Elevated serum erythropoietin concentration is associated with coordinated changes in red blood cell and reticulocyte indices of pregnant women at term.

The aim of this study was to evaluate the relationship between the erythropoietin (EPO) concentration and both the advanced cellular indices reflecting the haemoglobin contents of red blood cells and reticulocytes and the serum markers of iron status. The study population comprised pregnant women at term (n = 210). The serum EPO, transferrin receptor (TfR), ferritin, the percentages of hypochromic red blood cells (%HYPOm) or reticulocytes (%HYPOr) and the cellular haemoglobin in mature red blood cells (CHm) or in reticulocytes (CHr) were measured in maternal blood before delivery. The EPO concentration was elevated above the reference limit (>31.5 mIU/mL) in 16 % of all pregnant women, and appeared to correlate in a linear fashion, especially with %HYPOm (r = 0.52, p<0.001), %HYPOr (r = 0.57, p<0.001) and CHr (r = -0.45, p<0.001). The significant (p<0.05) predictors of EPO in the multivariate stepwise regression analysis were %HYPOr, Hb, %HYPOm and MCV. In general, the lower the cellular haemoglobin content, the higher the overall maternal EPO production. In conclusion, elevated %HYPOm and %HYPOr reflecting iron-deficient erythropoiesis are associated with an increase in EPO concentration in maternal blood. This could be explained by subclinical iron deficiency being accompanied by a compensatory EPO response.

In patients who have stainable iron in the bone marrow an elevated plasma transferrin receptor value may reflect functional iron deficiency.

Elevated transferrin receptor (TfR) concentration may be either because of iron deficiency or an increased rate of erythropoiesis. We have studied the relationship between elevated TfR and advanced RBC and reticulocyte indices in an unselected population of hospitalized patients. The iron status in 95 consecutive hospitalized patients was assessed using bone marrow aspirate examination and analysis of the RBC and reticulocyte indices was performed using the Advia 120 haematology system. Of the 95 patients, a total of 17 had no stainable iron in the bone marrow and most of them also had an elevated TfR. Of the 78 patients with stainable iron stores, 15 also had an elevated TfR concentration (> or =2.4 mg/l). Six of them also had an elevated %HYPOm (> or =3.4%), and therefore were regarded as having functional iron deficiency. We evaluated the possible causes of elevated TfR concentrations in patients having stainable iron in the bone marrow, and this study suggests that functional iron deficiency explains a considerable proportion of these cases.

Effect of intracerebral 6-nitronoradrenaline, an endogenous catechol-O-methyltransferase (COMT) inhibitor, on striatal dopamine metabolism in anaesthetised rats.

6-Nitronoradrenaline, a bioactive compound recently identified in the brain, is known to inhibit catechol-O-methyltransferase. To study its effect on dopamine metabolism, it was administered into rat striatum via a microdialysis probe. Other nitrated catechols (6-nitrodopamine, 6-nitro-DOPAC and 5-nitro-HVA) were studied for comparison. Tolcapone, a selective catechol-O-methyltransferase inhibitor, was used as a positive reference compound. Both 6-nitronoradrenaline and tolcapone increased striatal extracellular dopamine levels during the perfusion (at 100 microM concentration but not at 10 microM) and decreased the efflux of homovanillic acid. Tolcapone, but not other nitrated catechols, increased 3,4-dihydroxyphenylacetic acid efflux. None of the compounds inhibited MAO-B activity at 100 microM or lower. At 1 mM, 6-nitrodopamine inhibited MAO-B by 60%. Compared to tolcapone, other nitrated catechols were very weak COMT inhibitors in vitro. Neither tolcapone nor 6-nitronoradrenaline modified the metabolism of L-dopa which was given peripherally. In binding studies, both 6-nitronoradrenaline and other nitrocatechols failed to affect the dopamine transporter even at high micromolar concentrations. In conclusion, exogenous 6-nitronoradrenaline can act as a COMT inhibitor in the striatum and elevate striatal dopamine levels without inhibiting dopamine reuptake. Whether endogenous 6-nitronoradrenaline can be formed also in vivo in the striatum and act as a regulator of dopaminergic tone remains to be determined.

Synthesis and in vitro pharmacology of a series of new chiral histamine H3-receptor ligands: 2-(R and S)-Amino-3-(1H-imidazol-4(5)-yl)propyl ether derivatives.

To investigate stereospecificity and the mechanism of activation of the histamine H3-receptor, a series of 2-(R and S)-amino-3-(1H-imidazol-4(5)-yl)propyl ether derivatives were synthesized. In these compounds, the structures of the well-known antagonist iodoproxyfan and the full agonists R- or S-(alpha)-methylhistamine were combined in one molecule. The obtained "hybrid" molecules were tested for H3-receptor affinity on rat cerebral cortex. Some selected compounds were further screened for H3-receptor functional activity with GTPgamma[35S] autoradiography studies using rat brain tissue sections. The affinity of all the synthesized compounds (-log Ki = 5.9-7.9) was lower than that found for iodoproxyfan or two of its analogues; however, the compounds showed stereospecificity. The S-configuration of the series of 2-amino-3-(1H-imidazol-4(5)-yl)propyl ether derivatives, which resembles the stereochemistry of R-(alpha)-methylhistamine, was more favorable. Incorporation of an amino group in the propyl chain of iodoproxyfan and analogues did not alter the antagonistic behavior for compounds with an aromatic side chain. However, when also the aromatic moiety was replaced by a cyclohexyl group, the compounds behaved as agonists. This indicates that an interaction between the side chain amino group and the H3-receptor protein is involved in H3-receptor activation. The 2-(S)-amino-3-(1H-imidazol-4(5)-yl)propyl cyclohexylmethyl ether (23) has H3-receptor agonistic properties with high affinity for the histamine H3-receptor (-log Ki = 7.9 +/- 0.2) and might serve as a useful tool for further studies concerning drug design and receptor-ligand interactions.