Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017160 (gastroenteritis)
 11,398 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pharmacokinetics, safety, and efficacy in marrow transplantation of FK506-based immunosuppression for graft-versus-host disease (GVHD) prophylaxis was evaluated in an open label pilot study of 18 patients. Patients more than 12 years of age (median, 35 years; range, 15 to 50 years) with advanced hematologic malignancies receiving HLA-matched sibling marrow grafts were randomized to receive FK506 alone, FK506 and methotrexate (MTX), or FK506 and methyl-prednisolone. Of 17 evaluable patients, all had evidence of sustained marrow engraftment. The median time to an absolute neutrophil count of greater than 500/microL was 15 days for patients receiving FK506 alone or FK506 plus methylprednisolone and 23 days for FK506 plus short MTX. Pharmacokinetic studies did not show any significant difference in clearance of FK506 when administered alone or in combination with methylprednisolone or MTX. The mean bioavailability after oral administration in these same three groups was 0.49 +/- 0.1, 0.27 +/- 0.12, and 0.16 +/- 0.08, respectively (P = .003). The decrease in bioavailability may have resulted from an exacerbation of radiation-induced gastroenteritis by MTX. The most significant adverse effect associated with the administration of FK506 was nephrotoxicity, which occurred in 14 of 18 patients (78%). The mean glomerular filtration rate, determined by clearance of (99MTc)DTPA, decreased to 56% (+/- 18%) of the pretransplant baseline level by week 8 (P = .002). Eight of 18 patients (44%) developed grades II-IV acute GVHD, predominantly of the skin and gastrointestinal tract. The actuarial probability of transplant-related mortality during the first 100 days was 24%. The actuarial probability of 1-year disease-free survival was 39%. In conclusion, although bioavailability of FK506 may be affected in patients receiving MTX, this study suggests that FK506 may have a role in the management of patients after allogeneic marrow transplantation.
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PMID:Tacrolimus (FK506) alone or in combination with methotrexate or methylprednisolone for the prevention of acute graft-versus-host disease after marrow transplantation from HLA-matched siblings: a single-center study. 754 71

Tacrolimus is an immunosuppressant used to prevent rejection of transplanted organs. It is metabolized in both the gut and the liver by the cytochrome P450 (CYP) 3A4 enzyme system and is a substrate for the P-glycoprotein (P-gp) drug efflux pump. As CYP3A4 enzymes and P-gp are present at differing concentrations throughout the gastrointestinal tract, the bioavailability of tacrolimus may be influenced by changes in gastrointestinal transit time in addition to changes in hepatic metabolism. We report the case of a pediatric renal transplant patient who experienced a three-fold increase in serum tacrolimus concentrations during an episode of gastroenteritis with chronic diarrhea.
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PMID:Increased tacrolimus levels in a pediatric renal transplant patient attributed to chronic diarrhea. 1073 Oct 62

While it is well known that diarrhea results in decreased trough levels of cyclosporin A, experience with levels of tacrolimus (FK506) and diarrhea is limited. We have therefore measured the tacrolimus trough levels of four male and two female recipients of solid organs before, during, and after gastroenteritis. The average age of these six patients was 31 (1-60) years. Four patients had received a kidney transplant, one patient had undergone simultaneous kidney-pancreas transplantation, and another patient had received a liver transplant. Rotavirus was identified in the feces specimen of a 1-year-old child that had undergone liver transplantation. All patients showed an elevated tacrolimus trough level (peak 20-60 ng/ml) after onset of gastroenteritis. Under symptomatic therapy and adequate adjustment of tacrolimus dose, the gastroenteritis stopped and tacrolimus levels returned to the therapeutic range. We recommend that FK506 levels be carefully monitored during diarrhea in order to prevent intoxication.
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PMID:Increased tacrolimus levels during diarrhea. 1151 55

It is well known that during diarrhea episodes decreased cyclosporine and tacrolimus levels are often observed, usually requiring an increase in dose. An increase in tacrolimus trough levels is infrequently recognized as a potential cause of the adverse effect of severe diarrhea. Herein, we report the case of a renal transplant patient who displayed increased tacrolimus trough levels during an episode of gastroenteritis with severe diarrhea. The patient is 32-year-old male who received a renal transplant from his mother. Immunosuppression was initiated with tacrolimus in combination with mycophenolate mofetil and prednisone. The postoperative course was uneventful. The function of the transplanted kidney was normal. Eight months after transplantation he presented to our hospital with a history of high fever, abdominal pain, nausea and severe diarrhea. He was admitted with a diagnosis of enterocolitis of unknown etiology. The blood trough level of tacrolimus had increased from 6.7 ng/mL to 28.7 ng/mL after the onset of diarrhea. A therapeutic trough level of tacrolimus was reached 6 weeks after complete relief of diarrhea. Tacrolimus shows large variability in bioavailability after oral administration, both due to intestinal metabolism by cytochrome P450 (CYP3A4) and active secretion from enterocyte into intestinal lumen by P-glycoprotein. The epithelial cells of the intestine, may be destroyed abrogating P-glycoproteins during the course of enterocolitis, thereby increasing the levels of tacrolimus. It is recommended to monitor trough levels of tacrolimus during severe diarrhea of any nature to prevent tacrolimus-related complications.
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PMID:Increased tacrolimus trough levels in association with severe diarrhea, a case report. 1551 58

Tacrolimus has been used extensively for immunosuppressive therapy in pediatric liver transplant recipients. However, patients who are exposed to high levels of serum tacrolimus tend to be associated with a higher incidence of significant nephrotoxicity, neurotoxicity, pruritus, alopecia, diabetes and infection. We herein report a child who developed increased serum transaminase levels and liver steatosis as a result of raised trough blood level of tacrolimus (30 ng/ml for 3 days) in association with rotavirus gastroenteritis.
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PMID:Fatty liver due to high levels of serum tacrolimus after liver transplantation. 1790 28

Norovirus is a major cause of acute gastroenteritis worldwide and has emerged as an important issue of chronic infection in transplantation patients. Since no approved antiviral is available, we evaluated the effects of different immunosuppressants and ribavirin on norovirus and explored their mechanisms of action by using a human norovirus (HuNV) replicon-harboring model and a surrogate murine norovirus (MNV) infectious model. The roles of the corresponding drug targets were investigated by gain- or loss-of-function approaches. We found that the calcineurin inhibitors cyclosporine (CsA) and tacrolimus (FK506) moderately inhibited HuNV replication. Gene silencing of their cellular targets, cyclophilin A, FKBP12, and calcineurin, significantly inhibited HuNV replication. A low concentration, therapeutically speaking, of mycophenolic acid (MPA), an uncompetitive IMP dehydrogenase (IMPDH) inhibitor, potently and rapidly inhibited norovirus replication and ultimately cleared HuNV replicons without inducible resistance following long-term drug exposure. Knockdown of the MPA cellular targets IMPDH1 and IMPDH2 suppressed HuNV replication. Consistent with the nucleotide-synthesizing function of IMPDH, exogenous guanosine counteracted the antinorovirus effects of MPA. Furthermore, the competitive IMPDH inhibitor ribavirin efficiently inhibited norovirus and resulted in an additive effect when combined with immunosuppressants. The results from this study demonstrate that calcineurin phosphatase activity and IMPDH guanine synthase activity are crucial in sustaining norovirus infection; thus, they can be therapeutically targeted. Our results suggest that MPA shall be preferentially considered immunosuppressive medication for transplantation patients at risk of norovirus infection, whereas ribavirin represents as a potential antiviral for both immunocompromised and immunocompetent patients with norovirus gastroenteritis.
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PMID:Inhibition of Calcineurin or IMP Dehydrogenase Exerts Moderate to Potent Antiviral Activity against Norovirus Replication. 2880 16