Cyclosporins: Immunosuppressive agents with antitumor activity

Summary Initial screening of the 2 recently developed immunosuppressive agents, cyclosporin A and cyclosporin C, in 11 murine transplantable neoplasms revealed significant increase of lifespan with long-term survivors after i.p. injection to the ascites tumors, Taper liver, Sarcoma 180J and Ehrlich.This work was supported in part by grant CA-08748 from the National Cancer Institute, National Institutes of HealthDepartment of Health, Education and Welfare. The authors are indebted to Drs Dorris J. Hutchison, M.N. Teller and H. Stähelin for helpful discussions, and to Dr A. von Wartburg of Sandoz AG, Basel, for the supply of the cyclosporins.     

Characterization of the host-specific toxins produced byHelminthosporium sacchari,the causal organism of eyespot disease of sugarcane

Summary Investigation of the host-specific toxin complex fromH. sacchari has led to the isolation of 3 isomeric glycosidic components C₃₉H₆₄O₂₂, each active at 2×10^–11 moles. The 3 isomers consist of 4 galactose units linked to an aglycone residue C₁₅H₂₄O₂.Acknowledgments. The Boyce Thompson-Cornell group thanks J.F. Rissler, University of Maryland, A.K. Bose, Stevens Institute of Technology, R. Barker and A. Serriani, Cornell University, and C. Grinnalds and J. Golay, Boyce Thompson Institute for help with various aspects of this work. Supported in part by a grant to V.M. from the US Department of Agriculture (8100720). The Zürich group thanks Dr G.A. Strobel, Department of Botany and Microbiology, Montana State University, Bozeman, for supplying a potent toxin-producing strain (M 36), a susceptible clone of sugarcane (51 NG 97), and a reference sample of helminthosporoside, Dr. K. Hostettmann and Mme M. Hostettmann-Kaldas, Pharmazeutisches Institut ETH Zürich, for assistance in developing the DCC separation and Sandoz A.G., Basel, for financial support.     

Lack of correlation between structural features and function of synthetic agents tested for leukocyte chemotaxis

Summary A number of proteins, poly-L-amino acids, oligopeptides and lipids were tested for neutrophil, cosinophil and macrophage chemotactic activity. One myoglobin preparation was active. Based on the negative findings for all other substances, primary structure, secondary structure, degree of hydrophobicity, size and charge of a molecule, could be ruled out as structural features recognized by chemotactically responding phagocytes.I thank Dr J. H. Wissler for suggesting the reported experiments and Dr M. Landy and Prof. E. Sorkin for advice and criticism during preparation of this article. The excellent assistance by Mrs J. Kerschbaumer-Bech and Miss Margrit Bühlmann is gratefully acknowledged. This work was supported by Swiss National Foundation for Scientific Research, grant 3.8750.72, and by Sandoz-Stiftung, Basel.     

Inhibition by ergocornine and 2-Br-α-ergocryptin of spontaneous mammary tumor appearance in mice

Zusammenfassung Die subkutane Impantation von Ergocornin oder 2-Br--Ergokryptin (CB-154) hemmt die Bildung von spontanen Tumoren der Milchdrüse bei der Maus.

---

---

The authors are indebted to Drs.M. Taeschler andE. Flückiger, Sandoz Ltd., Basel, for their kind donation of ergocornine methanesulfonate and CB-154.     

Role of 5-hydroxytryptamine in prostaglandin E1-induced potentiation of hexobarbitone hypnosis in albino rats

Summary PGE₁ potentiated, while diclofenac, a prostaglandin synthesis inhibitor, antagonized hexobarbitone hypnosis in rats. PGE₁-induced potentiation of hexobarbitone sleep was inhibited by a 5HT synthesis inhibitor and by a 5HT receptor blocker, suggesting that this potentiation is 5HT mediated.Acknowledgment. The gift of the following drugs are gratefully acknowledged: PGE₁ (Dr.J. E. Pike, Upjohn), diclofenac (Ciba-Geigy), methysergide (Sandoz) and hexobarbitone (Bayer).     

Autoradiographic evidence for binding of3H-flunitrazepam (Rohypnol®) to melanin granules in the cat eye

Summary This autoradiographic study revealed after an i.v. injection an accumulation of³H-flunitrazepam in melanin granules of the pigment epithelium and of the choroid cells. It seems that after a short period, a large proportion of the strongly bound drug is released.Acknowledgments. I thank Dr E. Kovács and Mrs V. Beuck for help in treating the animals and Miss C. Böhler and Mr R. Krauer for excellent technical assistance.This drug, with a radiochemical purity of 99.2%, was prepared by Drs R. Schwob and J. Würsch, F. Hoffmann-La Roche & Co., Ltd, Basel, Switzerland.     

Bromocryptine treatment and puberty attainment in the female rat

Summary The influence of bromocryptine treatment on the timing of vaginal patency and 1st oestrus in female rats was studied. No significant influence of bromocryptine on these parameters was noted, and it is concluded that suppression of prolactin secretion has no effect on puberty attainment.Acknowledgment. We thank Professor E. Flückiger and Dr H. Friedli, Pharmaceutical Division, Sandoz Ltd, Basle, Switzerland, for the donation of bromocryptine mesylate.     

Amnesic effects of intravenous diazepam and lorazepam

Summary The amnesic effects of 2 benzodiazepine drugs, diazepam (Valium) and lorazepam (Ativan), have been investigated. Some of the effects were similar to those of certain clinical amnesic syndromes. The effects were more extensive than previous work has indicated.Acknowledgments. The authors are grateful to Dr J. Hope and Dr D. Gosh for clinical assistance and to Dr T.V.A. Harry of John Wyeth and Brother Ltd, Dr W.H. Franklin of Roche Products Ltd and Professor J.B. Chappell for advice and discussion. We thank John Wyeth and Brother Ltd for financial support and for supplying lorazepam.     

Effects of ergocornine and 2-Br-α-ergokryptin (CB-154) on the formation of mammary hyperplastic alveolar nodules and the pituitary prolactin levels in mice

Zusammenfassung Ergocornin und 2-Br--Ergokryptin (CB-154) unterdrücken die Formation von hyperplastischen alveolaren Noduli der Milchdrüse und vermindern Prolactin-Sekretion aus dem Hirnanhang in der Maus.

---

---

The authors wish to express their heartiest thanks to Drs. M.Taeschler and E.Flückiger, Sandoz Ltd., Basel, for their kind donation of ergocornine and CB-154.     

Effect of acetylcholine acetyl-hydrolase (E.C. 3.1.1.7) inhibition on the accumulation of pp' DDT in various brain regions of rats

Summary The concentration of pp' DDT given intraperitoneally in rats was determined in different brain regions. Maximum accumulation of pp' DDT was found in the corpus striatum, followed by cerebellum and cerebral cortex in that order; following pretreatment with paraoxon the concentrations of pp' DDT were increased in all brain regions studied. pp' DDT (1,1,1-trichloro-2,2-bis(4′-chlorophenyl ethane), used in the above studies was generously supplied by Montrose Chemical Corporation of California, USA. The authors are grateful to Mr M.Z. Hasan for analysis of the samples and to Sandoz, Basel, Switzerland for the gift of paraoxon.     

Phosphatidyl-N-(2 hydroxyethyl)-alanine synthesis of distearoyl L-α-glycerylphosphoryl-N-(2 hydroxyethyl)-alanine

Zusammenfassung Die erste Synthese eines Phosphatidyl-N-(2 hydroxyethyl)-alanins wird beschrieben.

---

---

Dedicated to Professor Dr.Erich Baer in honour of his 70th birthday.

---

The nomenclature used in this communication is that used byFischer andBaer for well-nigh 4 decades. However, according to the rules of IUPAC-IUB commission this should be 1,2-distearoylsn-glycero-3-phosphoryl-N-(2-hydroxyethyl)-alanine.

---

The authors thank the National Institute of Health (USA) and the Medical Research Council (Canada) for making the grants available to ProfessorE. Baer, which made this work possible.

---

The authors thank Dr.J. von Euw and Professor Dr.T. Reichstein of the University of Basel (Switzerland) for kindly providing the rotation. As the optical purity is a very important criterion of the activity of the phospholipids; this has been determined on the Schmid and Heansch polarimeter (visual) as well as on the Perkin Elmer polarimeter (photoelectric) with excellent agreement.     

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.     

Bromocriptine-induced removal of endoplasmic membranes from prolactinoma cells

Summary Adenomatous prolactin cells lose 39% of their cytoplasm volume within 7 days after the beginning of bromocriptine treatment. A simultaneous reduction of the rough-surfaced endoplasmic reticulum and the Golgi apparatus occurs. Their membranes are removed by rapid transport along the secretory pathway to the cell surface and to lysosomal destruction.We thank Prof. E. del Pozo, Sandoz Ltd, Basle, for the generous gift of injectable bromocriptine, Prof. E.R. Weibel, Dept. of Anatomy, University of Bern, for his technical advice, Dr U. Helfenstein, Institute of Biostatistics, University of Zürich, for his help in the statistical evaluation of the results and the EMDO-Foundation, Zürich, for financial support.     

Anticonvulsant action of YG 19-256 in baboons with photosensitive epilepsy

Summary YG 19-256, 4-(1,3,4,9b-tetrahydro-5 methyl-2H-indeno[1,2-c]pyridine-2-yl)-2-butanone methane sulphonate, 1–3 mg/kg i.v., abolished or reduced photically-induced myoclonic responses for 1.5–6.5 h in baboons,Papio papio, without producing signs of acute neurological toxicity.We thank the Medical Research Council, The Wellcome Trust and the British Epilepsy Association for financial support, and Drs D.M. Loew and H. Weber (Sandoz Ltd) for the gift of YG 19-256.     

Freeze tolerance in the frog,Rana sylvatica

Summary Wood frogs survive extracellular freezing at moderate subzero temperatures (–4°C) for at least 11 days. Freezing survival is aided by the accumulation of high concentrations of glucose as a cryoprotectant in blood and tissues. Glucose production was accompanied by a rapid decline in liver, but not muscle, glycogen levels suggesting that liver is the organ controlling cryoprotectant synthesis.Acknowledgments. This study was supported by grants to L.M.G. from the Kroc Foundation (Santa Ynez, California) and from the National Institute of Dental Research (Grant No. DE-03987). The authors wish to thank K. Yorko, M. Shakin, J. Finan and Mrs N. Manivannan for their technical and secretarial assistance.Acknowledgments. I thank Dr J. Ballantyne, Dr F. Schueler and I. McMurray for help with frog collections and Dr. W. Schmid, Dr J. Bogart and Dr F. Cook for helpful discussions. Supported by an N.S.E.R.C. operating grant and by a grant from the Atkinson Charitable Foundation.     

Structure and stereochemistry of attenuol,a new lignan fromKnema attenuata (Wall.) Warb.

Summary A new lignan attenuol has been isolated from the bark ofKnema attenuata (Wall.) Warb. Its structure (I) is deduced on the basis of analytical and spectral data. The compound has been assigned the absolute configuration as 2S,3R-dimethyl-1S-(p-hydroxyphenyl)-6,7-methylenedioxytetralin (III).Contribution No. 487 from the Ciba-Geigy Research Centre.Acknowledgments. We thank Dr H. Fuhrer and Dr P. Moser of Ciba-Geigy Ltd. Basle for the NMR spectral data and ORD determinations and Dr S. Selvavinayakam and his colleagues for the analytical results.     

Nuclear pores. can they expand and contract to regulate nucleocytoplasmic exchange?

Summary Recent evidence has revived the idea that translocation of macromolecules between nucleus and cytoplasm may be regulated via expansion and contraction of the entire diameter of the nuclear pore complex. The present investigation does not support this hypothesis.Acknowledgments. We are indebted to Dr J.H.M. Willison for discussion of his and Dr Rajaraman's results before their publication. We also wish to thank Dr C. Thurston, Dr D.H. Williamson and Dr K. Lambert for providing some of the specimens used in this investigation. N.J. Severs acknowledges the support of the Science Research Council and the Cancer Research Campaign.     

Influence of chronic treatment with 2-bromo-α-ergocryptine (CB-154) on the reproductive and lactational performance of the C3H/HeJ female mouse

Zusammenfassung C3H/HeJ-weibliche Mäuse, die vor der Paarung dauernd mit CB-154, einem stark wirkenden Mittel zur Unterdrückung der Prolactinsekretion, behandelt wurden, wiesen keine bedeutsame Schädigung ihrer Fortpflanzungsfähigkeit auf. CB-154 Dauerbehandlung von weiblichen Mäusen sowohl während der Paarung als auch während der Laktation führte zu einer bedeutsamen Herabsetzung der Fruchtbarkeit und Milchabsonderung.

---

---

Supported by NIH research grant No. CA-13777 and American Cancer Society research grant No. ET-59.

---

NIH Research Career Development Awardee No. CA-35027

---

CB-154 was provided through the courtesy of Dr.Richard Elton, Sandoz Pharmaceuticals, East Hanover, N. J., USA.

---

Thanks are given toMs. Carol Gribler for her assistance in this study.     

Testing of rifampicin on possible genetic effects onDrosophila melanogaster and human leukocyte chromosomes in vitro

Zusammenfassung Mutagenitätsuntersuchungen von Rifampicin anDrosophila melanogas (X-chromosomale rezessive Letalmutationen) und an menschlichen Leukozytenchromosomen in vitro ergaben keine Anhaltspunkte für eine genetische Wirksamkeit dieser Substanz.

---

---

We thank Mrs.R. Pieper for her carful technical assistance. We are also grateful to ProfessorR. Hess and Dr.J. Gelzer (Ciba-Geigy, Basel) for the supply of rifampicin.     

Differential effects of opiates on the incorporation of [14C] thiamine in the central nervous system of the rat

Summary Opiate agonist (morphine), pure antagonist (naloxone), mixed agonist-antagonist (nalorphine) and analgesically inactive enantiomorph (dextrorphan) produced differential stereoselective effects on the incorporation of [¹⁴C] thiamine in the central nervous system of the rats. The possible role of thiamine in opiate effects and its implications are discussed.To whom reprint requests should be addressed. The authors thank Dr. S. J. Mulé, Assistant Commissioner and Director, ODAS Testing and Research Laboratory, for his kind interest and support and Mrs J. Vardy, Mr A. Kramer and Mr V. Aschettino for assistance.