Ulrich Trechsel

N-terminal truncation of salmon calcitonin leads to calcitonin antagonists : structure activity relationship of N-terminally truncated salmon calcitonin fragments in vitro and in vivo

Structural requirements for binding to the bone calcitonin (CT) receptor and for CT bioactivity both in vitro and in vivo were assessed for a series of N-terminally truncated, N alpha-acetylated, fragments of salmon calcitonin (sCT). Sequential deletion of amino acid residues from the amino-terminus of [Ala7]sCT-(2-32) peptide amide first led to partial agonists and, upon deletion of residues 1 to 7, to a high affinity antagonist, N alpha-acetyl-sCT-(8-32)-NH2. The presence of two separate domains within the sCT sequence is proposed: (I) a binding domain comprising residues 9-32 and (II) an activation domain requiring residues 3 to 6. N alpha-acetyl-sCT-(8-32)-NH2, in several bioassays including plasminogen activator release from LLC-PK1 cells (pA2 = 7.31), cAMP production in UMR-106-06 cells (pA2 = 7.81) and in the fetal rat long bone resorption assay showed potent antagonistic properties.

Evidence for a Particularly Severe Secondary Hyperparathyroidism in Analgesic Abuse Nephropathy

Ca metabolism was compared in two groups of patients with chronic interstitial nephritis: in 21 patients (analgesic abuse nephropathy (AAN) group), nephropathy was due to exposure for 5-50 years (mean 21.1) to phenacetin-containing analgesics, whereas in 21 other patients (controls) it was due to exposure for 1-80 years (mean 21.4; NS) to other causes. Patients were followed for 2.5 +/- 0.6 and 1.6 +/- 0.6 years, respectively (mean +/- SEM; NS). Blood Ca, P, protein, creatinine, alkaline phosphatase, parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D) as well as arterial acid-base status and urinary excretion rate of Ca, P and creatinine were determined serially. Results were included only when P was maintained between 0.7 and 1.9 mmol/l. The range of creatinine levels studied was 95-1,600 mumol/l. No differences were found between the two groups with respect to creatinine clearance, blood P, protein, arterial pH and bicarbonate, and urinary excretion rates of Ca and P. Mean plasma Ca was significantly lower, and PTH was significantly higher in the AAN group than in the control group; mean plasma alkaline phosphatase activity was also significantly higher in the AAN group. In both groups Ca was negatively correlated with creatinine, but the slope of the regression line was steeper in the AAN group than in controls. The degree of hypocalcemia was related to the increase in plasma PTH and alkaline phosphatase, but not to the plasma level of 25(OH)D or 1,25(OH)2D.(ABSTRACT TRUNCATED AT 250 WORDS)