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Biomedical subjects

H Dieperink

Publications and source records attributed to H Dieperink.

At least 19 recordsLinked to original sources
PubMed2001

High-dose stabilized chlorite matrix WF10 prolongs cardiac xenograft survival in the hamster-to-rat model without inducing ultrastructural or biochemical signs of cardiotoxicity.

WF10 is a stabilized chlorite matrix with immunosuppressive effects. In vitro studies have demonstrated its ability to suppress T cells and delay or abolish antigen presentation. Hence, WF10 may prove useful to prolong graft survival after transplantation. In this study, we evaluated the use of high dose WF10 as a single drug regimen in the hamster-to-rat xenotransplantation model and searched for possible cardiotoxic side effects. WF10 prolonged cardiac xenograft survival, but did not induce tolerence or inhibit pathological signs of acute rejection. Hamsters from the donor population, receiving high dose WF10 for 5 days, were compared with a matched control group. Ultrastructural examination of cardiac tissue as well as biochemical analysis of the cardiac enzymes troponin I, myoglobin and MB isoenzyme of creatine kinase showed no signs of damage. Thus, while prolonging graft survival, high dose WF10 seems to be non-cardiotoxic and as such should not contribute to the differential diagnosis of acute graft failure.

Animals↗
PubMed2001

Effect of grapefruit juice on Sandimmun Neoral absorption among stable renal allograft recipients.

BACKGROUND: The oral formulation of cyclosporin A (CsA)-Sandimmun-has a highly variable absorption. The development of a CsA microemulsion-Sandimmun Neoral-resulted in increased bioavailability, and decreased variability of absorption. The first oral formulation (Sandimmun) interacted with numerous other drugs and grapefruit juice. Several of these interactions might be explained by decreased pre-systemic metabolism by a cytochrome-enzyme (e.g. CYP3A4) located in the enteral mucosa, and/or via the P-glycoprotein-mediated decreased transport of CsA back from enterocytes into the gut lumen. The purpose of this pharmacokinetic study was to investigate the interaction between Sandimmun Neoral and grapefruit juice. METHOD: Eight stable renal transplant recipients were studied during two 8-h sessions in a randomized cross-over design with 4 weeks interval. Following an overnight fast the patients ingested their habitual morning dose of Neoral either with water or with grapefruit juice. During the 8-h study period 10 blood samples were taken for determination of CsA concentration. These results formed the basis for calculation of area under curve (AUC), and half-life (t(1/2)). Maximum concentration (C(max)) and time until C(max) (t(max)) were obtained from the concentration-time profile. RESULTS: The median AUC increased by 38% (12-194%) (P<0.05) following co-administration of Neoral with grapefruit juice. There were no significant changes in C(max), t(max), and t((1/2)). CONCLUSION: Co-administration of Sandimmun Neoral with grapefruit juice resulted in an increased bioavailability of CsA, indicating unchanged pre-systemic enterocyte first-pass metabolism as compared to Sandimmun. There was no impact of an oral grapefruit juice load on systemic clearance of CsA. It seems prudent to advise renal allograft recipients treated with Sandimmun Neoral not to ingest their medication with grapefruit juice.

Absorption↗
PubMed1995

Nephrotoxicity of FK-506 in the rat. Studies on glomerular and tubular function, and on the relationship between efficacy and toxicity.

Recent studies in liver and kidney transplant recipients revealed a nephrotoxic adverse effect of the new macrolide immunosuppressant FK-506. Therefore the effect of FK-506 0.1 to 0.8 mg per kg per day was investigated in rats using clearance methods including lithium clearance. In rats given FK-506 or placebo during 1 week the nephrotoxicity of FK-506 was characterized by a slight reduction of inulin clearance. The end proximal delivery as measured by the lithium clearance was decreased by FK-506. In rats treated for 4 weeks with FK-506 0.8 mg/kg/day the glomerular filtration rate (GFR) had decreased to 23% of the GFR found in controls (P < 0.001), while end proximal delivery was only 8% of normal. Renal histopathological investigation showed a slight but statistically significant increase of tubular basophilia and atrophy in FK-506-treated rats. Skin transplantation studies in the same rat strain showed a dose-dependent immunosuppressive effect of FK-506. FK-506 0.8 mg/kg was significantly more immunosuppressive than 0.2 or 0.4 mg/kg, so it was concluded that the lower doses of FK-506 did not fully exploit the drug's immunosuppressive potential. Thus in a dosage inside the therapeutic range defined from skin transplantations, FK-506 generated a number of toxic effects including a considerable nephrotoxic effect. The FK-506 induced changes in glomerular and tubular function was a close match to the changes found in cyclosporin A nephrotoxicity. The present study suggests that FK-506 nephrotoxicity is caused by constriction of preglomerular vessels.

Animals↗
PubMed1994

Long-term cyclosporin A nephrotoxicity in the rat. Evaluation of a morphological scoring system and of co-treatment with isradipine.

Cyclosporin A (CyA) nephrotoxicity was examined in Spraque-Dawley rats given CyA (12.5 (n = 45) or 25 (n = 45) mg/kg/day perorally for 16 weeks. Control rats (n = 45) received CyA vehicle. All rats were given either isradipine (ISRA) 1 or 5 mg/kg/day orally, or isradipine vehicle. Fifteen rats died from interstitial pneumonia caused by Staphylococcus xylosus. A predefined morphological CyA nephrotoxicity scoring system, based on semiquantitative scores for basophilic tubules and for interstitial fibrosis, performed on hematoxylin-eosin-stained tissue, yielded mean scores for basophilic tubules of 0.2 (range 0-1) in controls, 1.4 (range 0-3) in rats given CyA 12.5 mg/kg/day (p < 0.001), and 1.7 (range 0-3) in CyA 25 mg/kg/day rats (p < 0.001 as compared to controls). Rats given CyA were grouped according to their score for interstitial fibrosis: 0.2 (range 0-1) in CyA 12.5 mg/kg/day and 1.7 (range 0-3) in CyA 25 mg/kg/day rats (p < 0.001). When scores for basophilic tubules and interstitial fibrosis were pooled, none of the control rats had a score above 1, while 47% of the low-dose and 95% of the high-dose rats scored above 1. Thus, this CyA nephrotoxicity scoring system provided an easy, efficacious, and reproducible identification of rats with morphological CyA nephrotoxicity, and may be of clinical interest in the assessment of CyA nephrotoxicity. Kidney tissue from rats not treated with isradipine was further investigated with periodic acid-Schiff (PAS) with and without diastase treatment, and with Sirius Red. The latter confirmed the increase in connective tissue following tubular atrophy in CyA-treated rats. PAS reaction disclosed diastase-resistant positivity in the glomerular arterioles (score in controls: mean 0.4, range 0-1, in CyA 12.5 mg/kg/day mean 2.2, range 1-3, p < 0.001 as compared to controls; in CyA 25 mg/kg/day mean 1.1, range 0-2, p < 0.005 as compared to controls, p < 0.05 as compared to CyA 12.5 mg/kg/day). Furthermore, the straight part of the distal tubules of rats given the highest CyA dose contained considerable amounts of glycogen. The significance of this finding is unknown. Renal functional studies confirmed previous results since CyA decreased inulin clearance (Cin) from 1.2 +/- 0.5 to 0.8 +/- 0.3 ml/min/g kidney weight (kW) (p < 0.05), and lithium clearance (CLi) was reduced from 263 +/- 113 to 119 +/- 61 microliters/min/gKW (p < 0.001). Isradipine had no significant effect.

Animals↗
PubMed1993

Segmental tubular sodium reabsorption in type 1 diabetes.

Segmental tubular sodium reabsorption in Type 1 (insulin-dependent) diabetes was measured in 36 patients in a cross-sectional study including one group (n = 13) without significant albuminuria (UalbV < 30 mg 24 h-1), one group (n = 16) with albuminuria in the range from 30 to 300 mg 24 h-1, and a group (n = 7) with nephropathy (UalbV > 300 mg 24 h-1). Lithium clearance was used to measure end proximal delivery. From end proximal delivery, 51Cr-EDTA clearance (GFR) and sodium clearance, segmental tubular reabsorption was calculated. For all patients, GFR was directly correlated with end proximal delivery (r = 0.62, p < 0.0005), while end proximal delivery was inversely correlated to fractional proximal reabsorption (r = -0.71, p < 0.0005). In the subgroup with UalbV less than 30 mg 24 h-1, the direct correlation between GFR and end proximal delivery was also significant (r = 0.77, p < 0.05). In the group with nephropathy (UalbV > 300 mg 24 h-1), mean GFR and end proximal delivery were decreased and fractional proximal reabsorption was increased, but there was still a positive correlation between GFR and end proximal delivery (r = 0.75, p < 0.05) and an inverse correlation between end proximal delivery and fractional proximal reabsorption (r = -0.85, p < 0.05). It is concluded that in these groups of diabetic patients the end proximal delivery is increased while GFR is increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Antagonist capacity of felodipine on cyclosporin A nephrotoxicity in the rat.

Functional and morphological cyclosporin A (CsA) nephropathy has been attributed to a CsA-induced constriction of the afferent glomerular arteriole. Calcium-channel blockade with nifedipine prevented the development of short-term functional nephrotoxicity in CsA-treated rats. This study investigated whether the calcium antagonist felodopine, a structural analogue of nifedipine, which reduces renal tubular fractional sodium reabsorption, could prevent both short- and long-term functional and long-term morphological CsA nephropathy. In short-term experiments, four groups of Spraque-Dawley rats (n = 39) were given CsA (either 0 or 12.5 mg/kg per day by daily gastric intubation for 2 weeks), and felodipine (0 or 30 mg/kg per day) in the diet. In long-term experiments, rats (n = 39) were given CsA (12.5 mg/kg per day for 16 weeks), and felodipine (0 or 30 mg/kg per day in the diet). Renal function was investigated with clearance methods (inulin, lithium, and sodium), and kidney morphology was studied by light-microscopy. In short-term experiments, CsA treatment reduced GFR (730 versus 1181 microliters/min per g kidney weight (KW), P < 0.05) and CLi (130 versus 271 microliters/min per gKW, P < 0.02). Felodipine decreased proximal fractional reabsorption (PFR) (67.5% versus 71.4%, P < 0.05) and increased CNa (15.9 versus 8.4 microliters/min per gKW, P < 0.02) as compared to controls. In CsA-treated rats felodipine increased C in (1260 versus 730 microliters/min per gKW, P < 0.05) and CLi (319 versus 130 microliters/min per gKW, P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1991

Flush perfusion of rabbit kidneys with autogeneic, allogeneic and xenogeneic blood.

A simple perfusion model was developed to study the events that lead to rejection of renal xenografts. Flush perfusion of the kidneys of 24 rabbits was carried out with blood from rabbits, cats, or humans. Light microscopy showed alterations with neutrophilic granulocytes margination of the vessels after only 15 min of perfusion. In the experiments with human blood the immunofluorescence microscopy showed deposits of immunoglobulins and complement factor III. This simple method is therefore a useful way of studying perfusion in renal xenografts.

Animals↗
PubMed1990

[Immunosuppression with cyclosporin induces clinical remission and improved beta cell function in patients with newly diagnosed insulin-dependent diabetes. A national and international multicenter study].

A prospective, randomized, double-blind, placebo-controlled international multicenter trial including 188 newly diagnosed insulin-dependent diabetic (IDDM) patients was undertaken with the aim of investigating whether immunosuppression for one year with ciklosporin (Cs) could induce and maintain clinical remission and improvement of beta-cell function. The relative odds for non-insulin-requiring remission at one year were increased approximately five times in the Cs-treated group. After three months Cs-treated patients achieved more than a doubling of beta-cell function compared to baseline than did placebo-treated patients, and the Cs-treated group maintained this improvement in beta-cell function for 12 months, whereas the placebo-group lost beta-cell function during the same period. Short duration of disease (less than or equal to six weeks of symptoms, less than or equal to two weeks of insulin treatment) was associated positively with remission, as was an elevated proinsulin/C-peptide ratio, especially in patients with the tissue-type HLA-DR 3,4; 4,X and X,X. Cs-treatment inhibited the formation of antibodies against insulin and islet cell components, but islet cell antibody status at entry was not predictive of remission. Cs-treatment caused a reversible decrement of kidney function as measured with serum creatinine and the calculated creatinine clearance, but studies of renal physiology and kidney biopsies performed on a limited subset of patients indicated that Cs treatment in IDDM patients for one year induced a slight chronic nephropathy in some of these.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Nephrotoxicity of cyclosporin A in patients with newly diagnosed type 1 diabetes mellitus.

Renal function was studied in 18 patients with Type 1 diabetes mellitus. All were participating in the Canadian-European randomized placebo-controlled cyclosporin trial in newly diagnosed Type 1 diabetic patients, nine being randomized to placebo, and nine to cyclosporin A. During treatment for 12 to 18 months, cyclosporin A caused significant reductions in the glomerular filtration rate (before drug withdrawal, cyclosporin 97 +/- 18 vs placebo 125 +/- 16 ml min-1 1.73-m-2, p less than 0.05), renal plasma flow (454 +/- 83 vs 536 +/- 70 ml min-1 1.73-m-2, p less than 0.05), and lithium clearance (17 +/- 3 vs 28 +/- 5 ml min-1 1.73-m-2, p less than 0.05). The fractional proximal reabsorption was increased (0.82 +/- 0.03 vs 0.78 +/- 0.03, p less than 0.05), and the fractional distal sodium reabsorption reduced (0.88 +/- 0.03 vs 0.94 +/- 0.02, p less than 0.05). These results are in accordance with the hypothesis that the nephrotoxic effect of cyclosporin A results from a preferential constriction of afferent glomerular vessels. One year after withdrawal of the drug, all variables were similar in the two groups, except for blood glucose control which was worse in the cyclosporin A treated group. When corrected for differences in blood glucose control it appeared that in three out of nine patients glomerular filtration rate had not completely returned to the reference range of the placebo group. We conclude that the nephrotoxic side-effects of cyclosporin A treatment for 1 year are reversible. There are, however, signs of minor and perhaps chronic renal injury.

Adult↗
PubMed1990

Hope for successful xenografting by immunosuppression with monoclonal antibody against CD4, total lymphoid irradiation and cyclosporine. Six months' survival of hamster heart transplanted into rat.

Hamster hearts were transplanted to rats, and the effects of combinations of total lymphoid irradiation (TLI), cyclophosphamide, cyclosporine A (CyA) and monoclonal antibodies (MAB) were investigated. Controls not immunosuppressed rejected their xenograft in 3 to 5 days, while combination immunosuppression including MABs against CD4 or IL-2-receptors extended graft survival significantly. In one case, the graft was still functioning 180 days after transplantation, which is the longest survival seen in this model. The use of specific MABs may open a new era for both xeno- and allo-transplantation.

Animals↗
PubMed1988

Long-term cyclosporin nephrotoxicity in the rat: effects on renal function and morphology.

This long-term study elucidates the development and reversibility of functional and morphological cyclosporin (CsA) nephropathy. Sprague-Dawley rats were given CsA (12.5 or 25 mg/kg per day) for 4, 8 or 16 weeks, or CsA during the first half of the 8- or 16-week period, and vehicle during the second half. Controls were given CsA vehicle throughout the study. Renal function was investigated with clearance methods (inulin, lithium, sodium and potassium). CsA-treated rats developed a focal renal interstitial fibrosis, the severity of which correlated to the accumulated CsA dose given (Kendall's tau = 0.56, P less than 0.0001). This renal lesion was not reversible. CsA reduced GFR and lithium clearance, and increased proximal fractional reabsorption. There was significant correlation (P less than 0.0001) between accumulated CsA dose and severity of functional impairment. Renal function improved following drug withdrawal, but in the compiled material, low-grade nephrotoxicity was evident 4 to 8 weeks after CsA withdrawal: GFR was decreased to 84% (P less than 0.02) of control levels. This indicates that CsA-induced renal focal interstitial fibrosis is progressive during treatment, and is not reversible, while functional CsA nephropathy is progressive but partly reversible if CsA is withdrawn.

Absorption↗