are synthesized by a series of endogenous enzymes, including N-acylphosphatidylethanolaminephospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), or phospholipase C (PLC), and their metabolism is mediated by several metabolic enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), N-acylethanolamine acid amidase (NAAA), or cyclooxygenase 2 (COX-2). Over the past decades, increasing the concentration of FAEs and ECs through the inhibition of degrading enzymes has been considered to be a viable therapeutic approach to enhance their antinociceptive and anti-inflammatory effects, as well as to protect the nervous system.

Presente y futuro del tratamiento farmacológico de la obesidad / Present and future of the obesity pharmacological treatment

La obesidad es un trastorno metabólico crónico que se caracteriza por la acumulación de tejido adiposo. El tratamiento basado en la dieta y el ejercicio es la indicación de elección; sin embargo, esto no es suficiente, dado que la cantidad de personas con sobrepeso y obesidad en las sociedades industriales aumenta constantemente, lo cual le confiere características de epidemia. Aún grados menores de obesidad producen un aumento de la morbimortalidad cardiovascular, con un gran costo sanitario y económico. En aquellos pacientes en los que el tratamiento no farmacológico haya fracasado y que presenten un IMC mayor menor 30 o mayor menor 27 kg/m² más dos factores de riesgo se debería contemplar el uso de fármacos antiobesidad. En la actualidad contamos con dos fármacos, el orlistat y la sibutramina, que están autorizados para el uso crónico en esta patología, asociados con la dieta y el ejercicio. Además, numerosas moléculas se encuentran en diferentes fases de investigación. El conocimiento de los múltiples y diferentes mecanismos que intervienen en la regulación del metabolismo nos permitirá no sólo conocer esta "enfermedad" sino tratarla adecuadamente.