Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to investigate two promising immunosuppressive agents, didemnin B (DB) and FK506 (FK), during pregnancy to assess potential adverse maternal or fetal effects. Pregnant C3H mice were randomized into control and high- and low-dose treatment groups for each drug. Animals received daily injections from day 1 to day 16, and on day 17 of gestation the maternal condition, litter size, fetal resorption rates, and fetal/placental unit weights were determined. Immunoglobulin (IgG) levels were obtained for DB treatment groups. Delayed type hypersensitivity was assessed in virgin females. Both DB and FK had dose-dependent immunosuppressive activity in the DTH assay, and DB caused elevated IgG concentrations. High doses of DB caused diarrhea and maternal wasting with no fetal survival; with low-dose DB, maternal weight gain was depressed, but pregnancy outcome was not different from control animals. High-dose FK had no obvious detrimental effects on maternal health but caused resorption of all fetuses; administration of low-dose FK resulted in a higher number of resorptions, but fetuses that survived did not appear different from controls. We conclude that these immunosuppressive drugs can have adverse effects on pregnancy, but the maternal and fetal toxicity are dose-dependent.
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PMID:The effect of two new immunosuppressive agents, FK506 and didemnin B, in murine pregnancy. 171 60

Acute cyclosporine (CsA) nephrotoxicity is characterized by a reduction of glomerular filtration rate (GFR), hypomagnesemia and tubular injury. The mechanisms of CsA's immunosuppressive action and presumably its nephrotoxicity are mediated through inhibition of the renal phosphatase, calcineurin. FK506 (FK), which has a different chemical structure and binding immunophilin, also inhibits calcineurin. We compared the renal effects of these drugs to those of rapamycin (RAPA), which although similar in structure and intracellular binding to FK, does not work by changing calcineurin activity. Rats were given CsA (15 mg/kg/s.c.), FK (6 mg/kg/p.o.), RAPA (3 mg/kg/p.o.) or vehicle (V) for two weeks on a low salt diet. CsA and FK strikingly decreased urinary excretion of nitric oxide, renal blood flow and GFR, whereas RAPA did not. In contrast, all these three drugs caused significant hypomagnesemia associated with inappropriately high fractional excretion of magnesium, suggesting renal magnesium wasting. In addition, with all three drugs there were lesions in the rat kidneys consisting of tubular collapse, vacuolization and nephrocalcinosis. We thus showed that only the calcineurin inhibitors produced glomerular dysfunction in an acute experimental model of nephrotoxicity. The mechanism of hypomagnesemia and tubular injury induced by all three immunosuppressive drugs is unclear but may be independent of calcineurin. The mechanism of renal vasoconstriction on the other hand may be related to inhibition of calcineurin.
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PMID:Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506. 888 67

FK506 (tacrolimus) and dexamethasone are potent immunosuppressants known to induce significant side effects on mineral homeostasis, including hypercalciuria and hypomagnesemia. However, the underlying molecular mechanisms remain unknown. The present study investigated the effects of FK506 and dexamethasone on the expression of proteins involved in active Ca(2+) reabsorption: the epithelial Ca(2+) channel TRPV5 and the cytosolic Ca(2+)-binding protein calbindin-D(28K). In addition, the renal expression of the putative Mg(2+) channel TRPM6, suggested to be involved in transcellular Mg(2+) reabsorption, was determined. Administration of FK506 to rats by daily oral gavage during 7 d significantly enhanced the urinary excretion of Ca(2+) and Mg(2+) and induced a significant hypomagnesemia. FK506 significantly decreased the renal mRNA expression of TRPV5 (62 +/- 7% relative to controls), calbindin-D(28K) (9 +/- 1%), and TRPM6 (52 +/- 8%), as determined by real-time quantitative PCR analysis. Furthermore, semiquantitative immunohistochemistry showed reduced renal protein abundance of TRPV5 (24 +/- 5%) and calbindin-D(28K) (29 +/- 4%), altogether suggesting that downregulation of these transport proteins is responsible for the FK506-induced Ca(2+) and Mg(2+) wasting. In contrast, dexamethasone significantly enhanced renal TRPV5 (150 +/- 15%), calbindin-D(28K) (177 +/- 23%), and TRPM6 (156 +/- 20%) mRNA levels along with TRPV5 (211 +/- 8%) and calbindin-D(28K) (176 +/- 5%) protein abundance in the presence of significantly increased Ca(2+) and Mg(2+) excretion. This indicated that these proteins are directly or indirectly regulated by dexamethasone. In conclusion, FK506 and dexamethasone induce renal Ca(2+) and Mg(2+) wasting, albeit by different mechanisms. Downregulation of specific Ca(2+) and Mg(2+) transport proteins provides a molecular mechanism for FK506-induced hypercalciuria and hypomagnesemia, whereas dexamethasone positively regulates these proteins.
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PMID:Downregulation of Ca(2+) and Mg(2+) transport proteins in the kidney explains tacrolimus (FK506)-induced hypercalciuria and hypomagnesemia. 1497 56