PubMed · 5007163
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F A Klipstein, C H Halsted, E A Robles, E Mezey. 1972-01-20. Intoxicated enterocytes?. https://pubmed.ncbi.nlm.nih.gov/5007163/
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An important issue regarding the long-term use of antiarrhythmic drugs concerns the safety of these agents, particularly with regard to cardiac toxicity. Propafenone is an effective drug for preventing supraventricular tachyarrhythmia, but the incidence of side effects during longterm therapy in patients with such arrhythmias has not been adequately reported. A total of 480 patients received oral propafenone as therapy for symptomatic atrial fibrillation, atrial flutter, or supraventricular tachycardia. During the follow-up (mean 14.4 months), 290 patients (60%) discontinued propafenone therapy, but in only 70 patients (15%) was the reason for discontinuation an adverse drug reaction. Overall, 284 patients (59%) experienced at least 1 adverse reaction, and the incidence was related to dose and age >65 years. The overall incidence of side effects was not related to structural heart disease; however, cardiovascular toxicity including arrhythmia aggravation, congestive heart failure, and serious conduction disturbances occurred more often in those with heart disease (20% vs 13%). Sixteen patients died during drug therapy, but in only 1 case was the drug considered contributory. For patients with a supraventricular arrhythmia, propafenone was well tolerated and was infrequently discontinued because of side effects. The incidence of serious cardiac toxicity when propafenone was used to treat supraventricular arrhythmia was low, and these side effects were more frequent in patients with structural heart disease.
The B subunits of Escherichia coli heat-labile enterotoxin (EtxB) and cholera toxin (CtxB) assemble in vivo into exceptionally stable homopentameric complexes, which maintain their quaternary structure in a range of conditions that would normally be expected to cause protein denaturation. Recently, we showed that the simultaneous protonation of two of the COOH-terminal carboxylates in pentameric EtxB was required to cause its disassembly at pH values below 2.0 (Ruddock, L., Ruston, S. P., Kelly, S. M., Price, N. C., Freedman, R. B., and Hirst, T. R.(1995) J. Biol. Chem. 270, 29953-29958). Here, we investigate the influence of environmental parameters on the kinetics of reassembly of acid-generated EtxB monomers in vitro. Such monomers were found to undergo a further acid-mediated conformational change, with an activation energy of 76 +/- 2 J.mol-1.K-1, consistent with isomerization of the cis-proline residue at position 93, and which prevented subsequent EtxB reassembly. By using rapid neutralization of acid-generated monomers, a high proportion of the B-subunits adopted an assembly-competent conformation, which resulted in up to 75% of the protein reassembling into a stable pentameric complex, indistinguishable from native EtxB pentamers. The rate-limiting step in reassembly, over a concentration range of 50-200 microg/ml, was shown to be due to an intramolecular event, which exhibited a pH dependence with a pKa of 7.0. Modification of EtxB with amine-specific probes revealed that the protonation state of the NH2-terminal alanine residue was responsible for the pH dependence of reassembly. The implications of these findings for the biogenesis of Escherichia coli enterotoxin and related enterotoxins in vivo, are considered.
In this study, we evaluate the significance of increased urinary chromium concentrations as a marker of chromium exposure and potential health risk. Six human volunteers ingested trivalent chromium [Cr(III)] and hexavalent chromium [Cr(VI)] at doses that are known to be safe but are much higher than typical dietary levels. The following dosing regimen was used: d 1-7, 200 micrograms/d chromium picolinate (a dietary supplement); d 8-10, Cr(VI) ingestion at the U.S. Environmental Protection Agency (EPA) reference dose (RfD) of 0.005 mg/kg/d; d 11-13, no dose; d 14-16, Cr(III) ingestion at the U.S. EPA RfD of 1.0 mg/ kg/d; and d 17-18, postdose. Urine voids were collected throughout the dosing periods and analyzed for chromium. Our findings are as follows: (1) ingestion of 200 micrograms/d of chromium picolinate yielded significantly elevated urine concentrations such that each participant routinely exceeded background, (2) ingestion of the Cr(VI) RfD (0.005 mg/kg/d) yielded individual mean urinary chromium levels (1.2-23 micrograms/L) and a pooled mean urinary chromium level (2.4 micrograms/L) that significantly exceeded background, and (3) ingestion of the Cr(III) RfD yielded no significant increase in urinary chromium concentrations, indicating that little, if any, absorption occurred. Our work identified three critical issues that need to be accounted for in any future studies that will use urinary chromium as a marker of exposure. First, a minimum urinary chromium concentration of approximately 2 micrograms/L should be used as a screening level to critically identify individuals who may have experienced elevated exposures to chromium. Second, if Cr(III) levels in soils are known to be less than 80,000 ppm and the Cr(III) is insoluble, urinary chromium concentrations are not an appropriate marker of exposure. Third, newer forms of chromium supplements that contain organic forms of Cr(III) must be considered potential confounders and their contribution to residential chromium uptake must be carefully evaluated.