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M Azria

Publications and source records attributed to M Azria.

7 recordsLinked to original sources
PubMed1992

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.

Acetylation↗
PubMed1992

Endogenous production of specific antibodies does not decrease hypocalcemic response to calcitonin in young rabbits.

In order to evaluate the potential inhibition of the acute anti-osteoclastic activity of salmon calcitonin (SCT) by specific antibodies (Ab), we compared the SCT-induced hypocalcemic effect in young male rabbits with significant titers of high affinity Ab and in matched animals without Ab. Immunization of rabbits was performed by repetitive s.c. injections of SCT and Freund adjuvant. Ab were present in four-fifths of SCT-treated rabbits (Ab+). Their titer varied from 0.8 x 10(-9) to 30 x 10(-9) M/liter and their constant of affinity from 0.97 x 10(9) to 4.2 x 10(9) L/M. Intravenous injection of 1 IU/kg SCT to Ab+ rabbits induced a significant decrease (P less than 0.01) of ionized serum calcium (Ca2+) after 30 minutes (mean +/- SD: -9 +/- 0.6%) and until the 240th minute of the test (-16.7 +/- 4.7%), with a maximum after 120 minutes (-22.6 +/- 2%). This was not significantly different from the hypocalcemic effect measured after the same procedure performed in matched animals without Ab (Ab-): significant decrease in Ca2+ (P less than 0.01) after 30 minutes (-8.2 +/- 2.2%), maximal after 150 minutes (-23.2 +/- 4.9%), and lasting until 210 minutes (-14.5 +/- 3.7%). We conclude that, in the particular model of the male young rabbit, specific anti-SCT Ab do not block or reduce the acute anti-osteoclastic activity of SCT.

Animals↗
PubMed1987

The effect of rectal and nasal administration of salmon calcitonin in normal subjects.

In order to ascertain the blood levels and the biologic responses obtained after administration of two noninjectable forms of salmon calcitonin (SCT) (i.e., a nasal spray and a suppository), two doses of 200 IU each were administered at 3 hour intervals nasally to 8 normal subjects, and rectally to 9 normal subjects. Five untreated subjects served as controls. All were given a standardized diet for 2 days before the test. Plasma salmon-calcitonin, ionized calcium, phosphate, sodium, proteins, creatinine, and alkaline phosphatase were measured repeatedly after the administration of the drug. Modifications in fractionated urinary calcium, phosphate, sodium, and creatinine excretions (and hydroxyproline for the 8 subjects treated by the nasal spray) were compared with the values measured on the previous day. Plasma concentrations of SCT were found to increase sharply with both routes of administration, the peaks being high and short after rectal administration, low but more sustained after nasal application. Despite these differences, almost similar biologic effects could be demonstrated: transient hypocalcemia, increased calciuria, phosphaturia, and natriuria. Urinary hydroxyproline excretion decreased. Plasma sodium did not increase, whereas it did in the controls. In conclusion, nasal sprays and suppositories of SCT appear to exert the known biologic effects of SCT, and might be favored for long-term treatment in diseases representing indications for calcitonin therapy.

Administration, Intranasal↗
PubMed1987

Effectiveness of salmon calcitonin administered as suppositories in tumor-induced hypercalcemia.

Although calcitonin is a natural, nontoxic, and rapid inhibitor of bone resorption, its use in the treatment of hypercalcemia is limited because of its transient efficacy and the need for repeated parenteral administration. In normal subjects, suppositories of calcitonin have been shown to be biologically active. Peak plasma concentrations of salmon calcitonin after rectal administration in six normal subjects were similar to those measured after parenteral administration. To evaluate the efficacy of calcitonin suppositories in disease states, 10 patients with moderate hypercalcemia due to malignancy were treated with salmon calcitonin, administered as suppositories containing 300 MRC units, three times a day for seven days. The mean plasma calcium level decreased significantly from 2.96 +/- 0.09 mmol/liter to 2.57 +/- 0.09 after one week (p less than 0.005) and rose again after discontinuation of treatment to 2.86 +/- 0.09 mmol/liter one week later. Urinary calcium and hydroxyproline values decreased during treatment and rose after discontinuation of treatment. The plasma calcium level decreased rapidly in six patients, becoming normal in five; three patients showed only a partial response, and one patient had no response at all. No side effects were observed, and clinical improvement was noted in nine of the 10 patients. Little or no response was observed in patients with extremely high urinary calcium or, to a lesser extent, high hydroxyproline excretion. There was a significant negative correlation between the maximal decrease in plasma calcium concentration and initial urinary calcium excretion (r -0.78, p less than 0.01). Thus, salmon calcitonin administered by the rectal route appears to be an easy, safe, and effective treatment of moderate hypercalcemia without apparent side effects.

Administration, Rectal↗
PubMed1985

Decreased responsiveness to chronic salmon calcitonin treatment in rat kidney and calvaria studied using quantitative enzyme cytochemistry.

Growing rats were treated with daily im doses of salmon calcitonin (sCT) (2, 15 and 100 IU/kg) for various times (1, 4 and 24 weeks). The effects on intracellular enzyme activities in bone and kidney were monitored using quantitative cytochemical methods previously developed for the identification of specific target tissue responses to calcitonins. The basal alkaline phosphatase activities in both kidney and bone were decreased by long-term treatment at all time periods and doses tested. No change was noted in basal Ca ATPase activities in kidney after treatment. The capacity of target tissues in chronically treated and control rats to respond to an acute iv dose of sCT was also compared. Acute provocation tests in treated and control rats showed that the renal alkaline phosphatase response was decreased in the rats receiving long-term treatment. Moreover, the direction of response was reversed in chronically treated rats when bone alkaline phosphatase and renal Ca-dependent ATPase activity was measured after acute provocation with sCT, i.e. bone alkaline phosphatase was stimulated instead of being inhibited and renal Ca ATPase was inhibited instead of being stimulated. The application of quantitative cytochemical techniques has demonstrated intracellular changes in enzyme activities in both kidney and bone. The impaired sCT responsiveness can be detected at shorter times of treatment (1 week) and lower doses (2 IU/kg) than has previously been possible by measurement of indices of mineral metabolism in plasma or urine.

Alkaline Phosphatase↗
PubMedDate not supplied

Disposition of sandostatin, a new synthetic somatostatin analogue, in rats.

The distribution, excretion, and metabolism of Sandostatin, a long-acting octapeptide analogue of somatostatin, have been studied in the rat after iv administration. Similar plasma levels and excretion values were observed by using radioimmunoassay and HPLC-liquid scintillation techniques. For the latter technique Sandostatin was radiolabeled with either 14C or 3H. The plasma pharmacokinetics of Sandostatin were as follows: Vdss = 0.4 liter/kg, C/t = 4.2 ml/min, and t1/2 2.0 hr; this half-life was by far longer than that of somatostatin. The in vitro protein binding amounted to 59% in rat plasma; no Sandostatin was taken up by blood cells. The tissue concentrations of Sandostatin were similar when determined either by radioimmunoassay or by quantitative whole-body autoradiography; this suggests that the distribution of 3H or 14C radioactivity observed 0.5 hr after iv administration mostly represented unchanged Sandostatin. Kidney and liver were the only tissues in which Sandostatin levels were higher than in blood; high radioactivity levels were observed in the blood vessel walls, whereas levels in brain were insignificant. Unchanged drug accounted for most of the radioactivity found in plasma, urine, and bile, whereas only traces of unchanged drug were detected in feces. These results demonstrated the metabolic stability of Sandostatin in the tissues, primarily in the liver, and suggested an extensive degradation in the intestinal tract. The degradation products consisted of smaller peptides and free amino acids. About 50% and 20% of the applied dose were excreted as unchanged Sandostatin in bile and urine, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗