Drug features that are associated with StevensJohnson syndrome (SJS) have not been fully characterized. A molecular target analysis of the drugs associated with SJS in the FDA Adverse Event Reporting System (FAERS) may contribute to mechanistic insights into SJS pathophysiology. The publicly available version of FAERS was analyzed to identify disproportionality among the molecular targets, metabolizing enzymes, and transporters for drugs associated with SJS. The FAERS in-house version was also analyzed for an internal comparison of the drugs most highly associated with SJS. Cyclooxygenases 1 and 2, carbonic anhydrase 2, and sodium channel 2 alpha were identified as disproportionately associated with SJS. Cytochrome P450 (CYPs) 3A4 and 2C9 are disproportionately represented as metabolizing enzymes of the drugs associated with SJS adverse event reports. Multidrug resistance protein 1 (MRP-1), organic anion transporter 1 (OAT1), and PEPT2 were also identified and are highly associated with the transport of these drugs. A detailed review of the molecular targets identifies important roles for these targets in immune response. The association with CYP metabolizing enzymes suggests that reactive metabolites and oxidative stress may have a contributory role. Drug transporters may enhance intracellular tissue concentrations and also have vital physiologic roles that impact keratinocyte proliferation and survival. Data mining FAERS may be used to hypothesize mechanisms for adverse drug events by identifying molecular targets that are highly associated with druginduced adverse events. The information gained may contribute to systems biology disease models.
That Ang II levels are elevated in sucrose-induced hypertension and decreased after vanadium therapy suggests that the renin-angiotensin system plays a role in the induction of hypertension in this model. On the other hand, the elevation of endothelin-1 levels associated with a decreased systolic blood pressure might be secondary to vanadium stimulation of endothelial cells. The data suggest that endothelin-1 is not involved in sugar-induced elevations of the blood pressure.
Plasma, heart, and extracardiac tissue verapamil concentrations were measured after sustained intravenous infusions in 11 dogs to determine the differential tissue accumulation of verapamil. A steady state verapamil concentration of 327 ± 50 ng/ml decreased the mean arterial blood pressure from 104 ± 9 to 90 ± 6 mm Hg (p = 0.08) and the P-R interval increased from 118 ± 4 to 176 ± 13 ms (p < 0.001) with second-degree atrioventricular block developing in 6 animals. Verapamil accumulated in organs in the following order: Lung ≥ kidney > spleen > ventricular myocardium = liver > atrial myocardium > cerebral cortex > fat = skeletal muscle. Levels in the ventricular free wall were consistently greater than atrial levels, but no difference was observed between left versus right-sided cardiac chambers. In summary, affinity of different organs for verapamil is highly variable and organ-specific; furthermore, differential intracardiac chamber accumulation occurs.
Although nicardipine may decrease vascular responsiveness to sympathetic activation, the baroreflex-mediated vasoconstrictor response to upright tilt remains intact. In contrast, isosorbide impairs the systemic vascular response to orthostatic stress in elderly patients with stable coronary artery disease.
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