Profound hypothermia in golden hamsters (Mesocricetus auratus) induced by serotonergic potentiating and noradrenergic inhibiting drugs

Profound hypothermia (6 degrees C) was induced in cold exposed golden hamsters (Mesocricetus auratus) by a combination of drugs that potentiate brain serotonergic activity (fluoxetine and pargyline) and inhibit noradrenergic activity (alpha-methyl-p-tyrosine). Individual drugs and combinations of 2 were ineffective.     

Chitin synthesis inhibiting insect growth regulators do not inhibit chitin synthase

Summary Tunicamycin, an antibiotic, and 5 insect growth regulators (diflubenzuron, Bay Sir 6874, Bay Sir 8514, CGA-19255 and Lilly 494) do not inhibit chitin synthase obtained from 4-day-oldStomoxys calcitrans pupae.     

Effect of pancreatic polypeptide on DNA-synthesis in the pancreas

Summary Bovine pancreatic polypeptide increases DNA-synthesis in the rat pancreas; no effect is observed in stomach (oxyntic area), duodenum or liver. BPP neither augments or inhibits the trophic action of cholecystokinin.Acknowledgment. Pure pancreatic polypeptide was donated by Dr. R. E. Chance (Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Ind, USA). G. R. Greenberg is supported by a Fellowship of the Medical Research Council of Canada.     

Über die metabolischen wirkungen einiger neuerβ-adrenergischer Stimulatoren

Summary Actions of various adrenergic drugs (adrenaline, noradrenaline, isoprenaline, metaproterenol, terbutaline, salbutamol, soterenol, quinterenol, chlorprenaline) on the glycemia and on free fatty acids of the rat have been described.

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Der Autor dankt fÜr die technische Mitarbeit den Herren B.Ungaro, L.Giordano und C.Vacca sowie fÜr die freundliche Überlassung von Noradrenalin, Adrenalin, Isoprenalin, Metaproterenol und Kö 592 der C. H. Boehringer Sohn A.G., von Terbutalin der AB Draco-Astra, von Salbutamol der Allen and Hanburys Ltd., von Soterenol dem Mead Johnson Res. Center, von Chlorprenalin den Lilly Res. Lab. und von Quinterenol der Chas. Pfizer Co.     

Co-localization of glucagon and pancreatic polypeptide in testudine pancreas

Summary Immunocytochemistry was carried out on sections of pancreas from the gopher tortoise,Gopherus polyphemus. Combined immunofluorescent and peroxidase-anti-peroxidase techniques showed unequivocally that some of the cells were immunoreactive for both glucagon and pancreatic polypeptide (PP). Antibodies directed against avian PP, bovine PP, and human PP all have a positive reaction. Co-localization of glucagon and PP in the pancreas of the gopher tortoise indicates that the occurrence of these hormones in the same cells is widespread in higher vertebrates.Acknowledgments. This work was supported in part by grants from the University of Cape Town, the M. Crossley bequest, the N. Atkinson bequest, and Herman and Caporn bequests. The generous gifts of antisera by Dr Chance and the late Dr Kimmel, and the gift of hormones by the Lilly Research Laboratories are gratefully acknowledged. The excellent technical assistance of J. Thompson and J. B. De Haan is also gratefully acknowledged. Please send all correspondence to the USA address.     

Antihypertensive and cardiac effects of two novelβ-adrenoceptor blocking drugs

Summary Two new-adrenoceptor blocking drugs with acute antihypertensive and positive inotropic effects are described: Compound A (2-[4-(3-tert. butylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole) and MK-761 (2-(3-tert. butylamino-2-hydroxypropoxy)-3-cyanopyridine hydrochloride). In SH rats both compounds, given orally, lowered arterial pressure and were more potent than hydralazine. The antihypertensive effect of compound A but not of MK-761 was antagonized by timolol. Both compounds had positive inotropic activity on cat heart papillary muscles; these effects were antagonized by timolol. The pretreatment of animals with reserpine greatly reduced the positive inotropic effect of MK-761 but not of compound A. The acute antihypertensive and positive inotropic effects of compound A are likely to be at least partially due to stimulation of-adrenoceptors, e.g. intrinsic sympathomimetic activity. The effects of MK-761 on the same parameters appear to be mediated by different mechanisms.     

Interaction between 6-hydroxydopamine and rhodopsin in vivo in the rat retina

Résumé Nous avons observé que l'injection de la 6-hydroxydopamine dans l'humeur vitrée des rats adaptés à la lumière bloquait le rétablissement de la sensibilité rétinale pendant l'adaptation à l'obscurité subséquente au traitement. Il est possible que cette observation soit une conséquence de la réaction du produit de l'oxydation de la 6-hydroxydopamine avec les groupes nucléophiliques de la rhodopsine.

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This study was partially supported by Postdoctoral Training Grant No. MH 10965 to S.F.P. and by Eli Lilly Co., Research to Prevent Blindness, Inc., and NSF No. GB-39853 to L.T.G. Samples of 6-aminodopamine were kindly supplied by Drs.R. N. Adams (University of Kansas, Lawrence, Kansas) andE. L. Engelhardt (Merck Sharp and Dohme Res. Labs. West Point, Pa.) andp-quinone by Dr.P. A. Wehrli (Hoffmann-La Roche, Nutley, New Jersey). The authors thank Mr.L. Tomey for excellent technical assistance.     

Activity of sulfa drugs and dihydrofolate reductase inhibitors againstCandida albicans

Summary Growth ofCandida albicans can be inhibited by sulfa drugs which prevent biosynthesis of folic acid. The dihydrofolate reductase (E.C. 1.5.1.3) inhibitors aminopterin and methotrexate also exhibit anticandidal activity, but trimethoprim does not. Kinetic evaluations withC. albicans dihydrofolate reductase indicate that methotrexate and aminopterin are tight-binding inhibitors whereas trimethoprim binds poorly.     

Interaction of vinblastine analogues with tubulin

Summary Studies of the interaction between vinblastine-like alkaloids and their receptor, i.e. tubulin, are reported. They shed some light on the structure-activity relationships in this medicinally important series: the configurations at C₁₄ and C₁₆ as well as the presence of the methoxycarbonyl group on C₁₆ seem to play an essential role in the determination of biological activity.This work was supported by CNRS (A.T.P. No 3232).We thank Dr D. Pantaloni for interesting discussions, Drs N. and Y. Langlois for discussions and for supplying synthetic material, and Eli Lilly Laboratories for gifts of vinblastine, vincristine and leurosidine.     

Increase of proteolytic activity inLactobacillus casei by X-ray irradiation

Summary A study was conducted on the effect of X-ray irradiation on proteolytic activity ofLactobacillus casei (RTS). Substantial increase (82%) in the proteolytic activity was noted among the isolates of X-ray irradiation survivors after 18,000 R.     

Phenobarbital and SKF-525A on vinblastine and vincristine toxicity in mice

Summary The effect of SKF-525A and phenobarbirtal on the LD₅₀ values of vinblastine and vincristine suggests that the toxicity of these agents in mice does not arise from a toxic metabolite.This work was supported by PHS Grant No. GM 15956. The author wishes to thankMary-Lucille Mantz for her valuable technical assistance and the Eli Lilly Company for graciously providing generous samples of VLB and VCR. The ample gift of SKF-525A from Smith, Kline and French Laboratories is also gratefully acknowledged.     

Effect of benzimidazole on nicotinamide adenine dinucleotide phosphate phosphomonosterase activity in wheat leaves

Summary Nicotinamide adenine dinucleotide phosphate phosphomonoesterase was isolated and partially purified from wheat (Triticum aestivum L. var. Selkirk) leaves. The enzyme hadK _NADP value of 1.4×10^–4 M and a pH optimum of 5.9.In vitro activity of this enzyme was unaffected by precursors of NAD (nicotinamide and nicotinic acid) or cytokinis (kinetin and benzimidazole). However, when detached wheat leaves were treated with solutions of these compounds, the precursors lowered the specific activity while the cytokinins enhanced the activity. It is suggested that spatial separation and compartmentation of the enzyme and its substrate NADP account for the similar effect of benzimidazole on both.This work was supported by a grant No. A2698 from the National Research Council, Canada.     

Influence of heparin and serotonin on basophil leucocytes of rabbit blood

Résumé Chez le lapin, l'injection intraveineuse d'héparine a été suivie d'une diminution significative du nombre des basophiles du sang au cours de 6 h. La sérotonine a produit pendant ce temps une augmentation du nombre total des leucocytes, et au bout de 24 h, une augmentation spécifique du nombre des basophiles.Les basophiles n'ont pas changé de nombre après l'injection de protamine ou de réserpine.

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This work was supported by grants from the Danish Rheumatism Association, and Eli Lilly and Co., Indianapolis, Indiana, U.S.A., to Dr.Asboe-Hansen.

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Author on leave from the Histology Department, Faculty of Medicine, Cairo University (Egypt).     

Inhibition of neural tube closure by ionophore A23187 in chick embryos

Summary Ionophore A23187 inhibited closure of the chick neural tube through its effects on cytoskeletal components.This study was supported in part by grants from the Research Council and the Charles and Johanna Busch Memorial Fund of Rutgers University. Ionophore A23187 was provided through the courtesy of Dr R.L. Hamill, Lilly Research Laboratories, Indianapolis, Indiana, USA.     

Free amino acid patterns and other chemical constituents of rabbits' blood and blood vessels

Zusammenfassung Die Verteilung der freien Aminosäuren, von Protein, Fett und Cholesterin im Blut und in verschiedenen Gefässen normaler und hypercholesteremischer Kaninchen wurde untersucht. Geschädigte Aortaabschnitte erhielten mehr Protein, Fett und Cholesterin, aber weniger freie Aminosäuren als normale.

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Supported by grant H-2534 (C-3) from the National Heart Institute, N.I.H., and by a grant from the Eli Lilly Co.     

Starvation-induced changes in the autoradiographic localisation of valine uptake by rat small intestine

Summary We report here the effects of a 72-h fast on the localisation of Na-dependent [³H]-valine uptake by rat small intestine. Starvation results in the earlier appearance of valine transport during cell migration and an enhanced accumulation of the amino acid at the villus tip.Acknowledgments. We wish to thank MW Smith, PS James and IS King (AFRC Institute of Animal Physiology, Babraham, Cambridge) for facilities and advice regarding autoradiography. Financial support from the British Digestive Foundation and Eli Lilly and Company is appreciated.     

Targeting O 6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy

O ⁶-methylguanine-DNA methyltransferase (MGMT) repairs the cancer chemotherapy-relevant DNA adducts, O ⁶-methylguanine and O ⁶-chloroethylguanine, induced by methylating and chloroethylating anticancer drugs, respectively. These adducts are cytotoxic, and given the overwhelming evidence that MGMT is a key factor in resistance, strategies for inactivating MGMT have been pursued. A number of drugs have been shown to inactivate MGMT in cells, human tumour models and cancer patients, and O ⁶-benzylguanine and O ⁶-[4-bromothenyl]guanine have been used in clinical trials. While these agents show no side effects per se, they also inactivate MGMT in normal tissues and hence exacerbate the toxic side effects of the alkylating drugs, requiring dose reduction. This might explain why, in any of the reported trials, the outcome has not been improved by their inclusion. It is, however, anticipated that, with the availability of tumour targeting strategies and hematopoetic stem cell protection, MGMT inactivators hold promise for enhancing the effectiveness of alkylating agent chemotherapy.     

Ribonucleotide reductases and radical reactions

Ribonucleotide reductases (RNRs) catalyse the reduction of ribonucleotides to deoxyribonucleotides. They play a pivotal role in the regulation of DNA synthesis and are targets for antiproliferative drugs. Ribonucleotide reductases are unique enzymes in that they all require a protein radical for activity. Class I nonheme iron RNRs (mammals, plants, Escherichia coli) use a tyrosyl/cysteinyl radical pair, class II adenosylcobalamin RNRs (prokaryotes, archaea) a cysteinyl radical, class III iron-sulphur RNRs (facultative anaerobes) a glycyl radical. Here we describe the reactivity of these radicals with respect to the natural ribonucleotide substrates as well as to a variety of enzyme inhibitors, radical scavengers, nitric oxide, superoxide radicals and substrate analogues. Received 3 December 1997; received after revision 26 February 1998; accepted 27 February 1998     

A note on the subcellular distribution of brain protein in differentially-housed mice

Résumé Utilisant une technique subcellulaire pour étudier la distribution de la protéine dans des cerveaux de souris, on a constaté certaines différences.

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This study was supported in part by a grant from the Eli Lilly Company.