Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins

In the pharmaceutical industry, improving the early detection of drug-induced hepatotoxicity is essential as it is one of the most important reasons for attrition of candidate drugs during the later stages of drug development. The first objective of this study was to better characterize different cellular models (i.e., HepG2, HepaRG cells, and fresh primary human hepatocytes) at the gene expression level and analyze their metabolic cytochrome P450 capabilities. The cellular models were exposed to three different CYP450 inducers; beta-naphthoflavone (BNF), phenobarbital (PB), and rifampicin (RIF). HepG2 cells responded very weakly to the different inducers at the gene expression level, and this translated generally into low CYP450 activities in the induced cells compared with the control cells. On the contrary, HepaRG cells and the three human donors were inducible after exposure to BNF, PB, and RIF according to gene expression responses and CYP450 activities. Consequently, HepaRG cells could be used in screening as a substitute and/or in complement to primary hepatocytes for CYP induction studies. The second objective was to investigate the predictivity of the different cellular models to detect hepatotoxins (16 hepatotoxic and 5 nonhepatotoxic compounds). Specificity was 100% with the different cellular models tested. Cryopreserved human hepatocytes gave the highest sensitivity, ranging from 31% to 44% (depending on the donor), followed by lower sensitivity (13%) for HepaRG and HepG2 cells (6.3%). Overall, none of the models under study gave desirable sensitivities (80–100%). Consequently, a high metabolic capacity and CYP inducibility in cell lines does not necessarily correlate with a high sensitivity for the detection of hepatotoxic drugs. Further investigations are necessary to compare different cellular models and determine those that are best suited for the detection of hepatotoxic compounds

Calcium channel blockers cannot prevent pure vasospastic myocardial infarction.

Coronary artery spasm is a recognized cause of myocardial infarction. This report describes a case of myocardial infarction attributed to pure coronary spasm which was halted by a double perfusion with streptokinase and nitroglycerin. Further coronary artery spasm leading to a myocardial infarction could not be avoided several weeks later, although the patient was left on calcium channel blocker therapy. The two attacks were not preceded by warning angina pectoris, contrary to accepted belief. The best objective of end-point drug therapy and its assessment in vasospastic angina are discussed

Letter from Kezia Payne DePelchin at Houston to her sister, Sallie Payne, April 15, 1879

4 handwritten pages, more on experiences of the epidemic, deaths, reflections on doctors, nurses and patients, and animals left after their owners die

Letter from Kezia Payne DePelchin at Memphis to her sister, Sallie Payne, September 17 & 23, 1878

14 handwritten pages, writing from a tenement house, nursing a sick woman until death and caring for the dead woman's child, Arthur

Memphis durante la peste, carta al editor

1 clipping, letter to the editor, "Memphis in the Plague"This document is an Spanish translation of the "Memphis in the Plague, letter to the editor of the Telegram." Translated by Lorena Gauthereau-Bryson. The language of the original document is Englis

Letter from Kezia Payne DePelchin at Memphis to her sister, Sallie Payne, September 3, 1878

8 handwritten pages, journey to Memphis, first patient, Howard Associatio

Memphis in the Plague, letter to the editor of the Telegram

1 clipping, letter to the editor, "Memphis in the Plague

Travel journal of Kezia Payne DePelchin, 1881-1882

78 handwritten pages describing travel in Europe and the United StatesTravel journal of the author in which she describes her trips to Madeira Island, Funchal (Madeira), Portugal; Lynchburg, Virginia; New Orleans, Louisiana; Philadelphia, Pennsylvania; Brooklyn and New York City, New York; Liverpool, England; Glasgow, Dunfermline, Scotland; and Edinburgh, Aberdour, Scotland