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EN
We evaluated the influence of cyclosporin A (CsA) used alone or together with new purine nucleoside analogues (PNAs): 2-chlorodeoxyadenosine (2-CdA) and fludarabine (F-ara-A) on the colony growth of normal and chronic myelogenous leukemia (CML) granulocyte-macrophage progenitor cells (CFU-GM) in cultures in vitro. The assay was based on the method described by Iscove et al. in our modification. Specimens of bone marrow were collected from 15 patients with CML in the chronic phase and from 10 hematologically normal patients. CsA at the concentrations of 1, 2 and 4 mug/ml was used alone and at the concentration of 4 mug/ml it was preincubated with MNCs and after 30 minutes PNAs were added to the culture medium. 2-CdA at the concentrations of 5, 10, 20 nM and 0.4, 0.8, 1.6 muM of F-ara-A were used. After 14 days of incubation the colonies were scored under inverted microscope. We observed that CsA used alone at all three concentrations in a statistically significant degree inhibited the colony growth of CML CFU-GM, as compared to the control (p<0.02) and it did not significantly influence the normal colony growth. IC50 for CsA was 3.9 mug/ml in case of normal CFU-GM and 2.7 mug/ml in case of CML CFU-GM. After the use of CsA in combination either with the highest concentrations of 2-CdA or F-ara-A, statistically significant differences, as compared to CsA used alone were observed (p=0.008; p=0.03 for CsA with 2-CdA; and p=0.0007; p=0.005 for CsA with F-ara-A; respectively for normal and CML CFU-GM). However, there were no significant differences between the combinations of drugs and PNAs used alone. In case of the combination of CsA with the highest concentrations of both PNAs significant differences in the colony growth inhibition between normal and CML CFU-GM were observed (p=0.002 and p=0.005, respectively for 2-CdA and F-ara-A). In conclusion, at the used concentrations of the drugs a subadditive action was observed either between CsA and 2-CdA or between CsA and F-ara-A.
EN
In attempt to avoid a detrimental synergism between CsA and renal ischemia in the immediate postoperative perion, ALG (425 limphocytotxic units/kg) with small doses of CsA (6-8 mg/kg) and P were applied as the initial immunosuppressive therapy in 14 recipients of cadaveric kidneys. ALG was administered for 5 to 14 days and 2 days before withdrawing ALG, Aza (2 mg/kg) was intorduced. Results of this protocol were compared with those of 19 pts treated with CsA (12 mg/kg) and P. All the pts were followed for at least 12 months. The duration of was significantly reduced in the ALG/CsA/P group (psmaller than 0.02). The sCr concentration after 12 months of observation was significantly lower(p smaller than 0.05), no alterations in urinalysis were detected. the number of was decreased. The acute rejection rates were equivalent in both groups, however 3 of 4 rejections in ALG/CsA/P group were resistant to steroids and occurred in pts with shortened period of ALG administration. The one year patient and graft survival in the ALG/CsA/P and control groups were respecitvely: 78.5%, 71.4% and 89.4%, 78.9%. Severe infectious complications in the group treated with ALG/CsA/P occurred in pts who were subsequently treated with OKT3.
EN
Kynurenic acid (KYNA), the only known endogenous glutamate antagonist, is produced in the brain by kynurenine aminotransferases (KATs) I and II. Mitochondrial toxins, 1-methyl-4-phenylpyridinium (MPP+) and 3-nitropropionic acid (3-NPA), were previously shown to reduce KYNA synthesis via interference with KAT I and II. Data presented here demonstrate that immunophilin ligand, FK506 (10-130 muM), but not CsA (1-50 muM), or ryanodine receptor blocker, dantrolene (1-100 muM), enhances the formation of KYNA in cortical slices. FK506, but not CsA or dantrolene, abolished the inhibition of KYNA synthesis evoked by MPP+ and 3-NPA. None of studied compounds influenced the activity of KAT I and KAT II. FK506 is the first among currently used drugs that might stimulate KYNA synthesis. This effect does not seem to arise from the interference with KATs or calcineurin activity.
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