ABSTRACT
For quantitative analysis of related substances in TSD-1 active pharmaceutical ingredient, structures of prepared impurities were confirmed by NMR and UHPLC-MS, and a high performance liquid chromatographic method was established to determine the related substances in TSD-1. The analytical column was an Agilent ZORBAX Eclipe XDB-C8 (250 mm × 4.6 mm, 5 µm). The mobile phase A was 50 mmol·L-1 ammonium acetate solution (adjusted pH to 5.8 with acetic acid) and the mobile phase B was acetonitrile. The whole run was carried out by gradient elution at a flow rate of 1.0 mL·min-1. The detection wavelength was set at 240 nm and the column temperature was 30 ℃. The resolutions among peaks of TSD-1, impurity A, impurity B, TSD-D, and TSD-F were good. The calibration curves (n = 7) of TSD-1, impurity A, impurity B, TSD-D and TSD-F were linear in their respective weight ranges of 0.242-48.4 µg·mL-1 (r = 1.000 0), 0.244-9.75 µg·mL-1 (r = 0.999 9), 0.244-4.80 µg·mL-1 (r = 0.999 9), 0.254-1.02 µg·mL-1 (r = 0.999 9), and 0.247-0.987 µg·mL-1 (r = 0.999 9). The lower limits of quantitation were 0.244, 0.244, 0.254, and 0.247 µg·mL-1 for impurity A, impurity B, TSD-D, and TSD-F, respectively, and the average recovery of each impurity ranged from 99.08% to 103.00% with high accuracy. TSD-D and TSD-F were not detected in the three batches of TSD-1 active pharmaceutical ingredients, and impurity A and impurity B were not detected beyond the limit. The established HPLC method is simple, accurate, and suitable for determination of related substances of TSD-1, which can provide a valuable reference for the subsequent development of TSD-1.
ABSTRACT
Los estudios CURE, TRITON-TIMI 38 y PLATO han demostrado beneficio clínico con el uso de doble antiagregación plaquetaria con clopidogrel, prasugrel o ticagrelor adicionados a la aspirina en pacientes con síndrome coronario agudo y han contribuido a incrementar exponencialmente su prescripción. La publicación de nuevos ensayos aleatorizados con hallazgos que contrastaron con los beneficios obtenidos en estos estudios y de algunos artículos de opinión que han cuestionado la validez de los resultados hace necesario, al menos, replantear su indicación generalizada y el real beneficio clínico de estas drogas. En este artículo se discuten los resultados de estos tres ensayos, como también los cuestionamientos metodológicos que se les han efectuado, focalizando en el real beneficio clínico de estas drogas. Asimismo, considerando que en determinados subgrupos puede existir perjuicio, se discute este punto y se propone un esquema sencillo que permita seleccionar a los pacientes que más se benefician con estos tratamientos.
CURE, TRITON-TIMI 38 and PLATO studies have demonstrated clinical benefit with the use of dual antiplatelet therapy with clopidogrel, prasugrel or ticagrelor in addition to aspirin in patients with acute coronary syndrome, and have contributed to exponentially increased prescription. The publication of new randomized trials with findings contrasting with the benefits obtained in these studies and of some opinion articles which have questioned the validity of the results, make it necessary, at least, to rethink the general indication and actual clinical benefit of these drugs. In this article we discuss the results of these three trials as well as the methodological objections that have been posed to them, focusing on the real clinical benefit of these drugs. Likewise, the probability of prejudice in certain subgroups is discussed and a simple scheme that allows the selection of patients most likely to benefit from these treatments is postulated.