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Biomedical subjects

A R Mueller

Publications and source records attributed to A R Mueller.

At least 73 records · Page 4Linked to original sources
PubMed1994

The effects of administration of nitric oxide inhibitors during small bowel preservation and reperfusion.

The effects of nitric oxide (NO) during small bowel preservation and reperfusion were studied in a rat model of heterotopic, syngeneic LEW-->LEW transplantation. A 6-hr preservation interval was chosen, which leads consistently to moderate graft injury permitting graft and recipient survival. To evaluate the function of NO during preservation and reperfusion, two inhibitors (NitroG-L-arginine methyl ester [L-NAME] and NG-monomethyl-L-arginine [NMA]) were administered and compared with a transplanted group receiving no treatment. The extent of preservation and reperfusion injury were delineated by histologic study and by the measurement of mucosal glutaminase on tissue specimens obtained 20 min after revascularization and 24 hr and 4 weeks postoperatively. Serum and mucosal NO(2-)+NO3- levels were determined at the same time points. Graft function and survival was inferior in all cases where NO production was inhibited. When recipients were treated with NO inhibitors, graft function and survival was more impaired when L-NAME was administered compared with NMA administration. Donor and graft pretreatment with NO inhibitors impaired graft function but not survival, and was less detrimental than recipient treatment. Mucosal NO(2-)+NO3- levels significantly increased in untreated transplanted animals 20 min after reperfusion. This increase was abolished in groups treated with NO inhibitors. Serum NO(2-)+NO3- levels increased significantly after 24 hr, and this increase was even more pronounced when NO inhibitors were administered. Furthermore, liver function deteriorated after inhibition of NO, indicating a more severe inflammatory response of the recipient after NO inhibition. These data indicate that mucosal NO production within the graft during preservation, and especially during reperfusion, has beneficial effects, but increased serum NO(2-)+NO3- levels coincided with inferior graft condition due to preservation and reperfusion injury.

Animals↗
PubMed1994

The effect of FK506 versus cyclosporine on glucose and lipid metabolism--a randomized trial.

In order to evaluate the effect of cyclosporine (CsA) versus FK506 on glucose and lipid metabolism, an oral glucose tolerance test (OGTT) was performed in 101 patients after orthotopic liver transplantation (OLT) (mean interval after OLT: 511 days). The liver graft recipients had been randomized prospectively to two groups prior to OLT to receive either immunosuppression with CsA, azathioprine, and corticosteroids (CsA group) or FK506 and corticosteroids (FK group). Along with the OGTT, serum insulin, insulin C-peptide and glucagon as well as serum lipids were monitored. There was no statistically significant difference in the occurrence of impaired glucose tolerance (IGT) or manifest diabetes mellitus disease between the two groups. In fact, not a single patient developed new-onset diabetes in any group. In male and female patients, serum levels of cholesterol and triglycerides increased significantly under FK506 and CsA treatment after OLT. Cholesterol was significantly higher in the CsA group in men, in women this was marked, but not significant. While triglycerides were significantly higher in women on CsA treatment, there was no such difference in men. In conclusion, both CsA and FK506 proved to have similar effects on glucose metabolism, while there was a different spectrum of serum lipid alterations.

Adolescent↗
PubMed1994

Neurotoxicity after orthotopic liver transplantation. A comparison between cyclosporine and FK506.

Neurotoxicity represents a serious complication following orthotopic liver transplantation. Neurotoxicity may be evoked by various perioperative factors or develop due to drug-specific toxicity of immunosuppression. We evaluated the incidence of neurotoxicity in 121 patients, 61 randomly assigned to FK506 and 60 to CsA-based immunosuppression. The incidence of moderate or severe neurotoxicity was markedly higher in patients treated with FK506 in the early postoperative period (21.3% vs. 11.7% in patients receiving CsA), after retransplantation (100% vs. 0% in patients receiving CsA), and late (8 of 10 patients; P < or = 0.05 vs. CsA). Furthermore late neurotoxicity was highly associated with severe infections and MOFS, which had a lethal outcome in more than 50% of the patients. Patients who subsequently died developed neurologic symptoms in 67% of the cases. These patients also experienced moderate or severe neurotoxicity significantly more often in the early postoperative period compared with patients with a successful outcome (50% vs. 17.3%; P < or = 0.01). However, various blood and serum parameters, including ALT, bilirubin, urea, creatinine and glucose, when analyzed alone or in multivariate fashion, also correlated significantly with the incidence and severity of early postoperative neurotoxicity, indicating that neurotoxicity following LTX may be caused by various factors and is not exclusively a drug-specific side effect of immunosuppression.

Adolescent↗
PubMed1994

Nephrotoxicity following orthotopic liver transplantation. A comparison between cyclosporine and FK506.

Nephrotoxicity represents a serious side effect of immunosuppression following liver transplantation. In order to compare the nephrotoxic action of CsA and FK506 in a clinical setting, we evaluated the incidence of early and late nephrotoxicity in 121 patients, 60 of whom were randomly assigned to CsA- and 61 to FK506-based immunosuppression. Early postoperative renal insufficiency (between PODs 0 and 30; SCr 1.5-3 mg/dl) was observed to a similar extent in patients treated with CsA (38.3%) and FK506 (42.6%). Early postoperative acute renal failure (ARF) (SCr > 3 mg/dl) was observed in 18.0% of patients in the FK506 treatment group and 18.3% of patients receiving CsA therapy. Approximately half the patients with ARF required hemodialysis (CsA: 11.7%; and FK506: 8.2%). All patients with early postoperative ARF requiring hemodialysis survived for more than one year. New onset of late ARF (between PODs 30 and 365) was observed in 6.6% of patients receiving FK506 therapy and in 1.7% in the CsA treatment group as a result of severe infection with multiple organ failure syndrome (MOFS). There was 100% mortality in patients with late ARF requiring hemodialysis. Etiology and prognosis of early and late ARF seem to be completely different. Early ARF was associated with severe coagulopathy and a rise in bilirubin and free hemoglobin, and was accompanied by impaired liver function. Mean onset of hemodialysis in CsA-treated patients was POD 1 and in FK506-treated patients POD 6, which disclosed a different time course of drug-specific nephrotoxicity of CsA and FK506 in early ARF. In contrast, late ARF occurred in both treatment groups only as a part of the MOFS in association with severe infections, an observation consistent with the assumption of overimmunosuppression rather than a primary nephrotoxic effect. Late renal insufficiency appeared in 23.3% of CsA- and in 29.4% of FK506-treated patients, and represented a slowly progressing form of drug-specific nephrotoxicity of CsA and FK506. These preliminary results demonstrate a similar outcome in terms of both early and late nephrotoxicity, but longer follow-up will delineate the overall efficacy and toxicity in humans.

Acute Kidney Injury↗
PubMed1994

Neurotoxicity after orthotopic liver transplantation in cyclosporin A- and FK 506-treated patients.

Neurotoxicity is a serious complication following orthotopic liver transplantation leading to increased morbidity and mortality. Neurotoxicity may be evoked by various perioperative factors, or may be due to drug-specific toxicity of immunosuppression. In the present study we evaluated the incidence of central nervous system (CNS) toxicity occurring within the early postoperative period of 121 patients, 61 randomly assigned to FK 506- and 60 to CsA-based immunosuppression as part of a multicentre study. The incidence of moderate or severe CNS toxicity was higher in patients treated with FK 506 (21.3%) than in patients receiving CsA (11.7%). The duration of symptoms was also greater in patients treated with FK 506 than in patients receiving CsA. The incidence of moderate or severe neurotoxicity after retransplantation was markedly greater in patients treated with FK 506 (100% of the patients).

Central Nervous System Diseases↗
PubMed1994

Nephrotoxicity after orthotopic liver transplantation in cyclosporin A and FK 506-treated patients.

Nephrotoxicity represents a serious side-effect of immunosuppression following orthotopic liver transplantation. In order to preserve the therapeutic potential of cyclosporin (CsA) and FK 506 in human liver transplantation and to differentiate the nephrotoxic action of either drug in a clinical setting, we evaluated the incidence of early and late nephrotoxicity in 121 patients, 60 randomly assigned to CsA- and 61 to FK 506-based immunosuppression. Early postoperative renal insufficiency (between POD0 and 30; SCr 1.5-3 mg/dl) was observed to a similar extent in patients treated with CsA (36.7%) and FK 506 (42.6%). Early postoperative acute renal failure (ARF; SCr > 3 mg/dl) occurred in 18.3%, regardless of the immunosuppressive management. Approximately 50% of patients with ARF required hemodialysis (CsA: 11.7%; and FK 506: 8.3%). Mean onset of hemodialysis in CsA-treated patients was POD1 and in FK 506-treated patients, POD6, which demonstrated a different time course of drug-specific nephrotoxicity of CsA and FK 506 in early ARF. All patients with early postoperative ARF requiring hemodialysis survived more than 1 year (100% survival). New onset of late ARF (between POD30 and 365), however, occurred in 6.5% under FK 506 and in 1.7% under CsA immunosuppression due to severe infections with the multiple organ failure syndrome. This observation was consistent with the assumption of over-immunosuppression rather than a primary nephrotoxic effect. Mortality of patients with late ARF requiring hemodialysis was 100%. Late renal insufficiency appeared in 23.3% of CsA- and in 29.4% of FK 506-treated patients, and represented a slowly progressing form of drug-specific nephrotoxicity. These preliminary results demonstrated a similar outcome in terms of early and late nephrotoxicity, but longer follow-up will delineate its overall efficacy and toxicity in humans.

Creatinine↗
PubMed1993

Hyaluronic acid and purine nucleoside phosphorylase in vascular and luminal effluents of small bowel grafts as parameters of preservation injury.

Reliable parameters reflecting the degree of graft injury after small bowel preservation are currently not established. We investigated hyaluronic acid (HA) and purine nucleoside phosphorylase (PNP) as indicators of preservation injury before small bowel transplantation. In the first part of the study, intestinal grafts were harvested, perfused with saline, and flushed either immediately or after 1, 6, 12, 24, and 48 hr of cold storage (n = 6/group). HA and PNP were assayed in vascular and luminal effluents. In the second part of the study, 24 grafts were transplanted after preservation periods of 1, 6, 9, and 12 hr (n = 6/group) to assess if HA and PNP are predictors of postoperative graft survival. HA levels in vascular effluents and PNP activities in luminal effluents correlated with duration of preservation time and predicted graft survival. Utilizing both parameters significantly increased the predictive accuracy.

Animals↗
PubMed1993

Evidence that small bowel preservation causes primarily basement membrane and endothelial rather than epithelial cell injury.

The main site of injury induced during small bowel preservation is perceived to be the basement membrane and the endothelium of the highly vascularized mucosa, an aspect evaluated here in further detail. The effects of preservation were studied using a specific basement membrane stain (laminin antibody), an endothelial cell stain (factor 8 antibody) and standard histology. In addition, mucosal glutaminase activity reflecting enterocyte integrity was measured as monitor of the extent of preservation injury. Using a rat model, small bowel grafts were harvested, the vascular bed and bowel lumen were flushed, and the grafts were stored (4 degrees C) for 1, 6, 9, and 12 hr and transplanted into syngeneic hosts. After cold storage prior to transplantation, full-thickness small bowel biopsies were obtained for the various tissue preparations. Histologic evaluation at the end of the preservation period revealed separation of the villous epithelium from the lamina propria that increased with extending preservation time. Tissue staining with the laminin antibody disclosed progressive changes with increasing preservation intervals. Staining with the factor 8 antibody demonstrated also progressive changes, but failed to reflect in a gradual fashion increasing endothelial cell injury. Histologic injury became more pronounced after transplantation and reperfusion, then showing destruction of epithelial cells; the extent of injury correlated with the duration of preservation. Glutaminase activity was maintained after cold storage, indicating that the enterocytes remained intact during this period, but when assayed after reperfusion, glutaminase decreased with increasing preservation intervals and increasing histologic mucosal damage. We conclude that cold ischemic injury involves primarily the endothelium and the basement membrane, which progresses to global mucosal impairment with reperfusion.

Animals↗
PubMed1992

Mucosal glutamine utilization after small-bowel transplantation: an electrophysiologic study.

A short course of FK 506 after small bowel transplantation averts rejection in the rat and achieves indefinite survival of the recipient whose nutritional status is dependent on the function of the intestinal graft. Ex vivo electrophysiologic studies using the Ussing Cell were conducted to delineate functional competence of the graft by evaluating mucosal ion transport and glutamine utilization. Orthotopic small-bowel transplantation was performed in Lewis (LEW) rats as recipients of either Brown-Norway (BN) allografts or LEW syngeneic grafts. Allograft recipients received FK 506 either as a short course (2 mg/kg on Day 0-4 after transplantation) or continuously (2 mg/kg Day 0-4, then 0.5 mg/kg weekly). Ileal mucosa was harvested from small bowel grafts 9 and 60 days after transplantation and mounted in the Ussing Cell containing Hanks' balanced salt solution with/without L-glutamine (20 mM). Transmembrane potential difference (PD), which represents mucosal active ion transport, and mucosal resistance, an index of membrane integrity, were recorded. Nine days after transplantation, mucosal PD was the same in the ileum from syngeneic grafts, allografts treated with FK 506 and normal LEW and BN rats, and the addition of glutamine increased PD equally in all groups. In comparison, PD was markedly decreased in allografts undergoing rejection, and the glutamine response was blunted. Sixty days after transplantation, mucosal PD was reduced in allografts treated with a short course of FK 506, but normal in allografts receiving continuous immunosuppression with FK 506 and in syngeneic grafts. A decrease of mucosal resistance was not a feature of rejection nor a sequel of limited FK 506 therapy. Our data indicate that allograft rejection results in a significant decrease in mucosal PD and a poor response to glutamine. Control of rejection by FK 506 preserves normal electrophysiologic responses of the allograft mucosa.

Animals↗