Host: The Japanese Pharmacological Society
Name : The 97th Annual Meeting of the Japanese Pharmacological Society
Number : 97
Location : [in Japanese]
Date : December 14, 2023 - December 16, 2023
To better understand how drugs exert their effects in our human body, we should recognize that only a fraction of the mechanisms has been identified and described in the literature. In fact, affinities for all receptors, enzymes, and channels have not been measured during the development phase, and the safety in humans has been investigated in a limited number of cases within a short time frame. Accordingly, unexpected adverse events have been reported during post-marketing surveillance. Therefore, there will be numerous unknown effects of drugs buried in clinical data, which may contain not only adverse event mechanisms but also unexpected benefits. Then, how can we find out them? In this talk, I will introduce some of our achievements in finding unexpected beneficial effects of drugs from clinical real-world data (RWD).
(1) By statistical analysis of multiple RWD, we found that the anti-arrhythmic drug amiodarone caused interstitial lung injury with chronic inflammation of lung tissue leading to fibrosis, and that the concomitant use of the anti-thrombin drug dabigatran suppressed the incidence of such adverse events. Pharmacological studies revealed that this effect is due to the inhibition of PAR1-PDGFRα-MMP12 pathway by dabigatran.
(2) RWD showed that the anti-diabetic DPP4 inhibitors increased the risk of an autoimmune disease, bullous pemphigoid (BP), and that concomitant use of lisinopril, an antihypertensive drug widely used in the US, reduced the risk. Pharmacological studies revealed that lisinopril suppresses the development of BP by inhibiting cutaneous MMP9 expression through suppression of the ACE2-MasR pathway, rather than by acting on immune cell functions.
(3) Short-term administration of the antimicrobial fluoroquinolones increased the risk of tendinopathy after the use. Conventional treatment guidelines suggest that concomitant corticosteroid therapy increases the risk of tendinopathy. However, RWD analysis found a preventive effect of dexamethasone. Interestingly, dexamethasone also decreased the spontaneous incidence of tendinopathy in a aged cohort. From pharmacological studies, we found that fluoroquinolones impair tendon cells by DNA damage with generation of reactive oxygen species, whereas dexamethasone has a beneficial effect on tendon tissue function via increased expression of GPX3, a glutathione peroxidase that contributes as a radical scavenger.
