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Inhibitors of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Sarpogrelate, an antagonist of 5HT2A and 5-HT2B receptors, is a potent and selective CYP2D6 inhibitor in vitro (Cho et al. 2014), and it increases the AUC of metoprolol by 53% in healthy subjects (Cho et al. 2015). Sarpogrelate potently and selectively inhibits CYP2D6-mediated dextromethorphan O-demethylation with a Ki value of 1.24 μM, in a competitive manner. Its main metabolite, M-1, also markedly inhibits CYP2D6 activity with a Ki value of 0.120 μM and is as potent as quinidine (Ki = 0.129 μM), a well-known typical CYP2D6 inhibitor. In addition, sarpogrelate and M-1 strongly inhibit both CYP2D6-catalyzed bufuralol 1′-hydroxylation and metoprolol a-hydroxylation activities (Cho et al. 2014). However, sarpogrelate and M-1 do not significantly affect CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, or 3A4/5 in vitro (Cho et al. 2014). Sarpogrelate may cause pharmacokinetic drug–drug interactions via inhibition of CYP2D6.
Clinical outcomes and predictors of technical failure of endoscopic transpapillary gallbladder drainage in acute cholecystitis
Published in Scandinavian Journal of Gastroenterology, 2023
Junya Sato, Kazunari Nakahara, Yosuke Michikawa, Ryo Morita, Keigo Suetani, Akihiro Sekine, Yosuke Igarashi, Shinjiro Kobayashi, Takehito Otsubo, Fumio Itoh
Between January 2011 and December 2019, 249 consecutive patients underwent ETGBD for acute cholecystitis. Among them, seven were excluded because they underwent endoscopic transpapillary gallbladder aspiration without stent or drainage catheter placement. A total of 242 patients were enrolled in this study (Figure 1). The most common cystic duct directions and locations were the proximal branches in 187 patients, right branches in 169, and cranial branches in 231 (Table 1). Gallstones (83%) were the most common cause of cholecystitis. The stones were located in the cystic duct in 26 patients (11%) and gall bladder neck in 40 (17%). Mild cholecystitis was diagnosed in approximately half of the patients, moderate in 83 (34%), and severe in 40 (17%). In this study, 106 patients were administered antithrombotic agents including aspirin, cilostazol, ticlopidine, clopidogrel, prasugrel, sarpogrelate, icosapentate, warfarin, dabigatran, apixaban, and edoxaban.
Platelet proteomics: from discovery to diagnosis
Published in Expert Review of Proteomics, 2018
Christina Looße, Frauke Swieringa, Johan W. M. Heemskerk, Albert Sickmann, Christin Lorenz
As a first quantitative approach to unravel the molecular mechanisms of platelet activation, an inventory was made of the global human platelet proteome, resulting in the identification of about 4000 unique proteins, including multiple cell surface receptors, cytoskeletal, and signaling proteins [36,39]. Platelets appeared to be particularly rich in proteins of the proteasome and immunoproteasome, thus pointing to an active protein turnover mechanism [40]. Quantitative analyses were conducted of the proteome in platelets treated with different physiological agonists, causing platelet activation or inhibition. Findings here pointed to an unexpected, highly dynamic regulation of protein changes in both activated and inhibited platelets, with likely relevance for disease [41]. For instance, GPVI and ADP receptor activation were found to modify proteins involved in signaling and cytoskeletal rearrangements [42,43]. Inhibition of platelets with sarpogrelate revealed about 500 regulated proteins mainly involved in cell activation, coagulation, and vesicle-mediated transport. Out of these, three were chosen to provide a protein cluster that allows the monitoring of effects of sarpogrelate treatment in platelets [44].
A noninferiority confirmatory trial of prasugrel versus clopidogrel in Japanese patients with non-cardioembolic stroke: rationale and study design for a randomized controlled trial – PRASTRO-I trial
Published in Expert Opinion on Pharmacotherapy, 2018
Takehiko Nagao, Kazunori Toyoda, Kazuo Kitagawa, Takanari Kitazono, Hiroshi Yamagami, Shinichiro Uchiyama, Norio Tanahashi, Masayasu Matsumoto, Kazuo Minematsu, Izumi Nagata, Masakatsu Nishikawa, Shinsuke Nanto, Kenji Abe, Yasuo Ikeda, Akira Ogawa
The details of the statistical analysis used for efficacy and safety results will be published together with the efficacy and safety results. However, the rationale for the statistical analysis plan is presented here. The primary efficacy end point was assessed using a non-inferiority margin of 1.35. That is, non-inferiority was considered established if the upper limit of the 95% confidence interval for the risk ratio (RR) for the primary event in the prasugrel group against the clopidogrel group did not exceed the non-inferiority margin of 1.35. Because no previous study used end points that were similar to those in this trial, a non-inferiority margin was determined by predicting the incidence of ischemic stroke, myocardial infarction, and death from other vascular causes. This non-inferiority margin is in reference to the incidence of ischemic stroke plus vascular death in the Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention of Cerebral Infarction (S-ACCESS) trial [22]. The reason for referring to the results of this trial to determine the non-inferiority margin is that, when the present trial protocol was finalized in 2011, FDA guidance for the formulation of a non-inferiority margin (two-sided 95% confidence interval method) had not yet been published. When formulating a non-inferiority margin, we needed to utilize results from clinical studies of clopidogrel versus placebo. However, a systematic review revealed no previously published placebo-controlled study. Therefore, taking into account that the study would only be conducted in Japan, we determined that the non-inferiority margin was to be based on information from the S-ACCESS trial [22] as well as results from a randomized, double-blind study comparing clopidogrel with ticlopidine in Japanese patients with noncardioembolic cerebral infarction [23].