丁雙胍

丁雙胍
別名	N-Butylimidocarbonimidic diamide[來源請求]
識別
CAS號	692-13-7
PubChem	2468
ChemSpider	2374
SMILES	CCCCn:c(:[nH]):[nH]:c(:[nH]):[nH2];
EINECS	211-726-4
DrugBank	DB04830
KEGG	D00595
MeSH	Buformin
性質
化學式	C6H15N5
摩爾質量	157.22 g·mol−1
log P	-1.2
藥理學
給藥途徑	口服
	藥代動力學：
排泄	腎臟
相關物質
相關化學品	Carmustine; Methylarginine; Asymmetric dimethylarginine; Acecarbromal;
	若非註明，所有數據均出自標準狀態（25 ℃，100 kPa）下。

丁二胍，又名丁雙胍，藥品名丁福明（INN：（buformin）），是一種口服降血糖藥，於1957年被合成^[2]，主要用於二型糖尿病的治療，與二甲雙胍、苯乙雙胍同屬於雙胍類口服降血糖藥。

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化學性質

鹽酸丁二胍是白色或黃色，無味，晶體粉末，嚐起來有微酸苦味。

熔點 174 到 177°C，為強鹼，可溶於水、甲醇、乙醇，不溶於氯仿和醚類^[3]^[4]。

分配係數 (log P 辛醇-水) -1.20E+00；水溶性在25°C為 7.46E+05 毫克/升。蒸汽壓於25°C 為 1.64E-04 毫米汞柱 (估計值)。

作用機理

鹽酸丁二胍能夠延遲腸胃途徑的糖吸收，增加胰島素敏感性和細胞的糖攝入，並且抑制肝糖合成。鹽酸丁二胍和其他雙胍類口服降糖藥一樣，不是以直接降血糖為主要作用機理，而是對抗血糖水平過高。服用不會產生低血糖的現象，但能夠有效降低糖尿病人的空腹與餐後血糖^[5]。

劑量

日常給藥劑量為 150–300 毫克口服^[6]。

副作用與用藥禁忌

常見副作用為食慾匱乏，噁心，腹瀉，口中有金屬味和體重減輕。有糖尿病昏迷，酮酸中毒，嚴重感染或創傷者禁用。

毒性

鹽酸丁二胍由於可能導致乳酸堆積的機率增加，而在一些國家被下市。目前在羅馬尼亞、匈牙利、台灣和日本仍作為處方藥被應用。^[7]^[8]^[9]^[10]^[11]^[12]乳酸堆積症一般只在鹽酸丁二胍血漿濃度超過的 0.60 微克/毫升的病人中發生，在腎功能正常的患者中十分罕見。^[13]^[14]^[15]

抗癌作用

鹽酸丁二胍和二甲雙胍還有苯乙雙胍一樣，抑制癌細胞生長和發育^[16]^[17]^[18]^[19]^[20]。其抗癌機制是由於其可以阻斷瓦氏效應，並且將癌細胞的供能途徑從細胞基質糖解逆轉回依靠線粒體的丙酮酸途徑。^[21] ^[22]

參考文獻

[1]
F. Macdonald. Dictionary of pharmacological agents: Volumes 1-2 - Page 344, 1997
[2]
Seymour L. Shapiro et al. Salts Of N-Amylbiguanide. US Patent number: 2961377; Filing date: Aug 5, 1957; Issue date: 1960
[3]
Jacker HJ. [New Pharmacologic Products. 2. Buformin For Oral Therapy Of Diabetes]. Pharm Prax. 1964;10:247-9.
[4]
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
[5]
Enrique Ravina, Hugo Kubinyi. The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. Wiley. 2011 p 215
[6]
Gustav Kuschinsky, Heinz Lüllmann. Textbook of pharmacology. Academic Press p 225, 1973
[7]
Hankó B, Tukarcs E, Kumli P, Vincze Z. Antidiabetic drug utilization in Hungary. Pharm World Sci. 2005 Jun;27(3):263-5.
[8]
Hankó BZ, Reszegi CA, Kumli P, Vincze Z. [Practice of antidiabetic therapy in Hungary]. Acta Pharm Hung. 2005;75(2):77-86.
[9]
Jerry L. Schlesser, Gale Research Inc. Drugs available abroad. Derwent Publications, Ltd - 1990 p28
[10]
Verdonck L, Sangster B, van Heijst A, de Groot G, Maes R. Buformin concentrations in a case of fatal lactic acidosis. Diabetologia. 1981, 20 (1): 45–6. PMID 7202882. doi:10.1007/BF01789112.
[11]
Chou CH, Cheng CL, Huang CC. A validated HPLC method with ultraviolet detection for the determination of buformin in plasma. Biomed Chromatogr. 2004 May;18(4):254-8.
[12]
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
[13]
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
[14]
Berger W, Mehnert-Aner S, Mülly K, Heierli C, Ritz R. [10 cases of lactic acidosis during biguanide therapy (buformin and phenformin)]. Schweizerische medizinische Wochenschrift. 106:1830-1834, 1976
[15]
Deppermann D, Heidland A, Ritz E, Hörl W. [Lactic acidosis--a possible complication in buformin-treated diabetics (author's transl)]. Klin Wochenschr. 1978, 56 (17): 843–53. PMID 713413.
[16]
Sakae Saito, Aki Furuno, Junko Sakurai, Asami Sakamoto, Hae-Ryong Park, Kazuo Shin-ya, Takashi Tsuruo, and Akihiro Tomida. Chemical Genomics Identifies the Unfolded Protein Response as a Target for Selective Cancer Cell Killing during Glucose Deprivation. Cancer Research 2009;69(10):4225–34
[17]
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
[18]
Valery A. Alexandrov, Vladimir N. Anisimov, Natalia M. Belous, Inna A. Vasilyeva and Vera B. Mazon. The inhibition of the transplacental blastomogenic effect of nitrosomethylurea by postnatal administration of buformin to rats. Carcinogenesis Volume 1, Issue 12 Pp. 975-978, 1980
[19]
Anisimov VN, Ostroumova MN, Dil'man VM. 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. Volume 89, Number 6, 819-822, 1980
[20]
Vladimir N. Anisimov, Lev M. Berstein, Irina G. Popovich, Mark A. Zabezhinski, Peter A. Egormin, Margarita L. Tyndyk, Ivan V. Anikin, Anna V. Semenchenko, Anatoli I. Yashin. 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, 2005
[21]
Matthew G. Vander Heiden, Lewis C. Cantley, and Craig B. Thompson. Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science 324 (5930): 1029-1033, 2009.
[22]
Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005 Dec 9;310(5754):1642-6.

[1] [1]
F. Macdonald. Dictionary of pharmacological agents: Volumes 1-2 - Page 344, 1997

[2] [2]
Seymour L. Shapiro et al. Salts Of N-Amylbiguanide. US Patent number: 2961377; Filing date: Aug 5, 1957; Issue date: 1960

[3] [3]
Jacker HJ. [New Pharmacologic Products. 2. Buformin For Oral Therapy Of Diabetes]. Pharm Prax. 1964;10:247-9.

[4] [4]
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

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

[6] [6]
Gustav Kuschinsky, Heinz Lüllmann. Textbook of pharmacology. Academic Press p 225, 1973

[7] [7]
Hankó B, Tukarcs E, Kumli P, Vincze Z. Antidiabetic drug utilization in Hungary. Pharm World Sci. 2005 Jun;27(3):263-5.

[8] [8]
Hankó BZ, Reszegi CA, Kumli P, Vincze Z. [Practice of antidiabetic therapy in Hungary]. Acta Pharm Hung. 2005;75(2):77-86.

[9] [9]
Jerry L. Schlesser, Gale Research Inc. Drugs available abroad. Derwent Publications, Ltd - 1990 p28

[Verdonck-10] [10]
Verdonck L, Sangster B, van Heijst A, de Groot G, Maes R. Buformin concentrations in a case of fatal lactic acidosis. Diabetologia. 1981, 20 (1): 45–6. PMID 7202882. doi:10.1007/BF01789112.

[11] [11]
Chou CH, Cheng CL, Huang CC. A validated HPLC method with ultraviolet detection for the determination of buformin in plasma. Biomed Chromatogr. 2004 May;18(4):254-8.

[12] [12]
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

[13] [13]
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

[14] [14]
Berger W, Mehnert-Aner S, Mülly K, Heierli C, Ritz R. [10 cases of lactic acidosis during biguanide therapy (buformin and phenformin)]. Schweizerische medizinische Wochenschrift. 106:1830-1834, 1976

[Deppermann-15] [15]
Deppermann D, Heidland A, Ritz E, Hörl W. [Lactic acidosis--a possible complication in buformin-treated diabetics (author's transl)]. Klin Wochenschr. 1978, 56 (17): 843–53. PMID 713413.

[16] [16]
Sakae Saito, Aki Furuno, Junko Sakurai, Asami Sakamoto, Hae-Ryong Park, Kazuo Shin-ya, Takashi Tsuruo, and Akihiro Tomida. Chemical Genomics Identifies the Unfolded Protein Response as a Target for Selective Cancer Cell Killing during Glucose Deprivation. Cancer Research 2009;69(10):4225–34

[17] [17]
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

[18] [18]
Valery A. Alexandrov, Vladimir N. Anisimov, Natalia M. Belous, Inna A. Vasilyeva and Vera B. Mazon. The inhibition of the transplacental blastomogenic effect of nitrosomethylurea by postnatal administration of buformin to rats. Carcinogenesis Volume 1, Issue 12 Pp. 975-978, 1980

[19] [19]
Anisimov VN, Ostroumova MN, Dil'man VM. 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. Volume 89, Number 6, 819-822, 1980

[20] [20]
Vladimir N. Anisimov, Lev M. Berstein, Irina G. Popovich, Mark A. Zabezhinski, Peter A. Egormin, Margarita L. Tyndyk, Ivan V. Anikin, Anna V. Semenchenko, Anatoli I. Yashin. 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, 2005

[21] [21]
Matthew G. Vander Heiden, Lewis C. Cantley, and Craig B. Thompson. Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science 324 (5930): 1029-1033, 2009.

[22] [22]
Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005 Dec 9;310(5754):1642-6.

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