| 1. |
- Wanders, A., et al.
(författare)
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Abolition of the effect of cyclosporine on rat cardiac allograft rejection by the new immunomodulator LS-2616 (Linomide)
- 1989
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 47:2, s. 216-7
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Tidskriftsartikel (refereegranskat)abstract
- The effect of the quinoline-3-carboxamide LS-2616 (Linomide), given alone or together with cyclosporine, was studied in the first set cardiac allograft transplantation model in the rat. PVG rat hearts were transplanted heterotopically to Wistar/Kyoto rat recipients on day 0. The recipients were given LS-2616 orally on day -1 to rejection and/or CsA orally on days 0-9. In untreated animals rejection occurred on days 8-9, as judged by the absence of palpable pulsations. Treatment with CsA (5 or 10 mg/kg) resulted in prolongation of graft survival to days 17-21, i.e., the rejection occurred 8-10 days after cessation of treatment. LS-2616 in a dose of 160 mg/kg did not in itself have any impact on graft survival, but when given in doses of 40 or 160 mg/kg simultaneously with CsA (10 mg/kg), the effect of CsA was totally abolished. Animals treated with LS-2616 together with CsA had slightly lower trough blood levels than those treated with CsA alone. This interaction with CsA pharmacokinetics does not explain the results, as doubling of the CsA dose to 20 mg/kg, which well compensated for the difference in blood levels, was not sufficient to reverse the effect of LS-2616. To our knowledge this is the first compound known to abolish the effect of CsA. The mechanism is unknown, but is is possible that studies on the interaction between these two drugs will shed further light on the molecular basis of their modes of action.
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| 2. |
- Wanders, A., et al.
(författare)
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Effect of LS-2616 on the graft protection achieved by cyclosporin A, prednisolone, and 15-deoxyspergualin in heart-transplanted rats
- 1992
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Ingår i: Transpl Int. ; 5 Suppl 1, s. S462-3
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Tidskriftsartikel (refereegranskat)abstract
- The immunostimulator LS-2616 abolishes the effect of cyclosporin A in a rat cardiac transplantation model. The present paper compares the characteristics of rejection obtained under different immunosuppressive regimens with and without additional LS-2616 application in the same model. Cyclosporin A (CyA, 10 mg/kg daily), prednisolone (15 mg/kg daily), or 15-deoxyspergualin (2, 5, or 10 mg/kg daily), all given from the day of transplantation until day 9, protected the grafts during the treatment period. The addition of LS-2616 (160 mg/kg, day -1 until stop) resulted in a total abrogation of the immunosuppressive effect of CyA and prednisolone. However, LS-2616 could only partially or not at all reverse the effect of 15-deoxyspergualine. These results show a certain drug selectivity of LS-2616 in promoting rejection of immunosuppressed allografts. Further studies with LS-2616 may be of benefit in evaluating the mode of action of different immunosuppressive compounds and, thus, contribute to finding more effective antirejection therapies.
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| 3. |
- Wanders, A., et al.
(författare)
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Effects of prostaglandin E2 (PGE2) and drugs affecting PGE2 degradation on acute rejection of rat cardiac allografts
- 1992
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Ingår i: Scand J Thorac Cardiovasc Surg. ; 26:1, s. 33-7
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Tidskriftsartikel (refereegranskat)abstract
- Systemic administration of prostaglandin E2 (PgE2) has been reported to prolong graft survival of heart transplants. We investigated the influence of systemic injection of two compounds which inhibit the endogenous degradation of PgE2 (CL42A and CL68A) and of local infusion of PgE2 into the transplant on the survival time of rat cardiac allografts. Both CL42A and CL68A gave increased graft survival time in two rat strain combinations, though this was not predictable in individual rats. Locally infused PgE2 gave slight, but not significant prolongation of graft survival in some recipients. Combined PgE2 and cyclosporin A, however, gave significant prolongation of graft survival time compared with cyclosporin A treatment alone. When local PgE2 treatment was begun 5 days after transplantation, graft survival time was prolonged in almost all the rats. Manipulation of the local PgE2 concentration thus seemed to have a positive effect on graft survival, possibly due to down-regulation of certain cells of the immune system by PgE2.
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| 4. |
- Wanders, A., et al.
(författare)
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Evidence that LS-2616 (linomide) causes acute rejection of rat allografts protected by cyclosporine but not of long-term surviving allografts
- 1991
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 52:2, s. 234-8
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Tidskriftsartikel (refereegranskat)abstract
- The immunomodulator LS-2616 (Linomide) induces rejection of cyclosporine-protected rat cardiac allografts. The aim of this study was to characterize this rejection in the presence of CsA and to test LS-2616 in other models of permanent graft acceptance in the rat. PVG rat hearts were transplanted heterotopically to Wistar/Kyoto (Wi/Ky) rat recipients on day 0. The recipients were treated orally on days 0-9 with CsA (10-40 mg/kg) and/or with LS-2616 (2.5-160 mg/kg) starting at different times (day -7 -+5) until the day of complete rejection. The addition of LS-2616 (day -1--stop) to CsA (10 mg/kg) resulted in a dose-dependent antagonism of the immunosuppressive effect of CsA with daily doses of 2.5-160 mg/kg. Furthermore, the results were similar, irrespective of whether LS-2616 treatment (160 mg/kg) was started on day -7, -1, +1, +3, or +5. LS-2616 (160 mg/kg) pretreatment of the recipient for 7 days before transplantation was considerably less effective. CsA (20 mg/kg) for 14 days after a PVG to DA transplantation resulted in permanent graft survival. This was not abrogated by LS-2616. Neither was rejection induced in long-term surviving grafts of RT1.C incompatible Lewis recipients. Our data suggest that LS-2616 activates already stimulated and sensitized T cells that are otherwise controlled by CsA.
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| 5. |
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| 6. |
- Wollert, S, et al.
(författare)
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Inhibition of CD18-dependent adherence of polymorphonuclear leukocytes does not affect liver oxygen consumption in fecal peritonitis in pigs.
- 1993
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Ingår i: Circulatory shock. - 0092-6213. ; 41:4, s. 230-8
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Tidskriftsartikel (refereegranskat)abstract
- We tested the hypothesis that circulating polymorphonuclear leukocytes (PMNs), adhering to endothelium of the liver vascular bed are involved in the alterations of the liver oxygen delivery (DO2) and consumption (VO2) that is a result of fecal peritonitis in pigs. Twenty-two pigs were divided into three groups. Animals in group I (n = 7) served as controls. Fecal peritonitis was induced in groups II (n = 7) and III (n = 8). Animals in group III were pretreated with IB4, a monoclonal anti-CD18 antibody inhibiting adherence of PMNs to the endothelium. Peritonitis increased liver VO2 in groups II and III in spite of decreased liver DO2. In group I, circulating PMNs increased during the experimental period. Sepsis caused a decrease in the number of circulating PMNs in group II, an effect that was fully counteracted in group III, where the number of PMNs rose to control level. Myeloperoxidase activity and morphometric determination of PMN infiltration in liver biopsies virtually paralleled the circulating PMN count. Although fecal peritonitis is followed by a CD18-dependent leukopenia that can be counteracted by pretreatment with an anti-CD18 antibodies, this treatment does not affect the alteration in liver VO2 and DO2 observed.
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| 7. |
- Ahrenstedt, O, et al.
(författare)
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Increased luminal release of hyaluronan in uninvolved jejunum in active Crohn's disease but not in inactive disease or in relatives.
- 1992
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Ingår i: Digestion. - 0012-2823 .- 1421-9867. ; 52:1, s. 6-12
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Tidskriftsartikel (refereegranskat)abstract
- Recently obtained data suggest that there is a subclinic inflammatory activity in the apparently uninvolved intestinal mucosa in Crohn's disease (CD). As CD is characterized by an activation of connective tissue and fibrosis, we investigated the extent to which hyaluronan (HA), an essential component of the connective tissue, was released into the lumen of an isolated jejunal segment in CD patients and in relatives. Patients with active CD of the terminal ileum (CD activity index, CDAI, > 150; n = 14), patients with CD in remission (CDAI < 150 n = 10), first-degree relatives of the CD patients (n = 21) and healthy controls (n = 43) were orally intubated with a catheter allowing occlusion and perfusion of a segment of the proximal jejunum. The jejunal fluid concentration of HA was 65 +/- 45 micrograms/l in patients with active CD in the terminal ileum, significantly higher than the value for 43 healthy controls (42 +/- 23 micrograms/l; p < 0.05), and the corresponding values for patients in remission (42 +/- 23 micrograms/l) and for first-degree relatives of the CD patients (53 +/- 52 micrograms/l), were not increased compared to the control group. To localize HA in the tissue, small bowel biopsies were taken during surgery from patients with CD and from controls and affinity stained for HA. There was an intense staining for HA in the lamina propria of the villi, both in biopsies from patients with CD and from controls, but no staining in the epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)
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| 8. |
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| 9. |
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| 10. |
- Belew, M, et al.
(författare)
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Structure-activity studies on synthetic analogs to vasoactive peptides derived from human fibrinogen.
- 1980
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Ingår i: Biochimica et Biophysica Acta. - 0006-3002 .- 1878-2434. ; 632:1, s. 87-94
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Tidskriftsartikel (refereegranskat)abstract
- Counterparts to two vasoactive peptides previously isolated from fibrin(ogen) degraded by plasmin (EC 3.4.21.7) were synthesized by the solid phase procedure. The synthetic undecapeptide (Ser-Gln-Leu-Gln-Lys-Val-Pro-Pro-Glu-Trp-Lys) was isolated in a homogeneous state by chromatography on Sephadex G-25 and DEAE-Sepharose CL-6B and the pentapeptide (Ala-Arg-Pro-Ala-Lys) by chromatography on BioGel P-6 and column zone electrophoresis. The effect of these two peptides and of fifteen analogs to the pentapeptide on microvascular permeability in rat skin was investigated. The two synthetic counterparts were as potent as the natural peptides. With respect to the analogs, the influence of different functional groups was first studied. This was followed by attempts to minimize the active structure, induce or relieve rigidity of the peptide back-bone or otherwise accomplish modifications by a change in chirality at critical positions. Our results show that the tetrapeptide Arg-Pro-Ala-Lys has the same effect on microvascular permeability as the pentapeptide in the assay system used. Basic amino acids at both ends, as well as a proline residue adjacent to the N-terminal amino acid appear important for full or essentially full activity. On the other hand, substitution of the Ala at position 4 with several other amino acids did not result in a significant loss in biological potency.
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