The interaction of warfarin with antacid constituents in the gut

Summary A study was made of the effect of 4 constituents of antacid preparations on the absorption of the coumarin derivate warfarin sodium using an in vitro experimental model. The constituents tested were activated dimethicone (a silicone) magnesium trisilicate, bismuth carbonate and the adsorbant, kaolin. Slight decreased intestinal absorption was shown by magnesium trisilicate (19%) and bismuth carbonate (7%), the other 2 components showing no effects.     

Interaction of digoxin with activated dimethicone and other antacid constituents

Summary A study was made of the effect of activated dimethicone on the absorption of digoxin in relation to other commonly used antacid constituents using an in vitro experimental model. Dimethicone was found not to affect the absorption of digoxin in relation to aluminium hydroxide, bismuth carbonate, light magnesium carbonate and magnesium trisilicate whose effects on the absorption of digoxin were in agreement with values reported in the literature.     

The interaction of warfarin with antacid constituents in the gut.

A study was made of the effect of 4 constituents of antacid preparations on the absorption of the coumarin derivate warfarin sodium using an in vitro experimental model. The constituents tested were activated dimethiocone (a silicone) magnesium trisilicate, bismuth carbonate and the adsorbant, kaolin. Slight decreased intestinal absorption was shown by magnesium trisilicate (19%) and bismuth carbonate (7%), the other 2 components showing no effects.     

Effect of abrupt withdrawal of chronically administered β-blocking drugs on cardiac sensitivity in the rat

Summary Increased tachycardia to isoprenaline was observed in pithed rats 2 days after withdrawal of propanolol but not after withdrawal of atenolol (a cardioselective drug) or LL 21-945 (a long acting beta-blocking drug).Acknowledgments. We are grateful to Sandoz Ltd for a gift of LL 21-943 and to I.C.I. for gifts of propranolol and atenolol.     

Effects of alpha- and beta-adrenergic blockers on the actions of noradrenaline on body temperature in the newborn guinea-pig

Summary The effect of NA injected into the lateral cerebral ventricle on T_c was blocked by alpha-adrenergic receptor blockers, but not by beta-receptor blockers, whereas the effect of systemically administered NA was blocked by i.p. administered beta-receptor blockers, but not by alpha-blockers.Acknowledgments. The author is indebted to Ciba-Geigy Ltd for generous gift of phentolamine, and to Imperial Chemical Industries Ltd, for supplying propranolol and practolol.     

The effect of tolbutamide on early embryos ofXenopus laevis

Summary The effect of tolbutamide on the early development of Xenopus laevis has been studied. The results suggest that continuous exposure to 3×10^–4 M tolbutamide causes abnormal development.Acknowledgments. I wish to thank Mr F. Schaefer who prepared the histological material, and Hoechst U.K. Ltd for their gift of tolbutamide.     

Metabolically regulated cyclical contractures in microinjectedSpirostomum: A pharmacological study

Summary Spirostomum was treated extracellularly and intracellularly with a range of metabolites to investigate the intracellular regulation of cyclic calcium movements. The results indicate, close links between calcium movements and mitochondrial metabolism.We are grateful to Dr.A. Gaudemar, Institut de Chimie des Substances Naturelle, Gif-sur-Yvette, France for a gift of bongkrekic acid, to Dr.D. C. Aldridge, Biochemistry Dept., I. C. I. Ltd., Macclesfield, U. K. for a gift of avenceolide and toE. M. Ettienne for many hours of discussion. Dr.R. B. Hawkes is a Visiting Research Fellow at the Hebrew University of Jerusalem.     

Bemegride antagonism to the development of physical dependence on barbitone in rodents

Zusammenfassung Nachweis einer protektiven Wirkung bzw. Entwicklung einer Barbituratabhängigkeit durch die gleichzeitige Gabe des Analeptikums Bemegrid.

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This work was presented in part by C.I.A. in November, 1973 in partial fulfilment for the degree of B.Sc. (Hons) in the University of Melbourne.

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Acknowledgment. We gratefully acknowledge the generous gift of bemegride (Megimide) from Nicholas Pty Ltd, Australia.     

Cholecystokinin-like peptides in avian brain and gut

Summary Extracts of turkey brain and jejunum contain a factor closely resembling the COOH-terminal octapeptide of porcine cholecystokinin (CCK). Turkey antral extracts contain factors distinguishable in immunochemical and gel filtration properties from the mammalian forms of gastrin and CCK. *** DIRECT SUPPORT *** A2025089 00007Acknowledgments. Skilled technical assistance was given by Elaine Clarke, Carol Higgins and Gavin Laing. Pure natural human G17 and G34 were generously provided by Prof. R.A. Gregory and Dr H.J. Tracy; pure natural porcine CCK33 was a generous gift from Prof. Viktor Mutt; the Squibb Institute for Medical Research kindly provided supplies of synthetic CCK8, and synthetic caerulein was a gift from Farmitalia Ltd.     

Differential activation of two monoamine oxidase types by oxygen

Summary The stimulation of rat brain monoamine oxidase activity by oxygen is shown to be type-selective, type B being much more strongly stimulated than type A.Pargyline and clorgyline were gift samples from Abbott Laboratories, USA and May and Baker Ltd, England respectively     

Mitochondria and calpains mediate caspase-dependent apoptosis induced by doxycycline in HeLa cells

Doxycycline (Dc) has been demonstrated to inhibit cell growth and induce apoptosis in tumor cells, although its mechanism of action is not fully understood. The present study demonstrates that apoptosis can be induced in HeLa cells. Western blot data demonstrated that cytochrome c (Cyt c), Smac (the second mitochondria-derived activator of caspase), calpain I, caspase-9, −3 and −8 were involved in the apoptotic process, while the pan caspase inhibitor zVAD-fmk almost completely inhibited Dc-induced apoptosis. We further demonstrated that the release of mitochondrial proteins and the activation of calpains occurred upstream of the caspase cascade, in which caspase-9 was activated in response to the release of Cyt c, that caspase-8 activation was caspase and calpain dependent, and that caspase-3 was activated mainly by caspase-8 and −9. Caspase-8 played important roles in the activation of caspase-3 and induction of apoptosis, whereas the role of the caspase-9 was limited. Received 26 November 2005; received after revision 14 February 2006; accepted 1 March 2006     

Hydroxylation of menthols and cineoles withm-chloroperbenzoic acid

Summary Reaction of menthols and cineoles withm-chloroperbenzoic acid afforded tertiary, secondary, and primary alcohols, some of which were natural products having potent plant growth regulatory activity or were mammlianm metabolies.We thank Nippon Terpene Co. Ltd for their generous gift of the compounds used in this work and Drs M. Kido and Y. Fukuyama, Otsuka Pharmaceutical Co. Ltd, for measurement of high resolution mass spectra. The present work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare.     

Effect of des-Tyr1-γ-endorphin on serotonin metabolism in rat brain regions

Summary Intracerebroventicular (i.c.v.) administration of des-Tyr¹-γ-endorphin (0.1 and 1.0 μg) caused a decrease of the serotonin (5-HT) concentration of the hippocampus. The concentration of 5-HIAA and the pargyline-induced alterations in 5-HT and 5-HIAA were not affected. No effects were noticed in other brain regions. Acknowledgement. The skilful technical assistance of Ms Henny de Vos Burchart-Lodewijks and Mrs H.A. Spierenburg and J.A. Meijer is gratefully acknowledged. Des-Tyr¹-γ-endorphin was a gift of Dr. H.M. Greven, Organon International B.V., Oss, The Netherlands. To whom reprint requests should be addressed.     

Beta-carotene affects gene expression in lungs of male and female <Emphasis Type="Italic">Bcmo1</Emphasis><Superscript>−/−</Superscript> mice in opposite directions

Molecular mechanisms triggered by high dietary beta-carotene (BC) intake in lung are largely unknown. We performed microarray gene expression analysis on lung tissue of BC supplemented beta-carotene 15,15′-monooxygenase 1 knockout (Bcmo1 ^−/−) mice, which are—like humans—able to accumulate BC. Our main observation was that the genes were regulated in an opposite direction in male and female Bcmo1 ^−/− mice by BC. The steroid biosynthetic pathway was overrepresented in BC-supplemented male Bcmo1 ^−/− mice. Testosterone levels were higher after BC supplementation only in Bcmo1 ^−/− mice, which had, unlike wild-type (Bcmo1 ^+/+) mice, large variations. We hypothesize that BC possibly affects hormone synthesis or metabolism. Since sex hormones influence lung cancer risk, these data might contribute to an explanation for the previously found increased lung cancer risk after BC supplementation (ATBC and CARET studies). Moreover, effects of BC may depend on the presence of frequent human BCMO1 polymorphisms, since these effects were not found in wild-type mice.     

Production of antibodies to amanitins as the basis for their radioimmunoassay

Summary The production of antibodies against amanitins is described. By means of these antibodies, a radioimmunoassay was developed which allows detection of as little as 0.5 ng of amanitins in 1 ml of serum. By this method, the clearance of α-amanitin from the blood of poisoned mice was measured. Acknowledgments. We thank ProfessorT. Wieland and Dr.H. Faulstich (Heidelberg) for their generous gift of β-amanitin and [³H]O-methyl-demethyl-γ-amanitin. This work was supported by grants from C.N.R., Rome.     

δ-Protocadherins: unique structures and functions

δ-Protocadherins constitute a group of cadherins characterized by several conserved motifs in their cytoplasmic domains. We present a phylogenetic analysis that further divides this group into δ1-protocadherins (comprising protocadherin-1, −7, −9 and −11 or -X/Y) and δ2-protocadherins (comprising protocadherin-8, −10, −17, −18 and −19). The δ-protocadherin genes, which are located on different chromosomes in man and mouse, have a similar gene structure. They are expressed as multiple splice forms, differing mostly in their cytoplasmic domains. Some δ-protocadherins were reported to mediate weak cell-cell adhesion in vitro and cell sorting in vivo. In addition, individual δ-protocadherins might play important roles in signaling pathways, as they bind to proteins such as TAF1/Set, protein phosphatase-1α and the Frizzled 7 receptor. The spatiotemporally restricted expression of δ-protocadherins in different tissues and species and the results of their functional analysis, mainly in Xenopus, suggest that they play multiple, tightly regulated roles in vertebrate development. Received 18 July 2005; received after revision 26 August 2005; accepted 2 September 2005     

Ergot alkaloids and phosphodiesterase; ‘in vitro’ activities in several rat brain areas

Summary The ‘in vitro’ activity of ergotamine, dihydroergocristine, dihydroergocornine and dihydroergocryptine on the phosphodiesterase system at low and high K_m in several rat brain areas was examined. These drugs were found to exert an inhibitory effect in all the areas examined with regard to both systems, and particularly on low substrate concentration phosphodiesterases. Acknowledgments. Ergot alkaloids were a generous gift of Poli Industria Chimica, Milan.     

Water in enzyme reactions: biophysical aspects of hydration-dehydration processes

Water has been recognized as one of the major structuring factors in biological macromolecules. Indeed, water clusters influence many aspects of biological function, and the water-protein interaction has long been recognized as a major determinant of chain folding, conformational stability, internal dynamics, binding specificity and catalysis. I discuss here several themes arising from recent progress in understanding structural aspects of ‘direct’ and ‘indirect’ ligands in terms of enzyme-substrate interactions, and the role of water bridges in enzyme catalysis. The review also attempts to illuminate issues relating to efficiency, through solvent interactions associated with enzymic specificity, and versatility. Over the years, carbonic anhydrase (CA; carbonate hydro-lyase, EC 4.2.1.1) has played a significant role in the continuing delineation of principles underlying the role of water in enzyme reactions. As a result of its pronounced catalytic power and robust constitution CA was transformed into a veritable ‘laboratory’ in which active site mechanisms were rigorously tested and explored.     

Redundant and unique roles of coronin proteins in <Emphasis Type="Italic">Dictyostelium</Emphasis>

Dictyostelium discoideum harbors a short (CRN12) and a long coronin (CRN7) composed of one and two beta-propellers, respectively. They are primarily present in the cell cortex and cells lacking CRN12 (corA ⁻) or CRN7 (corB ⁻) have defects in actin driven processes. We compared the characteristics of a mutant cell line (corA ⁻ /corB ⁻) lacking CRN12 and CRN7 with the single mutants focusing on cytokinesis, phagocytosis, chemotaxis and development. Cytokinesis, uptake of small particles, and developmental defects were not enhanced in the corA ⁻ /corB ⁻ strain as compared to the single mutants, whereas motility and phagocytosis of yeast particles were more severely impaired. It appears that although both proteins affect the same processes they do not act in a redundant manner. Rather, they often act antagonistically, which is in accordance with their proposed roles in the actin cytoskeleton where CRN12 acts in actin disassembly whereas CRN7 stabilizes actin filaments and protects them from disassembly.     

The role of parathyroid hormone and calcitonin in magnesium absorption in the rat small intestine

Summary We studied duodenal and ileal magnesium (Mg) absorption in intact, parathyroidectomized (PTX), thyroid-(TX) and thyroparathyroidectomized (TPTX) rats with iodine hormones replaced, and, additionally, in PTX rats receiving bovine parathyroid hormone 1–34 and 1,25-dihydroxyvitamin D₃, respectively. Ma absorption was reduced after PTX and TPTX in the duodenum, but not in the ileum, whereas TX had no influence on duodenal or ileal Mg absorption. Both bovine parathyroid hormone 1–34 and 1,25-dihydroxyvitamin D₃ increased Mg absorption in the duodenum and the ileum in PTX rats.Acknowledgments. We are grateful to B. Schreiber, K. Schwille and I. Goldberg for technical and secretarial help. Supported by Deutsche Forschungsgemeinschaft (Schw 210/3). Reprint requests to P.O.S., University Hospital, Maximiliansplatz, D-8520 Erlangen.