Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/12/07 09:39:55」(JST)

wiki en

Buformin (1-butylbiguanide) is an oral antidiabetic drug of the biguanide class, chemically related to metformin and phenformin. Buformin was marketed by German pharmaceutical company Grünenthal as Silubin.

Chemistry and animal toxicology

Buformin hydrochloride is a fine, white to slightly yellow, crystalline, odorless powder, with a weakly acidic bitter taste. Its melting point is 174 to 177 °C, it is a strong base, and is freely soluble in water, methanol and ethanol, but insoluble in chloroform and ether.^[1]^[2] Toxicity: guinea pig LD50 subcutaneous 18 mg/kg; mouse LD50 intraperitoneal 140 mg/kg and 300 mg/kg oral.^[3] The partition coefficient (log P in octanol-water) is -1.20E+00; its water solubility is 7.46E+05 mg/l at 25 °C. Vapor pressure is 1.64E-04 mm Hg at 25 °C (EST); Henry's law constant is 8.14E-16 atm-m3/mole at 25 °C (EST). Its Atmospheric -OH rate constant is 1.60E-10 cm3/molecule-sec at 25 °C.^[4]

Mechanism of action

Buformin delays absorption of glucose from the gastrointestinal tract, increases insulin sensitivity and glucose uptake into cells, and inhibits synthesis of glucose by the liver. Buformin and the other biguanides are not hypoglycemic, but rather antihyperglycemic agents. They do not produce hypoglycemia; instead, they reduce basal and postprandial hyperglycemia in diabetics.^[5] Biguanides may antagonize the action of glucagon, thus reducing fasting glucose levels.^[6]

Pharmacokinetics

After oral administration of 50 mg of buformin to volunteers, almost 90% of the applied quantity was recovered in the urine; the rate constant of elimination was found to be 0.38 per hr. Buformin is a strong base (pKa = 11.3) and not absorbed in the stomach. After intravenous injection of about 1 mg/kg buformin-14-C, the initial serum concentration is 0.2-0.4 µg/ml. Serum level and urinary elimination rate are linearly correlated.^[7] In man, after oral administration of 50 mg 14-C-buformin, the maximum serum concentration was 0.26-0.41 µg/ml. The buformin was eliminated with an average half-life of 2 h. About 84% of the dose administered was found excreted unchanged in the urine.^[8] Buformin is not metabolized in humans. The bioavailability of oral buformin and other biguanides is 40%-60%. Binding to plasma proteins is absent or very low.^[9]^[10]^[11]

Dosage

The daily dose of buformin is 150–300 mg by mouth.^[12] Buformin has also been available in a sustained release preparation, Silubin Retard, which is still sold in Romania.

Side effects and contraindications

The side effects encountered are anorexia, nausea, diarrhea, metallic taste, and weight loss. Its use is contraindicated in diabetic coma, ketoacidosis, severe infection, trauma, other severe infections where buformin is unlikely to control the hyperglycemia, renal or hepatic impairment, heart failure, recent myocardial infarct, dehydration, alcoholism, and conditions likely to predispose to lactic acidosis.

Toxicity

Buformin was withdrawn from the market in many countries due to an elevated risk of causing lactic acidosis (although not the US, where it was never sold). Buformin is still available and prescribed in Romania (timed release Silubin Retard is sold by Zentiva), Hungary,^[13]^[14]^[15]^[16] Taiwan^[17] and Japan.^[18] The lactic acidosis occurred only in patients with a buformin plasma level of greater than 0.60 µg/ml and was rare in patients with normal renal function.^[19]^[20]^[21] In one report, the toxic oral dose was 329 ± 30 mg/day in 24 patients who developed lactic acidosis on buformin. Another group of 24 patients on 258 ± 25 mg/day did not develop lactic acidosis on buformin.^[22]

Anticancer properties

Buformin, along with phenformin and metformin, inhibits the growth and development of cancer.^[23]^[24]^[25]^[26]^[27] The anticancer property of these drugs is due to their ability to disrupt the Warburg effect and revert the cytosolic glycolysis characteristic of cancer cells to normal oxidation of pyruvate by the mitochondria.^[28] Metformin reduces liver glucose production in diabetics and disrupts the Warburg effect in cancer by AMPK activation and inhibition of the mTor pathway.^[29]

History

Buformin was synthesized as an oral antidiabetic in 1957.^[30]

Synthesis

Buformin synthesis:^[31] Shapiro, Freedman, U.S. Patent 2,961,377 (1960 to USV).

Buformin is obtained by reaction of butylamine and 2-cyanoguanidine.

References

^ Jacker, HJ (1964). "New Pharmacologic Products. 2. Buformin For Oral Therapy Of Diabetes". Pharm Prax. 10: 247–9.
^ Eustace George Coverly Clarke, Judith Berle, Pharmaceutical Society of Great Britain. Dept. of Pharmaceutical Sciences. Isolation and identification of drugs in pharmaceuticals, body fluids and post-mortem material, Volume 1. Pharmaceutical Press 1974, p226
^ Shroff, JR; Bandurco, V; Desai, R; Kobrin, S; Cervoni, P (Dec 1981). "Chemistry and hypoglycemic activity of benzimidoylpyrazoles". J Med Chem 24 (12): 1521–5. doi:10.1021/jm00144a031.
^ United States National Library of Medicine ChemLDplus advanced database
^ Enrique Ravina, Hugo Kubinyi. The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. Wiley. 2011 p 215
^ Miller, RA; Chu, Q; Xie, J; Foretz, M; Viollet, B; Birnbaum, MJ (Feb 2013). "Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP". Nature 494 (7436): 256–60. doi:10.1038/nature11808. PMID 23292513.
^ Beckmann, R (Mar 1968). "The fate of biguanides in man". Ann N Y Acad Sci. 148 (3): 820–32.
^ Beckmann, R; Lintz, W; Schmidt-Böthelt, E (Sep 1971). "Evaluation of a sustained release form of the oral antidiabetic butylbiguanide (Silubin retard)". Eur J Clin Pharmacol 3 (4): 221–8. doi:10.1007/bf00565010.
^ Marchetti, P; Giannarelli, R; Carlo, A; Navalesi, R (Oct 1991). "Pharmacokinetic optimisation of oral hypoglycaemic therapy". Clin Pharmacokinet 21 (4): 308–17. doi:10.2165/00003088-199121040-00006. PMID 1760902.
^ Gutsche H, Blumenbach L, Losert W, Wiemann H. Concentration of 14C-1-butylbiguanide in plasma of diabetic patients and its elimination after administration of a new Galenical formulation. Arzneimittelforschung 1976;26(6):1227-9
^ Ritzl, F; Feinendegen, LE; Lintz, W; Tisljar, U (1978). "Distribution and excretion of 14c-butylbiguanide in man". Arzneimittelforschung 28 (7): 1184–6.
^ Gustav Kuschinsky, Heinz Lüllmann. Textbook of pharmacology. Academic Press p 225, 1973
^ Hankó, B; Tukarcs, E; Kumli, P; Vincze, Z (Jun 2005). "Antidiabetic drug utilization in Hungary". Pharm World Sci. 27 (3): 263–5. doi:10.1007/s11096-004-5804-1.
^ Hankó BZ, Reszegi CA, Kumli P, Vincze Z. [Practice of antidiabetic therapy in Hungary]. Acta Pharm Hung. 2005;75(2):77-86.
^ Jerry L. Schlesser, Gale Research Inc. Drugs available abroad. Derwent Publications, Ltd - 1990 p28
^ Verdonck L, Sangster B, van Heijst A, de Groot G, Maes R (1981). "Buformin concentrations in a case of fatal lactic acidosis". Diabetologia 20 (1): 45–6. doi:10.1007/BF01789112. PMID 7202882.
^ Chou, CH; Cheng, CL; Huang, CC (May 2004). "A validated HPLC method with ultraviolet detection for the determination of buformin in plasma". Biomed Chromatogr 18 (4): 254–8. doi:10.1002/bmc.312.
^ Takeda Announces Submission Of Application For Additional Indication Of Actos In Japan; Concomitant Therapy With Biguanides For Type 2 Diabetes. Medical News Today. 28 Jan 2007
^ Wittmann P, Haslbeck M, Bachmann W, Mehnert H. [Lactic acidosis in diabetics on biguanides (author's translation)] Deutsche Medizinische Wochenschrift 102(1):5-10, 1977
^ Berger, W; Mehnert-Aner, S; Mülly, K; Heierli, C; Ritz, R (1976). "[10 cases of lactic acidosis during biguanide therapy (buformin and phenformin)].". Schweizerische medizinische Wochenschrift 106: 1830–1834.
^ Deppermann D, Heidland A, Ritz E, Hörl W (1978). "[Lactic acidosis--a possible complication in buformin-treated diabetics (author's transl)]". Klin Wochenschr 56 (17): 843–53. PMID 713413.
^ Luft, D; Schmülling, RM; Eggstein, M (Feb 1978). "Lactic acidosis in biguanide-treated diabetics: a review of 330 cases". Diabetologia 14 (2): 75–87. doi:10.1007/bf01263444.
^ Saito, Sakae; Furuno, Aki; Sakurai, Junko; Sakamoto, Asami; Park, Hae-Ryong; Shin-ya, Kazuo; Tsuruo, Takashi; Tomida, Akihiro (2009). "Chemical Genomics Identifies the Unfolded Protein Response as a Target for Selective Cancer Cell Killing during Glucose Deprivation". Cancer Research 69 (10): 4225–34. doi:10.1158/0008-5472.can-08-2689.
^ Vladimir N. Anisimov. "Insulin/IGF-1 signaling pathway driving aging and cancer as a target for pharmacological intervention. Experimental Gerontology Volume 38, Issue 10, October 2003, Pages 1041-1049
^ Alexandrov, Valery A.; Anisimov, Vladimir N.; Belous, Natalia M.; Vasilyeva, Inna A.; Mazon, Vera B. (1980). "The inhibition of the transplacental blastomogenic effect of nitrosomethylurea by postnatal administration of buformin to rats". Carcinogenesis 1 (12): 975–978. doi:10.1093/carcin/1.12.975.
^ Anisimov, VN; Ostroumova, MN; Dil'man, VM (1980). "Inhibition of the blastomogenic effect of 7,12-dimethylbenz(a)anthracene in female rats by buformin, diphenin, a polypeptide pineal extract and L-DOPA". Bulletin of Experimental Biology and Medicine 89 (6): 819–822. doi:10.1007/bf00836263.
^ Anisimov, Vladimir N.; Berstein, Lev M.; Popovich, Irina G.; Zabezhinski, Mark A.; Egormin, Peter A.; Tyndyk, Margarita L.; Anikin, Ivan V.; Semenchenko, Anna V.; Yashin, Anatoli I. (2005). "Central and Peripheral Effects of Insulin/IGF-1 Signaling in Aging and Cancer: Antidiabetic Drugs as Geroprotectors and Anticarcinogens". Annals of the New York Academy of Sciences 1057: 220–234. doi:10.1196/annals.1356.017.
^ Vander Heiden, Matthew G.; Cantley, Lewis C.; Thompson, Craig B. (2009). "Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation". Science 324 (5930): 1029–1033. doi:10.1126/science.1160809.
^ Shaw, RJ; Lamia, KA; Vasquez, D; Koo, SH; Bardeesy, N; Depinho, RA; Montminy, M; Cantley, LC (Dec 2005). "The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin". Science 310 (5754): 1642–6. doi:10.1126/science.1120781.
^ Seymour L. Shapiro et al. Salts Of N-Amylbiguanide. US Patent number: 2961377; Filing date: Aug 5, 1957; Issue date: 1960
^ Shapiro, S. L.; Parrino, V. A.; Freedman, L. (1959). "Hypoglycemic Agents. III.1—3N1-Alkyl- and Aralkylbiguanides". Journal of the American Chemical Society 81 (14): 3728. doi:10.1021/ja01523a060.

English Journal

Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria.

Bridges HR1, Jones AJ1, Pollak MN2, Hirst J1.
The Biochemical journal.Biochem J.2014 Sep 15;462(3):475-87. doi: 10.1042/BJ20140620.
The biguanide metformin is widely prescribed for Type II diabetes and has anti-neoplastic activity in laboratory models. Despite evidence that inhibition of mitochondrial respiratory complex I by metformin is the primary cause of its cell-lineage-specific actions and therapeutic effects, the molecu
PMID 25017630

Do metformin a real anticarcinogen? A critical reappraisal of experimental data.

Anisimov VN1.
Annals of translational medicine.Ann Transl Med.2014 Jun;2(6):60. doi: 10.3978/j.issn.2305-5839.2014.06.02.
Evidence has emerged that antidiabetic biguanides [phenformin (PF), buformin (BF) and metformin (MF)] are promising candidates for prevention of cancer. It was shown that antidiabetic biguanides postpone spontaneous carcinogenesis as well as inhibit carcinogenesis induced by chemical, radiation and
PMID 25333035

Glucose deprivation induces G2/M transition-arrest and cell death in N-GlcNAc2-modified protein-producing renal carcinoma cells.

Isono T1, Chano T2, Kitamura A1, Yuasa T3.
PloS one.PLoS One.2014 May 5;9(5):e96168. doi: 10.1371/journal.pone.0096168. eCollection 2014.
Some cancer cells can survive under glucose deprivation within the microenvironment of a tumor. Recently, we reported that N-linked (β-N-acetylglucosamine)2 [N-GlcNAc2]-modified proteins induce G2/M arrest and cell death under glucose deprivation. Here, we investigated whether such a response to gl
PMID 24796485

Japanese Journal

Regulation of Glyceraldehyde 3-Phosphate Dehydrogenase Expression by Metformin in HepG2 Cells

Yokoyama Yuichi,Kubota Masafumi,Iguchi Kazuhiro [他],Usui Shigeyuki,Kiho Tadashi,Hirano Kazuyuki
Biological and Pharmaceutical Bulletin 32(7), 1160-1165, 2009
… We previously reported that buformin suppressed the expression of glyceraldehyde 3-phosphate dehydrogenase (GAPD) and suggested that this decrease was one of the causes of lactic acidosis. …
NAID 130000117210

グリベンクラミドの効果減弱を来した2型糖尿病4症例におけるピオグリタゾンの有効性の検討

仲舛純一,村上啓治
糖尿病 = Journal of the Japan Diabetes Society 50(5), 313-318, 2007-05-30
グリベンクラミド（以下GC）血糖低下作用が減弱した症例へのインスリン（以下In）抵抗性改善薬であるピオグリタゾン（以下Pio）併用の有効性を報告する．症例は未治療2型糖尿病患者で女性1例男性3例である．全例に0.625 mgのGCで治療を開始した．全例で血糖値，HbA1cは低下し効果が確認された．投与継続中に効果の減弱が認められたため，3症例はGCの増量とブホルミン100 mgを追加投与した．一定 …
NAID 10019552687

Prediction of the Metabolic Interaction of Nateglinide with Other Drugs Based on in Vitro Studies

TAKANOHASHI Toshiyuki,KOIZUMI Tomonori,MIHARA Ryuichi,OKUDAIRA Kazuho
Drug Metabolism and Pharmacokinetics 22(6), 409-418, 2007
… We examined the effects of 18 drugs that may be prescribed together with nateglinide (metformin, buformin, aspirin, gemfibrozil, simvastatin, pioglitazone, rosiglitazone, carbamazepine, clarithromycin, gliclazide, clofibrate, fluconazole, bezafibrate, phenylbutazone, nifedipine, famotidine, ibuprofen and miconazole) on the conversion of nateglinide to its major metabolite (N-[trans-4-(1-hydroxy-1-methylethyl)-cyclohexanecarbonyl]-D-phenylalanine) using human liver microsomes. …
NAID 130004463001

Related Pictures

★リンクテーブル★

リンク元	「ブホルミン」
拡張検索	「buformin hydrochloride」

「ブホルミン」

Buformin
Clinical data
Routes of; administration	Oral
Pharmacokinetic data
Excretion	Renal
Identifiers
CAS Number	692-13-7
ATC code	A10BA03
PubChem	CID: 2468
DrugBank	DB04830
ChemSpider	2374
UNII	W2115E9C7B
KEGG	D00595
ChEMBL	CHEMBL39736
Chemical data
Formula	C6H15N5
Molecular mass	157.22 g·mol−1
	SMILES CCCCNC(=N)NC(=N)N ;
	InChI InChI=1S/C6H15N5/c1-2-3-4-10-6(9)11-5(7)8/h2-4H2,1H3,(H6,7,8,9,10,11) ; Key:XSEUMFJMFFMCIU-UHFFFAOYSA-N ;

　　[★]

英: buformin、buformin hydrochloride
化: 塩酸ブホルミン
商: ジベトス、ジベトン
関: 糖尿病治療薬、ビグアナイド系薬物

副作用

ジベトス錠50mg

乳酸アシドーシス（0.1%未満）
重篤かつ遷延性の低血糖症（0.1%未満）

「buformin hydrochloride」

　　[★]

塩酸ブホルミン

関: buformin

[1] Jacker, HJ (1964). "New Pharmacologic Products. 2. Buformin For Oral Therapy Of Diabetes". Pharm Prax. 10: 247–9.

[2] Eustace George Coverly Clarke, Judith Berle, Pharmaceutical Society of Great Britain. Dept. of Pharmaceutical Sciences. Isolation and identification of drugs in pharmaceuticals, body fluids and post-mortem material, Volume 1. Pharmaceutical Press 1974, p226

[3] Shroff, JR; Bandurco, V; Desai, R; Kobrin, S; Cervoni, P (Dec 1981). "Chemistry and hypoglycemic activity of benzimidoylpyrazoles". J Med Chem 24 (12): 1521–5. doi:10.1021/jm00144a031.

[4] United States National Library of Medicine ChemLDplus advanced database

[5] Enrique Ravina, Hugo Kubinyi. The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. Wiley. 2011 p 215

[6] Miller, RA; Chu, Q; Xie, J; Foretz, M; Viollet, B; Birnbaum, MJ (Feb 2013). "Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP". Nature 494 (7436): 256–60. doi:10.1038/nature11808. PMID 23292513.

[7] Beckmann, R (Mar 1968). "The fate of biguanides in man". Ann N Y Acad Sci. 148 (3): 820–32.

[8] Beckmann, R; Lintz, W; Schmidt-Böthelt, E (Sep 1971). "Evaluation of a sustained release form of the oral antidiabetic butylbiguanide (Silubin retard)". Eur J Clin Pharmacol 3 (4): 221–8. doi:10.1007/bf00565010.

[9] Marchetti, P; Giannarelli, R; Carlo, A; Navalesi, R (Oct 1991). "Pharmacokinetic optimisation of oral hypoglycaemic therapy". Clin Pharmacokinet 21 (4): 308–17. doi:10.2165/00003088-199121040-00006. PMID 1760902.

[10] Gutsche H, Blumenbach L, Losert W, Wiemann H. Concentration of 14C-1-butylbiguanide in plasma of diabetic patients and its elimination after administration of a new Galenical formulation. Arzneimittelforschung 1976;26(6):1227-9

[11] Ritzl, F; Feinendegen, LE; Lintz, W; Tisljar, U (1978). "Distribution and excretion of 14c-butylbiguanide in man". Arzneimittelforschung 28 (7): 1184–6.

[12] Gustav Kuschinsky, Heinz Lüllmann. Textbook of pharmacology. Academic Press p 225, 1973

[13] Hankó, B; Tukarcs, E; Kumli, P; Vincze, Z (Jun 2005). "Antidiabetic drug utilization in Hungary". Pharm World Sci. 27 (3): 263–5. doi:10.1007/s11096-004-5804-1.

[14] Hankó BZ, Reszegi CA, Kumli P, Vincze Z. [Practice of antidiabetic therapy in Hungary]. Acta Pharm Hung. 2005;75(2):77-86.

[15] Jerry L. Schlesser, Gale Research Inc. Drugs available abroad. Derwent Publications, Ltd - 1990 p28

[Verdonck-16] Verdonck L, Sangster B, van Heijst A, de Groot G, Maes R (1981). "Buformin concentrations in a case of fatal lactic acidosis". Diabetologia 20 (1): 45–6. doi:10.1007/BF01789112. PMID 7202882.

[17] Chou, CH; Cheng, CL; Huang, CC (May 2004). "A validated HPLC method with ultraviolet detection for the determination of buformin in plasma". Biomed Chromatogr 18 (4): 254–8. doi:10.1002/bmc.312.

[18] Takeda Announces Submission Of Application For Additional Indication Of Actos In Japan; Concomitant Therapy With Biguanides For Type 2 Diabetes. Medical News Today. 28 Jan 2007

[19] Wittmann P, Haslbeck M, Bachmann W, Mehnert H. [Lactic acidosis in diabetics on biguanides (author's translation)] Deutsche Medizinische Wochenschrift 102(1):5-10, 1977

[20] Berger, W; Mehnert-Aner, S; Mülly, K; Heierli, C; Ritz, R (1976). "[10 cases of lactic acidosis during biguanide therapy (buformin and phenformin)].". Schweizerische medizinische Wochenschrift 106: 1830–1834.

[Deppermann-21] Deppermann D, Heidland A, Ritz E, Hörl W (1978). "[Lactic acidosis--a possible complication in buformin-treated diabetics (author's transl)]". Klin Wochenschr 56 (17): 843–53. PMID 713413.

[22] Luft, D; Schmülling, RM; Eggstein, M (Feb 1978). "Lactic acidosis in biguanide-treated diabetics: a review of 330 cases". Diabetologia 14 (2): 75–87. doi:10.1007/bf01263444.

[23] Saito, Sakae; Furuno, Aki; Sakurai, Junko; Sakamoto, Asami; Park, Hae-Ryong; Shin-ya, Kazuo; Tsuruo, Takashi; Tomida, Akihiro (2009). "Chemical Genomics Identifies the Unfolded Protein Response as a Target for Selective Cancer Cell Killing during Glucose Deprivation". Cancer Research 69 (10): 4225–34. doi:10.1158/0008-5472.can-08-2689.

[24] Vladimir N. Anisimov. "Insulin/IGF-1 signaling pathway driving aging and cancer as a target for pharmacological intervention. Experimental Gerontology Volume 38, Issue 10, October 2003, Pages 1041-1049

[25] Alexandrov, Valery A.; Anisimov, Vladimir N.; Belous, Natalia M.; Vasilyeva, Inna A.; Mazon, Vera B. (1980). "The inhibition of the transplacental blastomogenic effect of nitrosomethylurea by postnatal administration of buformin to rats". Carcinogenesis 1 (12): 975–978. doi:10.1093/carcin/1.12.975.

[26] Anisimov, VN; Ostroumova, MN; Dil'man, VM (1980). "Inhibition of the blastomogenic effect of 7,12-dimethylbenz(a)anthracene in female rats by buformin, diphenin, a polypeptide pineal extract and L-DOPA". Bulletin of Experimental Biology and Medicine 89 (6): 819–822. doi:10.1007/bf00836263.

[27] Anisimov, Vladimir N.; Berstein, Lev M.; Popovich, Irina G.; Zabezhinski, Mark A.; Egormin, Peter A.; Tyndyk, Margarita L.; Anikin, Ivan V.; Semenchenko, Anna V.; Yashin, Anatoli I. (2005). "Central and Peripheral Effects of Insulin/IGF-1 Signaling in Aging and Cancer: Antidiabetic Drugs as Geroprotectors and Anticarcinogens". Annals of the New York Academy of Sciences 1057: 220–234. doi:10.1196/annals.1356.017.

[28] Vander Heiden, Matthew G.; Cantley, Lewis C.; Thompson, Craig B. (2009). "Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation". Science 324 (5930): 1029–1033. doi:10.1126/science.1160809.

[29] Shaw, RJ; Lamia, KA; Vasquez, D; Koo, SH; Bardeesy, N; Depinho, RA; Montminy, M; Cantley, LC (Dec 2005). "The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin". Science 310 (5754): 1642–6. doi:10.1126/science.1120781.

[30] Seymour L. Shapiro et al. Salts Of N-Amylbiguanide. US Patent number: 2961377; Filing date: Aug 5, 1957; Issue date: 1960

[31] Shapiro, S. L.; Parrino, V. A.; Freedman, L. (1959). "Hypoglycemic Agents. III.1—3N1-Alkyl- and Aralkylbiguanides". Journal of the American Chemical Society 81 (14): 3728. doi:10.1021/ja01523a060.

匿名

検索

案内

案内

buformin