[Effect of interventive measures on drug compliance. Results of a clinical study].
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Attitude to Health↗
Biomedical subjects
E Weber
Publications and source records attributed to E Weber.
Levels of pro-neo-endorphin/dynorphin-derived peptides in the hypothalamo-posterior pituitary system of male and female Brattleboro rats.
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Animals↗
Immunoreactive dynorphin-(1-8) and corticotropin- releasing factor in subpopulation of hypothalamic neurons.
Immunoreactive corticotropin-releasing factor (CRF) and dynorphin-(I-8) were visualized in rat hypothalamus by immunohistofluorescence with specific antibodies. In brains from colchicine-treated, adrenalectomized rats, neuronal perikarya with immunoreactive CRF were observed in the paraventricular nucleus of the hypothalamus. The CRF occurred together with the dynorphin-(1-8). However, the CRF immunoreactivity occurred only in a subpopulation of the dynorphin-(1-8) immunoreactive cells. These findings suggest that there may be a functional interrelationship of CRF with dynorphin-related opioid peptides and provide further evidence that neurons may contain more than one bioactive substance.
Animals↗
Biological and biochemical characterization of an interleukin 1-like factor from rat C6 glioma cells.
It has been previously reported that lipopolysaccharide-stimulated murine astrocytes produce a factor which enhances the proliferative response of thymocytes to lectins. The present report demonstrates that a rat astrocytoma cell (C6 cells)-derived factor appears to be similar to macrophage-derived interleukin 1 (IL 1) in its biological activities and biochemical characteristics. Upon injection into mice, supernatants of C6 cells induce the production of serum amyloid A. The C6 cell-derived factors enhance the response of thymocytes to phytohemagglutinin and the growth of fibroblasts whereas no effect on the growth of neuroblasts and of a strictly interleukin 2 (IL 2)-dependent T cell line was observed. On an AcA 54 column the C6-derived factors acting on thymocytes and fibroblasts coeluted as a single peak of Mr = 13 500 to 18 000; the semipurified factor was found to enhance the lymphocytes' production of IL 2. These observations demonstrate that cells not belonging to the mononuclear phagocyte lineage are able to produce factors identical or closely related to IL 1.
Animals↗
[Characterization of the water-binding capacity of proteins].
A general method for determining the water-absorbing capacity of proteins is described. To calculate their water-absorbing capacity, the proteins are centrifuged off and then added with portions of water to determine the amount of water required for just obtaining an aqueous supernatant (in case of insoluble proteins) or for obtaining a paste which is beginning to flow (in case of soluble proteins). The correlation between the "modified centrifugation method" and the Grau-Hamm pressing method for determining the "juice loss", a method that is currently used in practice, is demonstrated by some examples.
Absorption↗
Lack of interaction between the tetracyclic antidepressant maprotiline and the centrally acting antihypertensive drug clonidine.
The well known interaction between tricyclic antidepressants and the centrally acting antihypertensive drug clonidine, namely impairment of the antihypertensive effect of clonidine, is thought to be related to blockade of noradrenaline uptake or competition at central alpha-receptors. The tetracyclic antidepressant maprotiline has been shown to be a potent inhibitor of noradrenaline uptake and it might, therefore, interfere with the antihypertensive action of clonidine. The possible interaction of clonidine and maprotiline was studied in 8 healthy subjects using doses in the therapeutic range. The study followed a double-blind, cross over design, in which clonidine alone (0.3 mg p.o.), clonidine (0.3 mg p.o.) plus maprotiline (100 mg in 4 divided doses over 22 h), maprotiline alone (100 mg in 4 divided doses over 22 h) and placebo were given by the double-dummy technique. Several pharmacodynamic parameters were measured for 12 h after administration of the drugs (supine and erect blood pressure, heart rate, saliva production and sedation). Concurrent administration of maprotiline did not alter the effect of clonidine and neither the size nor the time of the maximal response after clonidine were influenced by maprotiline. It is concluded that [1] blockade of noradrenaline uptake is not associated with the interaction of tricyclic antidepressants and clonidine, and [2] maprotiline should be preferred to tricyclic antidepressants in hypertensive patients on clonidine therapy if a concomitant depressive illness has to be treated.
Adult↗
Effect of single and multiple doses of sulphinpyrazone on antipyrine metabolism and urinary excretion of 6-beta-hydroxycortisol.
Sulphinpyrazone decreases the plasma clearance of tolbutamide and S-warfarin and increases the clearance of R-warfarin, theophylline and antipyrine. In order to determine whether sulphinpyrazone is an inducer or inhibitor or both of oxidative drug metabolism, antipyrine and its metabolites as well as 6-beta-hydroxycortisol were measured in urine before, 24 h and after 23 days of chronic administration of sulphinpyrazone (4 X 200 mg/day). During chronic treatment sulphinpyrazone increased the ratio of 6-beta-hydroxycortisol to the 17-hydroxycorticosteroids by 70% (p less than 0.02). The renal clearance of the main oxidative metabolites of antipyrine (4-hydroxyantipyrine, 3-hydroxymethylantipyrine and norantipyrine) were increased after sulphinpyrazone (p less than 0.02). Except for norantipyrine, no change in total excretion of antipyrine and its metabolites occurred after 24 h or after 23 days. It is concluded that sulphinpyrazone induces the enzymes which metabolize antipyrine and cortisol.
Adult↗
Intestinal absorption of levodopa in man.
In four healthy subjects the intestinal absorption of levodopa (l-dopa) was investigated by measuring the plasma concentration of the amino acid following the administration of l-dopa at three different sites in the small intestine. In order to minimize presystemic clearance of l-dopa, the subjects were pretreated with the peripheral decarboxylase inhibitor benserazide 3 X 50 mg every 8 h on the previous day and 1 X 50 mg 2 h prior to administration of the l-dopa. L-dopa 100 mg dissolved in 0.05 N HCl and 50 mg benserazide dissolved in 0.05 N HCl were coadministered. Under these conditions no difference in tmax, cmax or AUC of l-dopa was observed between administration of the drug into the proximal or the distal part of duodenum, or into the upper part of jejunum. The results indicate that in healthy subjects, during inhibition of peripheral decarboxylase, the rate and extent of l-dopa absorption does not differ at any site in the upper small intestine.
Adult↗
Non-linear elimination processes of theophylline.
After intravenous and oral administration of theophylline to four healthy subjects, the plasma concentration-time curve of theophylline could be described by linear pharmacokinetics, although total clearance in all subjects decreased when the dose was increased; the doses were theophylline 193.2 mg and 386.4 mg i.v. and 161 mg and 322 mg p.o. Total clearance was 65.5 +/- 11.3 ml/min. Renal clearance changed from 15.2 +/- 9.5 ml/min in the first two hours after administration to 4.9 +/- 5.5 ml/min between 16 and 24 h (p less than 0.001). 1,3-dimethyluric acid (DMU), the major metabolite of theophylline, was determined in urine and in plasma. The renal clearance of DMU was constant at 496.7 +/- 180 ml/min. There was some evidence that at high plasma concentrations of theophylline the formation of DMU might be a zero-order process. The renal excretion rate of 1-methyluric acid (1-MU) paralleled that of DMU, which is in accordance with the assumption that DMU is demethylated to 1-MU. 3-methylxanthine (3-MX) was excreted in urine at a constant rate over 10 h, the rate being equivalent to the dose, which is contrary to the assumption of Michaelis-Menten-kinetics. 3-methyluric acid was found to be a minor metabolite of theophylline and 1-methylxanthine (1-MX) could not be detected. The cumulative amounts excreted in urine, expressed as a percentage of the dose and corrected for molecular weight, were theophylline 16.6 +/- 6.5%, DMU 44.3 +/- 7.0%, 1-MU 24.3 +/- 4.8%, 3-MX 12.9 +/- 3.4% and 3-MU 2.2 +/- 1.8%.
Adult↗
Fluorographic detection of tritium-labelled proteins in immunoelectropherograms with the water-soluble fluor, sodium salicylate.
A method is described for detecting by fluorography tritium-labelled proteins in immunoelectropherograms performed on agarose gels. The technique is based on the impregnation of immunoplates with sodium salicylate immediately after electrophoresis without the formation of a mixed agarose--polyacrylamide gel prior to processing the immunoelectropherograms for fluorography. Sodium salicylate, an inexpensive and water-soluble compound, has been found to serve as a satisfactory fluor for enhanced detection of radioactivity in agarose gels.
Autoradiography↗
Dual effect of glia maturation factor on astrocytes. Differentiation and release of interleukin-1 like factors.
C6 glioma cells, and primary cultures of mouse astrocytes, stimulated with lipopolysaccharide (LPS) release an interleukin-1 like factor (IL-1) which enhances lectin-induced T-lymphocyte proliferation and promotes the release of interleukin-2 (IL-2) by ConA-stimulated thymocytes. In the present study, the glia maturation factor (GMF) was found not only to induce differentiation of glioblasts, but also to elicit the secretion of IL-1 like factors by cultured mouse astrocytes and their precursor cells. GMF was also effective in triggering IL-1 release by macrophages. Contamination of the 23 000 MW GMF preparation with LPS was excluded by the Limulus lysate assay and by using C3H/HeJ LPS-nonresponder mice whose glia and macrophages responded to GMF but not to LPS, by IL-1 release. Through its ability to induce glial differentiation and IL-1 release, GMF may represent an important endogenous signal, triggering both reactive gliosis and the development of an immune response within the central nervous system.
Animals↗
Variation of cytoplasmic rat uterine androgen receptors.
The number of testosterone binding sites present in rat uterine cytosol varied regularly during the estrous cycle, reaching a trough at metestrus and a peak at proestrus. Treating ovariectomized and adrenalectomized rats for 2 days with estradiol resulted in a 3-4-fold increase in the number of binding sites per uterus. Estradiol withdrawal induced a decrease in uterine androgen receptors. Testosterone or progesterone treatment also increased the number of these sites, but to a lesser degree. When administered together with estradiol, testosterone did not enhance the stimulatory effect of the latter, whereas progesterone even reduced it. Testosterone or progesterone did not prevent the number of receptors from declining after estradiol withdrawal. Thus the changes in the number of cytoplasmic androgen receptors in the uterus during the rat estrous cycle is mainly controlled by the rise and fall of the serum levels of estradiol.
Animals↗
Nonlinear mezlocillin kinetics due to dose-dependent metabolism.
Dose-dependent kinetics of intravenous bolus-dose mezlocillin, a newly developed ureidopenicillin, have been reported by several investigators. In eight healthy subjects we examined renal, biliary, and total clearance at different steady-state levels. After infusion of doses of 22.4 +/- 1.5, 11.4 +/- 0.7, and 5.6 +/- 0.4 mg/min mean plasma steady-state levels of 88.4 +/- 15.9, 40.3 +/- 7.5, and 18.4 +/- 4.6 micrograms/ml were achieved. Metabolic clearance was estimated as the difference between total clearance and the sum of renal and biliary clearance, assuming that no other route of excretion plays an important role in the elimination of the drug. Total clearance varied between 355.7 +/- 59.3 and 286.5 +/- 54.6 ml/min when doses of 5.6 +/- 0.4 and 22.4 +/- 1.5 mg/min were given. Since neither renal clearance (137.6 +/- 32.6 ml/min) nor biliary clearance (98.6 +/- 42.5 ml/min) was shown to be dose dependent, nonlinear mezlocillin kinetics must be due to dose dependent metabolic clearance (108.4 +/- 26.2 versus 60.2 +/- 32.3 ml/min at 5.6 +/- 0.4 and 22.4 +/- 1.5 mg/min). The apparent Km was 27.5 micrograms/ml and apparent Vmax 4.3 mg/min. The apparent Km is so low that after therapeutic doses of mezlocillin the kinetics are nonlinear for several hours.
Adult↗
Monoclonal antibody to the message sequence Tyr-Gly-Gly-Phe of opioid peptides exhibits the specificity requirements of mammalian opioid receptors.
Six myeloma cell hybrids producing antibodies to human beta-endorphin were isolated from a single mouse spleen. The monoclonal antibodies displayed different binding patterns with the antigen. We report the characterization of one antibody which recognizes the tetrapeptide Tyr-Gly-Gly-Phe representing the message sequence found at the NH2 terminus of all naturally occurring mammalian opioid peptides. Competition experiments in radioimmunoassay and immunohistochemistry show that the antibody fails to bind the beta-endorphin precursor beta-lipotrophin, does not discriminate among opioid peptides that share the same message sequence but have different COOH-terminal extensions, and does not react with pharmacologically inactive derivatives of beta-endorphin. The antibody recognition of the message sequence of natural opioid peptides is sensitive to those molecular changes that affect their receptor binding competence.
Amino Acid Sequence↗
Metorphamide: isolation, structure, and biologic activity of an amidated opioid octapeptide from bovine brain.
Acid acetone extracts of caudate nucleus from bovine brain were found to contain an amidated opioid octapeptide with the following structure: Tyr-Gly-Gly-Phe-Met-Arg-Arg-Val-NH2. The peptide has been named metorphamide. Bovine metorphamide appears to be derived by proteolytic cleavage from proenkephalin, the common precursor to [Met5]enkephalin and [Leu5]enkephalin. The cleavage within the precursor giving rise to the carboxyl terminus of metorphamide occurs at a single arginine residue and is followed by transformation of a carboxyl-terminal glycine into an amide group. Metorphamide was detected in bovine caudate nucleus extracts by radioimmunoassay, and it was purified to homogeneity by gel filtration and reversed-phase high performance liquid chromatography. Amino acid composition analysis and automated Edman degradation in the gas-phase sequencer confirmed the postulated amino acid sequence. Carboxyl-terminal amidation of bovine metorphamide was shown by stability to carboxypeptidase A digestion and full crossreactivity in a radioimmunoassay that required the carboxyl-terminal amide as part of the recognition site. A synthetic replicate of metorphamide as well as several synthetic analogs were tested for opioid activity in several bioassays and binding assays, and metorphamide was found to have a high mu-binding activity. Metorphamide is the only known naturally occurring opioid peptide that has a high mu-binding activity. The kappa-binding activity is approximately equal to 50% that of the mu-binding activity, but delta-binding activity is negligible.
Amino Acid Sequence↗
Relative contents and concomitant release of prodynorphin/neoendorphin-derived peptides in rat hippocampus.
The contents and molecular forms of five different prodynorphin-derived opioid peptides were compared in extracts of rat hippocampus by radioimmunoassay after C18-HPLC resolution. Dynorphin (Dyn) A(1-17) immunoreactivity (ir) and Dyn B-ir were heterogeneous in form; Dyn A(1-8)-ir, alpha-neoendorphin (alpha neo)-ir and beta-neoendorphin (beta neo)-ir each eluted as single homogeneous peaks of immunoreactivity. The fraction of immunoreactivity having the same retention as the appropriate synthetic standard was used to estimate the actual hippocampal content of each peptide. Comparison of these values showed that the concentrations of Dyn B, alpha neo, and Dyn A(1-8) were nearly equal, whereas both Dyn A(1-17) and beta neo were 1/5th to 1/10th the value of the other three. Calcium-dependent K+-stimulated release of these prodynorphin-derived opioids from hippocampal slices was detected. The stimulated rates of release were highest for Dyn B-ir followed by alpha neo-ir, then beta neo-ir and Dyn A(1-8)-ir with Dyn A(1-17)-ir lowest. The relative rates of stimulated release were in agreement with the relative proportions of peptide present within the tissue. This evidence of the presence and release of these opioid peptides considerably strengthens the hypothesis that this family of endogenous opioids plays a neurotransmitter role in the hippocampus.
Amino Acid Sequence↗
Immunohistochemical distribution of dynorphin B in rat brain: relation to dynorphin A and alpha-neo-endorphin systems.
A specific antiserum was prepared against dynorphin B, an endogenous opioid peptide contained in a recently isolated 4,000-dalton dynorphin. The antiserum did not crossreact with dynorphin A, alpha-neo-endorphin, beta-neo-endorphin, dynorphin-(1-8), or [Leu]enkephalin. In immunohistochemical staining experiments on frozen sections through rat brains from normal and colchicine-treated animals, the antiserum labeled the same neuronal fiber systems previously described as containing both dynorphin A and alpha-neo-endorphin immunoreactive material. The alpha-neo-endorphin/dynorphin A immunoreactive perikarya in the hypothalamic magnocellular nuclei also were labeled by the dynorphin B antiserum. In addition, the dynorphin B antiserum revealed groups of immunoreactive neuronal cell bodies in several other hypothalamic and extrahypothalamic areas, including brain-stem, midbrain, central nucleus of amygdala, and in the dorsomedial, lateral, and anterior nuclei of hypothalamus. These perikarya had not been detected in previous studies that used dynorphin A and alpha-neo-endorphin antisera. The findings are in agreement with recent studies demonstrating a common precursor for dynorphin A, dynorphin B, and alpha-neo-endorphin. The apparently wider distribution of dynorphin B immunoreactive cell bodies compared to alpha-neo-endorphin/dynorphin A immunoreactive perikarya may be a reflection of differential processing of the precursor in different brain regions.
Animals↗
Measurement of total opioid peptides in rat brain and pituitary by radioimmunoassay directed at the alpha-N-acetyl derivative.
A sensitive assay, which cross-reacts with and is specific for diverse opioid peptides, is described. This is based on the prior acetylation of samples and subsequent radioimmunoassay with an antiserum highly specific for the acetylated NH2 terminus of opioid peptides. The result is a procedure that can be used to investigate multiple forms of opioid peptides in extracts of biological material. The sensitivity of the assay is approximately 15 fmol of beta-endorphin per incubation tube, i.e., approximately 100-fold greater sensitivity than the radioreceptor assay used in our laboratory. The peptide concentration required for 50% displacement of trace ranged from 0.65 nM (beta-endorphin) to 1.6 nM (Met-enkephalin). The assay apparently shows an absolute requirement for a free (or acetylated) NH2 terminus corresponding to either a Leu- or Met-enkephalin sequence. Use of the assay with and without prior acetylation of sample provides a method for estimation of the ratio of acetylated:nonacetylated opioid peptides in crude or fractionated extracts. The procedure is used to investigate the forms of opioid peptide found in rat brain and pituitary.
Acetylation↗