Circadian rhythm and pulsatility of parathyroid hormone secretion in man

OBJECTIVE: We wished to investigate the circadian rhythm and pulsatility of parathyroid hormone (PTH) secretion in man, as conflicting results have been published. DESIGN AND PATIENTS: To investigate the circadian rhythm during daytime, we sampled (a) peripheral blood at hourly intervals in 12 healthy young men from 0900 h until 1700 h. For observation of pulsatility, we sampled (b) peripheral blood at 1-minute intervals for 1 hour in three healthy men and three healthy women (mean 27.7 years, range 21-56 years) and (c) at 1-minute intervals for 30 minutes in 21 patients with surgically confirmed primary hyperparathyroidism (pHPT). MEASUREMENTS: The serum levels of intact PTH were measured by two-site immunoradiometric assay and special care was taken to reduce intra-assay variability, especially at the normal PTH concentration. In series (a), ionized calcium, total calcium and phosphate were also determined. RESULTS: A circadian rhythm during daytime was found for intact PTH in healthy men and women with a nadir at 0930 h and a peak in the afternoon. Ionized calcium and total calcium (protein-adjusted) decreased and phosphate increased in the afternoon. These changes were all statistically significant (P < 0.02). Pulsatility of PTH: Statistical cluster analysis of the data showed no pulsatility either in healthy persons or in patients with primary hyperparathyroidism. In two healthy women and one healthy man slight changes of longer duration were discovered, but no complete pulses. In five patients with primary hyperparathyroidism, larger differences between the highest and lowest concentrations of intact PTH were found, but no complete pulses. CONCLUSIONS: Our data show a significant circadian rhythm during daytime of intact PTH and only minor changes from minute to minute. The alterations in PTH-levels occurred at longer time intervals in healthy persons. In some patients with primary hyperparathyroidism, decreases of PTH-levels were found. The circadian rhythm of PTH may be due to slight changes in calcium or phosphate concentration.     

Disposition of oral and intravenous pravastatin in MRP2-deficient TR- rats.

The aim of this study was to characterize the role of the efflux transporter Mrp2 (Abcc2) in the pharmacokinetics of orally and intravenously administered pravastatin in rats. Eight Mrp2-deficient TR- rats and eight wild-type rats were given an oral dose of 20 mg/kg pravastatin. Four TR- animals and four wild-type animals were studied after intravenous administration of pravastatin (5 mg/kg). The TR(-) rats showed a 6.1-fold higher mean area under the plasma concentration-time curve (AUC) of pravastatin (p < 0.001) after oral administration and a 4.7-fold higher AUC (p < 0.01) after intravenous administration of pravastatin as compared with the wild-type animals. The mean systemic (total) clearance of pravastatin was 4.6-fold higher (39.2 versus 8.50 l/h/kg, p < 0.001) and the mean V 4.3-fold higher (14.1 versus 3.29 l/kg, p < 0.01) in the wild-type rats. The mean renal clearance of pravastatin in the TR(-) rats was 16.5-fold increased as compared with the wild-type animals (0.695 versus 0.042 l/h/kg, p < 0.05). The increased systemic exposure to oral pravastatin in the TR- rats was associated with a greater inhibitory effect on 3-hydroxy-3-methylglutaryl CoA reductase, as shown by smaller lathosterol to cholesterol concentration ratios. These results suggest that the reduced biliary pravastatin excretion in the Mrp2-deficient TR- rats is partly compensated for by increased urinary excretion of pravastatin. Furthermore, intestinal Mrp2 does not appear to play a major role in the oral absorption of pravastatin in normal rats.     

In vitro and in vivo effects of BT563, an anti-interleukin-2 receptor monoclonal antibody

Abstract BT563, a murine anti-IL-2R MoAb, was found to be more potent than anti-Tac in inhibiting proliferation in the mixed lymphocyte reaction. Results obtained with 33 B3.1 in these experiments were similar to those with BT563. The anti-IL-2R MoAb 2A3 was shown to be a suitable agent for monitoring the effect of BT563 on peripheral blood. IL-2R-positive cells were not detected in peripheral blood samples from 1 h after the first dose until 8 days after the last dose. Plasma trough levels were measured in patients receiving 5 or 10 mg daily. The administration of BT563 to allograft recipients did not lead to clinically significant side effects.     

Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage.

We tested the hypothesis that astrocytic matrix metalloproteinase-9 (MMP-9) mediates hemorrhagic brain edema. In a clinical case of hemorrhagic stroke, MMP-9 co-localized with astrocytes and neurons in peri-hematoma areas. In a mouse model where blood was injected into striatum, MMP-9 was colocalized with astrocytes surrounding the hemorrhagic lesion. Because MMP-9 is present in blood as well as brain, we compared four groups of wild type (WT) and MMP-9 knockout (KO) mice: WT blood injected into WT brain, KO blood into KO brain, WT blood into KO brain, and KO blood into WT brain. Gel zymography showed that MMP-9 was elevated in WT hemorrhagic brain tissue but absent from KO hemorrhagic brain tissue. Edematous water content was elevated when WT blood was injected into WT brain. However, edema was ameliorated when MMP-9 was absent in either blood or brain or both. To further assess the mechanisms involved in astrocytic induction of MMP-9, we next examined primary mouse astrocyte cultures. Exposure to hemoglobin rapidly upregulated MMP-9 in conditioned media within 1 to 24 h. Hemoglobin-induced MMP-9 was reduced by the free radical scavenger U83836E. Taken together, these data suggest that although there are large amounts of MMP-9 in blood, hemoglobin-induced oxidative stress can trigger MMP-9 in astrocytes and these parenchymal sources of matrix degradation may also be an important factor in the pathogenesis of hemorrhagic brain edema.