Using Artificial Intelligence-based Methods to Address the Placebo Response in Clinical Trials.

The placebo response is a highly complex psychosocial-biological phenomenon that has challenged drug development for decades, particularly in neurological and psychiatric disease. While decades of research have aimed to understand clinical trial factors that contribute to the placebo response, a comprehensive solution to manage the placebo response in drug development has yet to emerge. Advanced data analytic techniques, such as artificial intelligence (AI), might be needed to take the next leap forward in mitigating the negative consequences of high placebo-response rates.

Stratification of patients based on the Neuropathic Pain Symptom Inventory: development and validation of a new algorithm.

The personalization of neuropathic pain treatment could be improved by identifying specific sensory phenotypes (ie, specific combinations of symptoms and signs) predictive of the response to different classes of drugs. A simple and reliable phenotyping method is required for such a strategy. We investigated the utility of an algorithm for stratifying patients into clusters corresponding to specific combinations of neuropathic symptoms assessed with the Neuropathic Pain Symptom Inventory (NPSI).

Amiloride analogs induce the phosphorylation of elongation factor-2 in vascular endothelial cells.

5-(N-Ethyl-N-isopropyl)amiloride (EIPA), a potent inhibitor of Na+/H+ antiport, reduced [35S]methionine incorporation in proteins and induced the phosphorylation of a Mr 95,000 protein in bovine aortic endothelial cells. This protein was previously shown to become phosphorylated in response to ATP, bradykinin, and A23187 (1) and was identified as elongation factor-2 (2). The action of EIPA was independent of changes in cytosolic pH, because it was neither mimicked by sodium acetate nor inhibited by ammonium chloride, and it was reproduced by 2',4'-dimethylbenzamil, an analog of amiloride that is inactive on the Na+/H+ antiport.

Effects of amiloride analogues on the production of prostacyclin by aortic endothelial cells.

1. The release of prostacyclin (PGI2) from bovine aortic endothelial cells stimulated by adenosine 5'-triphosphate (ATP) was decreased by amiloride analogues bearing alkyl groups on the 5-amino nitrogen atom, like 5-(N-ethyl-N-isopropyl)amiloride (EIPA), which are inhibitors of the Na+/H+ exchanger. Analogues substituted on a terminal guanidino nitrogen atom were not inhibitory.

Cholera and pertussis toxins amplify prostacyclin synthesis in aortic smooth muscle cells.

Pretreatment of bovine aortic smooth muscle cells in culture with pertussis toxin (PT) or cholera toxin (CT) potentiated the synthesis of prostacyclin (PGI2) induced by 5-hydroxytryptamine (5-HT) and phorbol-12-myristate, 13-acetate (PMA). The production of PGI2 by explants from the bovine aortic media was also synergistically stimulated by 5-HT and CT, whereas PT was inactive. These data are consistent with the hypothesis that guanosine 5'-triphosphate binding proteins are directly involved in the control of phospholipases which release free arachidonic acid for prostaglandin synthesis.