CLINICAL EVALUATION OF FORMAMIDINYLIMINOUREA, A NEW BIGUANIDE ORAL BLOOD SUGAR LOWERING COMPOUND: COMPARISON WITH OTHER HYPOGLYCEMIC AGENTS
Authors: L P KRALL, R F BRADLEY
Journal: Annals of Internal Medicine (1959)

Article1 March 1959CLINICAL EVALUATION OF FORMAMIDINYLIMINOUREA, A NEW BIGUANIDE ORAL BLOOD SUGAR LOWERING COMPOUND: COMPARISON WITH OTHER HYPOGLYCEMIC AGENTSLEO P. KRALL, M.D., ROBERT F. BRADLEY, M.D.LEO P. KRALL, M.D.Search for more papers by this author, ROBERT F. BRADLEY, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-50-3-586 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThe search for orally effective hypoglycemic agents preceded the advent of insulin by several years. Although this report evaluates the biguanides and compares them to other hypoglycemic agents, a look at the compounds in earlier use, particularly the guanidines, shows that the roots of the problem go back over 40 years.THE EARLIER HYPOGLYCEMIC AGENTSEarly observation that tetany resulting from parathyroidectomy was accompanied by hypoglycemia1and increased levels of guanidine in the blood2led in 1918 to Watanabe's3correlation between a marked effect of guanidine on intermediary metabolism and decreased blood glucose levels. Frank, Stern and Nothmann4showed that...Bibliography1. UnderhillBlatherwick FPNR: Studies in carbohydrate metabolism, J. Biol. Chem. 18: 87, 1914. CrossrefGoogle Scholar2. PatonFindlay DNL: The parathyroids—tetania parathyreopriva: its nature, cause and relations to idiopathic tetany, Quart. J. Exper. Physiol. 10: 203, 1916. CrossrefGoogle Scholar3. Watanabe CK: Studies in the metabolic changes induced by administration of guanidine bases, J. Biol. Chem. 33: 253, 1918. CrossrefGoogle Scholar4. FrankSternNothmann ERM: Die Guanidin und Demethylguanidin Toxikose des Säugetier und ihre physio-pathologische Bedeutung, Ztschr. f. d. ges. exper. Med. 24: 343, 1921. CrossrefGoogle Scholar5. FrankNothmannWagner EMA: Über synthetisch dargestellte Körper mit insulinartiger Wirkung auf den normalen und diabetischen Organismus, Klin. Wchnschr. 5: 2100, 1926. CrossrefGoogle Scholar6. FrankNothmannWagner EMA: Die Synthalin Behandlung des Diabetes mellitus, Deutsche med. Wchnschr. 52: 2067 and 2107, 1926. CrossrefGoogle Scholar7. FrankWagner EA: Über die experimentelle und klinische Wirkung des Decadekamethylendiguanids, Klin. Wchnschr. 7: 1996, 1928. CrossrefGoogle Scholar8. FrankWagner EA: Der gegenwartige Stand der Synthalinbehandlung des Diabetes mellitus, Ergebn. d. ges. Med. 13: 451, 1929. Google Scholar9. Duncan GG: Synthalin in treatment of diabetes mellitus, Am. J. M. Sc. 175: 196, 1928. CrossrefGoogle Scholar10. StahlBahn RK: Zur Kenntnis der Thrombophlebitis und Sepsis postanginosa, Deutsche med. Wchnschr. 53: 1687, 1927. CrossrefGoogle Scholar11. Morawitz P: Unsere Erfahrungen mit Synthalin, München. med. Wchnschr. 74: 571, 1927. Google Scholar12. Adler A: Über die Nebenwirkungen des Synthalin und ihre Beseitigung, Klin. Wchnschr. 6: 493, 1927. CrossrefGoogle Scholar13. Szczeklik R: Über die toxischen Nebenwirkungen des Synthalins, Wien. klin. Wchnschr. 40: 1075, 1927. Google Scholar14. RalliGuion ECM: Synthalin in the treatment of diabetes, J. Lab. and Clin. Med. 14: 699, 1929. Google Scholar15. Bertram F: Zum Wirkungsmechanismus des Synthalins, Deutsches Arch. f. klin. Med. 158: 76, 1927. Google Scholar16. Hornung S: Synthalin und Leberschadigung, Klin. Wchnschr. 7: 69, 1928. CrossrefGoogle Scholar17. BodoMarks RHP: Synthalin and carbohydrate metabolism, J. Physiol. 65: 83, 1928. CrossrefMedlineGoogle Scholar18. KarrBelkPetty WGWPOH: The toxicity of Synthaline, J. Pharmacol. and Exper. Therap. 36: 61, 1929. Google Scholar19. Minot AS: The mechanism of the hypoglycemia produced by guanidine and carbon tetrachloride poisoning and its relief by medication, J. Pharmacol. and Exper. Therap. 43: 295, 1931. Google Scholar20. Creutzfeldt W: Alpha cell cytotoxins, Diabetes 6: 135, 1957. CrossrefMedlineGoogle Scholar21. Simola PE: Ueber die Wirkung des Synthalins im Tierorganismus, Ztschr. f. physiol. Chem. 168: 274, 1927. CrossrefGoogle Scholar22. StaubKüng HO: Zum Synthalinmechanismus, Klin. Wchnschr. 7: 1365, 1928. CrossrefGoogle Scholar23. MinotDoddSaunders ASKJM: Acidosis of guanidine intoxication, J. Clin. Investigation 13: 917, 1934. CrossrefMedlineGoogle Scholar24. DeboisDefauwHoet CJJ: Sur le mécanisme d'action d'un dérive polymethyle de la guanidine, Compt. rend. Soc. de biol. 97: 1420, 1927. Google Scholar25. MinotDoddBryan ASKR: Chemical action of sodium citrate as a cause of certain transfusion reactions, Am. J. Dis. Child. 45: 32, 1933. Google Scholar26. Martensson J: Effect of guanidine and Synthalin on the citric acid metabolism, Acta med. Scandinav. 125: 82, 1946. CrossrefGoogle Scholar27. Davis JC: Hydropic degeneration of the alpha cells of the pancreatic islets produced by Synthalin A, J. Path. and Bact. 64: 575, 1952. CrossrefMedlineGoogle Scholar28. Fodden IH: Experiments with chemicals noxious to the pancreatic alpha cells, Am. J. Clin. Path. 23: 994 and 1002, 1952. CrossrefGoogle Scholar29. Davis JC: Mitoses and the protective effect of anesthetics in Synthalin nephritis, J. Path. and Bact. 67: 17, 1954. CrossrefMedlineGoogle Scholar30. Hollunger G: Guanidines and oxidative phosphorylations, Acta pharmacol. et toxicol. 11, Supp. 1: 1, 1955. MedlineGoogle Scholar31. Allen FM: Blueberry leaf extract: physiologic and clinical properties in relation to carbohydrate metabolism, J. A. M. A. 89: 1577, 1927. CrossrefGoogle Scholar32. BlotnerMurphy HWP: Effect of certain liver extracts on the blood sugar of diabetic patients, J. A. M. A. 94: 1811, 1930. CrossrefGoogle Scholar33. JanbonChaptalVedelSchaap MJAJ: Accidents hypoglycémiques graves par un sulfamidothiazol (le VK 57 ou 2254 RP), Montpellier méd. 21-22: 441, 1942. Google Scholar34. Loubatières A: The hypoglycemic sulfonamides: history and development of the problem from 1942 to 1955, Ann. New York Acad. Sc. 71: 4, 1957. CrossrefMedlineGoogle Scholar35. FrankeFuchs HJ: Ein neues antidiabetisches Prinzip, Ergebnisse klinischer Untersuchungen, Deutsche med. Wchnschr. 80: 1449, 1955. CrossrefMedlineGoogle Scholar36. MarbleCamerini-Dávalos AR: Clinical experience with sulfonylurea compounds in diabetes, Ann. New York Acad. Sc. 71: 239, 1957. CrossrefMedlineGoogle Scholar37. SlottaTschesche KHR: Über Biguanide. II. Die Blutzucker-senkende Wirkung der Biguanide, Ber. deutsch. chem. Gesellsch. 62B: 1398-1405 (June) 1929. CrossrefGoogle Scholar38. UngarFreedmanShapiro GLSL: Pharmacological studies of a new oral hypoglycemic drug, Proc. Soc. Exper. Biol. and Med. 95: 190-192 (May) 1957. CrossrefMedlineGoogle Scholar39. PomeranzeFujiyMouratoff JHGT: Clinical report of a new hypoglycemic agent, Proc. Soc. Exper. Biol. and Med. 95: 193-194 (May) 1957. CrossrefMedlineGoogle Scholar40. KrallCamerini-Dávalos LPR: Early clinical evaluation of a new oral nonsulfonylurea hypoglycemic agent, Proc. Soc. Exper. Biol. and Med. 95: 345-347 (June) 1957. CrossrefMedlineGoogle Scholar41. WilliamsTannerOdell RHDCWD: Hypoglycemic actions of phenethyl-, amyl-, and isoamyl-diguanide, Diabetes 7: 87-92 (Mar.-Apr.) 1958. CrossrefMedlineGoogle Scholar42. KrallCamerini-Dávalos LPR: Clinical trials with DBI, a new nonsulfonylurea oral hypoglycemic agent, Arch. Int. Med. 102: 25-31 (July) 1958. CrossrefGoogle Scholar43. OdellTannerSteinerWilliams WDDCDFRH: Phenethyl-, amyl-, and isoamyl-biguanide in the treatment of diabetes mellitus, Arch. Int. Med. 102: 520 (Oct.) 1958. CrossrefGoogle Scholar44. NielsenSwansonTannerWilliamsO'Connell RLHEDCRHM: Effects on blood sugar of a new potent hypoglycemic compound, Arch. Int. Med. 101: 211, 1958. CrossrefGoogle Scholar45. Ungar G (a) : Personal communication. (b) Drury, D. R., Wick, A. N., and Morita, T. N.: Lactic acid oxidation in extrahepatic tissue, Am. J. Physiol. 180: 345, 1955. Google Scholar46. SchmidtHughesSmith LHHBCC: On the pharmacology of N1-parachlorophenyl-N5-isopropylbiguanide (Paludrine), J. Pharmacol. and Exper. Therap. 90: 233, 1947. MedlineGoogle Scholar47. ChenAnderson KKRC: The toxicity and general pharmacology of N1-parachlorophenyl-N5-isopropylbiguanide, J. Pharmacol. and Exper. Therap. 91: 157, 1947. MedlineGoogle Scholar48. GoodmanGilman LA: The pharmacological basis of therapeutics, 2nd Ed., 1955, The Macmillan Co., New York, p. 1177. Google Scholar49. WilliamsTybergheinHydeNielsen RHJMPRL: Studies related to the hypoglycemic action of phenethyldiguanide, Metabolism 6: 311-319, 1957. MedlineGoogle Scholar50. TybergheinWilliams JMRH (a) : Metabolic effects of phenethyldiguanide, a new hypoglycemic compound, Proc. Soc. Exper. Biol. and Med. 96: 29, 1957. (b) Fajans, S. S., Moorhouse, J. A., Doorenbos, H., Louis, L. H., and Conn, J. W.: Metabolic effects of phenethylformamidinyliminourea (DBI) in normal subjects and diabetic patients, Clin. Res. 6: 252, 1958. CrossrefMedlineGoogle Scholar51. Tyberghein JM: Unpublished data. Google Scholar52. SteinerWilliams DFRH: The effects of biguanide compounds upon respiratory enzymes, Clin. Res. 6: 55, 1958. Google Scholar53. WickLarsonSerif ANERGS: A site of action of phenethylbiguanide: a hypoglycemic compound, J. Biol. Chem. 233: 296 (Aug.) 1958. CrossrefMedlineGoogle Scholar54. Harper HA: Review of physiological chemistry, 5th Ed., 1955, Lange Medical Publications, Los Altos, California, p. 134. Google Scholar55. HoreckerHiatt BLHH: Pathways of carbohydrate metabolism in normal and neoplastic cells, New England J. Med. 258: 177, 1958. CrossrefMedlineGoogle Scholar56. StettenTopper DYJ: The metabolism of carbohydrates, Am. J. Med. 19: 96-110 (July) 1955. CrossrefMedlineGoogle Scholar57. LevineGoldsteinHuddlestonKlein RMSBSP: Action of insulin on the "permeability" of cells to free hexoses as studied by its effect on the distribution of galactose, Am. J. Physiol. 163: 70, 1950. CrossrefMedlineGoogle Scholar58. Stadie WC: On the mechanism of insulin action, Am. J. Med. 19: 257-273 (Aug.) 1955. CrossrefMedlineGoogle Scholar59. RenoldHastingsNesbettAshmore AEABFBJ: Studies on carbohydrate metabolism in rat liver slices. IV. Biochemical sequence of events after insulin administration, J. Biol. Chem. 213: 135, 1955. CrossrefMedlineGoogle Scholar60. FajansLouisHennesWajchenbergJohnsonGittlerAckermanConn SSLHARBLRDDDIPJW: Metabolic effects of sulfonylureas in normal man and in various types of diabetic patients, Ann. New York Acad. Sc. 71: 207, 1957. CrossrefMedlineGoogle Scholar61. PfeifferSteigerwaldSandritterBänderMagerBeckerRetiene EFHWAAUK: Vergleichende Untersuchungen von Morphologie und Hormongehalt des Kälberpancreas nach Sulfonylbarnstaffen (D860), Deutsche med. Wchnschr. 82: 1568, 1957. CrossrefMedlineGoogle Scholar62. RenoldMartinBoshellThorn AEDBBRGW: Studies on the site of action of the arylsulfonylureas in man, Ann. New York Acad. Sc. 71: 71, 1957. CrossrefMedlineGoogle Scholar63. PomeranzeGadek JRJ: Clinical evaluation of a new hypoglycemic drug, in preparation. Google Scholar64. WellerMacaulay CA: Preliminary observations on the use of a new hypoglycemic substance DBI, in preparation. Google Scholar65. SkillmanKrugerPetersonHamwi TGFALGGJ: Clinical studies with DBI, Clin. Res. 6: 253, 1958. Google Scholar66. Lenzner A: Personal communication. Google Scholar67. Camerini-DávalosMarbleRoot RAH: Clinical experience with orinase. A preliminary report, Metabolism 5: 904, 1956. MedlineGoogle Scholar68. Lambert TH: Clinical observations with a new oral hypoglycemic agent (DBI), Clin. Res. 6: 91, 1958. Google Scholar69. ButterfieldFryHolling JIKE: Effect of insulin, tolbutamide and phenethyldiguanidine on peripheral glucose uptake in man, Diabetes 7: 449-454, 1958. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Boston, Massachusetts*Received for publication May 12, 1958.Presented at the Thirty-ninth Annual Session of The American College of Physicians, Atlantic City, New Jersey, May 2, 1958.From the Joslin Clinic and New England Deaconess Hospital, Boston, Massachusetts.Requests for reprints should be addressed to Leo P. Krall, M.D., Joslin Clinic, 15 Joslin Road, Boston 15, Massachusetts. 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BARNES, M.D.Management of diabetes mellitusROLE OF ORAL BLOOD SUGAR-LOWERING AGENTS IN THE MANAGEMENT OF DIABETES 1 March 1959Volume 50, Issue 3Page: 586-613KeywordsGlucoseGlucose metabolismHospitalsHypoglycemicsIngestionInsulinLactic acidNauseaParathyroidectomyProteins ePublished: 1 December 2008 Issue Published: 1 March 1959 PDF downloadLoading ...