Tacrolimus Induced Organ Failure: Reversal by Activation of the Cytochrome P450-3a System

Tacrolimus is the cornerstone component of all immunosuppressive regimens. Despite its long record of use, very little is known about its acute toxicity syndrome. We describe five patients with acute organ failure, involving both native and transplanted organs, which was reversed by inducing the cytochrome P450-3A system. In all patients, the causative drug was stopped and phenytoin was given intravenously to accelerate tacrolimus metabolism. Within 24 h, tacrolimus trough levels fell daily at a significant level (p < 0.05) and all failed organs recovered their normal function within 48–72 h. Therefore, phenytoin metabolic induction appears to be a safe therapeutic option for patients with acute tacrolimus toxicity.

Systematic prompting the new physiological and morphological, biological responses of modified metabolic induction process of Calendula officinalis L under heat stress with couple of supplementary nutritional applications as safety of floriculture crops

The full text of this preprint has been withdrawn by the authors due to author disagreement with the posting of the preprint. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.

Fluorinated Galactoses Inhibit Galactose-1-Phosphate Uridyltransferase and Metabolically Induce Galactosemia-like Phenotypes in HEK-293 Cells

Genetic defects of human galactose-1-phosphate uridyltransferase (hGALT) and the partial loss of enzyme function result in an altered galactose metabolism with serious long-term developmental impairment of organs in classic galactosemia patients. In search for cellular pathomechanisms induced by the stressor galactose, we looked for ways to induce metabolically a galactosemia-like phenotype by hGALT inhibition in HEK293 cells. In kinetic studies, we provide evidence for 2-fluorinated galactose-1-phosphate (F-Gal-1-P) to competitively inhibit recombinant hGALT with a KI of 0.9 mM. Contrasting with hepatic cells, no alterations of N-glycoprofiles in MIG (metabolic induction of galactosemia)-HEK293 cells were revealed for an inducible secretory netrin-1 probe by MALDI-MS. Differential fluorescence-activated cell sorting demonstrated reduced surface expression of N-glycosylated CD109, EGFR, DPP4, and rhMUC1. Membrane raft proteomes exhibited dramatic alterations pointing to an affection of the unfolded protein response, and of targeted protein traffick. Most prominent, a negative regulation of oxidative stress was revealed presumably as a response to a NADPH pool depletion during reduction of Gal/F-Gal. Cellular perturbations induced by fluorinated galactoses in normal epithelial cells resemble proteomic changes revealed for galactosemic fibroblasts. In conclusion, the metabolic induction of galactosemia-like phenotypes in healthy epithelial/neuronal cells could support studies on the molecular pathomechanisms in classic galactosemia, in particular under conditions of low galactose stress and residual GALT activity.

Neurobehavioral Effects of Acute Exposure to Normal (n-) Paraffins

This article reports the results of neurobehavioral tests on C5-C10 normal paraffinic constituents (n-paraffins). Shortly after exposure, effects were evaluated in several domains including clinical effects, motor activity, functional observations, and visual discrimination performance. The representative C5 n-paraffin, n-pentane, did not produce any evidence of acute central nervous system (CNS) effects at levels up to 20 000 mg/m3. Similarly, there was no compelling evidence that n-octane (C8) produced CNS effects at 14 000 mg/m3, the highest concentration tested. n-decane (C10) produced minor, reversible acute CNS effects at 5000 mg/m3, with 1500 mg/m3 as the no-effect level. Consistent with literature data, there seemed to be a relationship between increasing molecular weight up to C10 and acute CNS effects. However, the CNS effects were reversible. Repeated exposures did not provide evidence of metabolic induction.