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Biomedical subjects

B Ryffel

Publications and source records attributed to B Ryffel.

At least 145 records · Page 8Linked to original sources
PubMed1986

Cyclosporine nephrotoxicity.

Cyclosporine (CSA) is a new immunosuppressant which has selectivity for the immune system and is without systemic side effects at therapeutic doses. In contrast to the cytotoxic class of immunosuppressants, no myelotoxic, teratogenic, mutagenic, or carcinogenic effects were observed. Nevertheless, overdosage may lead to renal dysfunction, which occurs mainly in rats, and often complicates its clinical use. The experimental data also showed that significant nephrotoxicity was only caused under specific conditions at therapeutic doses. These conditions included ischemia, heminephrectomy, concomitant administration of nephrotoxic drugs, and/or genetic predisposition. Thus, concomitant renal damage is a prerequisite in order to obtain overt nephrotoxicity at therapeutic CSA doses. Since these conditions cannot be avoided in patients, nephrotoxicity often occurs at therapeutic doses in man. The rat might be a suitable experimental model of CSA nephropathy displaying similar morphologic and functional changes as observed in man. This model also allows further investigations on the pathogenic mechanisms which are elusive at the present time.

Animals↗
PubMed1986

Alterations in molecular structure of renal mitochondria associated with cyclosporine A treatment.

We examined whether ultrastructural changes in renal mitochondria associated with Cyclosporine A treatment might reflect underlying alterations in mitochondrial molecular structure. A nonrejected renal transplant removed from a patient treated with Cyclosporine A showed a decreased level of beta subunit antigen of mitochondrial F1-ATPase compared to controls. This decrease was more marked in the medulla than in the cortex (56% vs. 70% of pooled controls). Spontaneously hypertensive rats treated with a high dose of Cyclosporine A showed a similar decrease of beta-subunit antigen in the renal medulla and decreased levels of two subunit antigens of cytochrome c oxidase, but had increased medullary levels of the alpha subunit antigen of the F1-ATPase. Such changes were not detected in a normotensive strain of rats. Our data indicate that Cyclosporine A administration is associated with structural alterations in renal mitochondria at the molecular level, predominantly in the medulla, and that additional renal damage due to ischemia or hypertension may predispose to this cyclosporine effect.

Adenosine Triphosphatases↗
PubMed1986

Pharmacokinetics of cyclosporine in toxicological studies.

Pharmacokinetic studies performed in toxicological studies indicate that CsA is well absorbed in rats and dogs with absolute bioavailability in the range of 10% to 30% when administered by gavage (olive oil). Exceptions are the guinea pig, the rabbit and marmoset with low bioavailability (less than 5%). CsA is also absorbed in rats when given mixed in the feed. Vehicles may have marked effects on the absolute bioavailability. The correlation between areas under the plasma concentration time curves (AUC) and dose levels is linear in most species up to a dose of 50 mg/kg/d. CsA steady state plasma levels are generally 2 to 3 times higher than after single administration. Measures to reduce CsA nephrotoxicity must consider possible changes of oral bioavailability and immunosuppressive activity as shown for dmPGE2. Drug interactions may be predicted in animal experiments.

16,16-Dimethylprostaglandin E2↗
PubMed1986

PGE2 reduces nephrotoxicity and immunosuppression of cyclosporine in rats.

Acute cyclosporine nephrotoxicity is characterized by the dose-dependent reduction of glomerular filtration rate both in patients and experimental animals. Administration of a vasodilator agent such as PGE2 might prevent glomerular vasoconstriction and hence reduce cyclosporine nephrotoxicity. The results of the present investigation in spontaneously hypertensive rats indicate that a synthetic PGE2 prevents cyclosporine nephrotoxicity. Pharmacokinetic studies revealed that CSA plasma peak levels and area under the plasma concentration-time curve were significantly decreased in PGE2 treated rats, indicating reduced bioavailability of oral CSA. Furthermore, the immunosuppressive effect of CSA was completely abolished by concomitant PGE2 administration. In summary, the preventive effect of a synthetic PGE2 analogue on CSA nephrotoxicity in rats is most likely due to a reduced enteral absorption of CSA, resulting in insufficient immunosuppression.

Animals↗
PubMed1986

Nephrotoxicity of cyclosporine in spontaneously hypertensive rats: effects on blood pressure and vascular lesions.

Cyclosporine (CSA) caused functional and morphologic renal changes in spontaneously hypertensive rats. The development of hypertensive arterial lesions were accelerated by CSA. Blood pressure was significantly increased especially in young rats. The influence of age of the animals, dose and duration of CSA administration on the development of vascular lesions and blood pressure was investigated.

Animals↗
PubMed1986

Problems of cyclosporine localization in the renal tissue.

The aim of the present investigation was to localize cyclosporine (CSA) in the rat kidney. The experimental approaches included autoradiography after i.v. injection of 3H-CSA, immunofluorescence after i.v. injection of fluorochrome labeled CSA and immunohistochemistry using the rabbit-alpha-CSA antibody. It was not possible to localize CSA in specific structures of the rat kidney. Finally, immunohistochemistry of human renal tissue gave only an unspecific staining of proximal tubular cells, which was lost when the antibody was absorbed on renal tissue homogenate. In vitro binding of 3H-CSA on renal homogenate indicated only unspecific absorption of the highly lipophilic compound; no specific binding was detected on cytosolic renal fractions. The failure to demonstrate CSA in tubular or arteriolar lesions might have been due to the fact that the affinity of binding is too low for detection, or that CSA does not accumulate within these structures.

Animals↗
PubMed1986

Experimental cyclosporine nephrotoxicity: risk of concomitant chemotherapy.

The role of cyclosporine (CSA) alone or in combination with various chemotherapeutics in the development of renal toxicity was evaluated in rats. Administration of 20 mg/kg/day CSA for 4 weeks caused renal functional and structural changes similar to those reported in man. The combined administration of CSA and various chemotherapeutic drugs with a nephrotoxic potential, such as gentamicin (at therapeutic doses), amphothericin B and ketoconazole, which are frequently used in immunosuppressed patients, did not aggravate the CSA induced toxicity in the rat model. Gentamicin at toxic doses, however, increased CSA nephrotoxicity. Thus, the nephrotoxicity induced by CSA has a different pathogenetic mechanism.

Amphotericin B↗
PubMed1986

Glomerulonephritis in NZB/W mice: therapeutic effect of cyclosporine.

Female NZB/W hybrid mice spontaneously develop autoimmune glomerulonephritis (GN) at the age of 3 to 6 months. The aim of the present study was to investigate the effects of cyclosporine (CS) on proteinuria and GN in mice at various stages of the disease, e.g., 12, 24 and 48 weeks of age. A 12 week course of CS (100 mg/kg/day) either abolished or prevented the development of proteinuria depending on the disease stage. Histologically, CS prevented the further development or even reversed GN. Immunoglobulin (Ig) and complement (C') deposition in the glomeruli were also reduced in CS-treated mice. These results indicate that CS has a therapeutic effect in murine autoimmune GN.

Age Factors↗
PubMed1986

Morphology of cyclosporine nephrotoxicity in the rat.

Cyclosporine (CSA) nephrotoxicity was investigated in the rat. Morphologically, CSA nephrotoxicity is characterized by the following features: (a) Tubular inclusion bodies (TIB) corresponding to autolysosomes and giant mitochondria; (b) tubular vacuolization (TV) due to dilatation of the endoplasmatic reticulum; (c) tubular microcalcification (TM); and (d) tubular regeneration (TR). The morphologic features are limited to (a and b) or predominate (c and d) in the proximal tubule. CSA tubulopathy as defined above is dose dependent, independent of the route of a drug administration, develops quickly (within a week), is reversible after CSA withdrawal, is more pronounced in male than in female rats and shows no clear cut differences in various rat strains. Body weight shows a dose dependent reduction. The functional changes are usually slight. No significant correlation exists between functional changes and morphologic lesions. The type of CSA nephrotoxicity in the rat is very similar to CSA-tubulopathy in man but associated with less severe functional changes.

Animals↗
PubMed1986

Successful treatment of autoimmunity in (NZB X NZW)F1 mice with cyclosporin and (Nva2)-cyclosporin: II. Reduction of glomerulonephritis.

Autoimmune (NZB X NZW)F1 mice were treated with the immunosuppressive agent, cyclosporin, and its new derivative (Nva2)-cyclosporin. Both compounds prevented the deposition of immunocomplexes in the kidneys, and the subsequent development of glomerulonephritis and proteinuria in young mice. They also reduced established proteinuria in old mice. Therefore, we feel that both cyclosporin and (Nva2)-cyclosporin may be useful in the treatment of human glomerulonephritis where there is an autoimmune component.

Age Factors↗