Phenformin

	WikiDoc Resources for Phenformin
Articles
Most recent articles on Phenformin Most cited articles on Phenformin Review articles on Phenformin Articles on Phenformin in N Eng J Med, Lancet, BMJ
Media
Powerpoint slides on Phenformin Images of Phenformin Photos of Phenformin Podcasts & MP3s on Phenformin Videos on Phenformin
Evidence Based Medicine
Cochrane Collaboration on Phenformin Bandolier on Phenformin TRIP on Phenformin
Clinical Trials
Ongoing Trials on Phenformin at Clinical Trials.gov Trial results on Phenformin Clinical Trials on Phenformin at Google
Guidelines / Policies / Govt
US National Guidelines Clearinghouse on Phenformin NICE Guidance on Phenformin NHS PRODIGY Guidance FDA on Phenformin CDC on Phenformin
Books
Books on Phenformin
News
Phenformin in the news Be alerted to news on Phenformin News trends on Phenformin
Commentary
Blogs on Phenformin
Definitions
Definitions of Phenformin
Patient Resources / Community
Patient resources on Phenformin Discussion groups on Phenformin Patient Handouts on Phenformin Directions to Hospitals Treating Phenformin Risk calculators and risk factors for Phenformin
Healthcare Provider Resources
Symptoms of Phenformin Causes & Risk Factors for Phenformin Diagnostic studies for Phenformin Treatment of Phenformin
Continuing Medical Education (CME)
CME Programs on Phenformin
International
Phenformin en Espanol Phenformin en Francais
Business
Phenformin in the Marketplace Patents on Phenformin
Experimental / Informatics
List of terms related to Phenformin

Phenformin
Clinical data
AHFS/Drugs.com	International Drug Names
ATC code	A10BA01 (WHO) ;
Identifiers
	IUPAC name 2-(N-phenethylcarbamimidoyl)guanidine;
CAS Number	114-86-3 ;
PubChem CID	8249;
DrugBank	DB00914 ;
ChemSpider	7953 ;
UNII	DD5K7529CE;
KEGG	D08351 ;
ChEBI	CHEBI:8064 ;
ChEMBL	ChEMBL170988 ;
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
Formula	C10H15N5
Molar mass	205.26 g/mol
3D model (JSmol)	Interactive image;
	SMILES N(=C(/N=C(\N)N)N)\CCc1ccccc1;
	InChI InChI=1S/C10H15N5/c11-9(12)15-10(13)14-7-6-8-4-2-1-3-5-8/h1-5H,6-7H2,(H6,11,12,13,14,15) ; Key:ICFJFFQQTFMIBG-UHFFFAOYSA-N ;
(what is this?) (verify)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Phenformin is an antidiabetic drug from the biguanide class. It was marketed as DBI by Ciba-Geigy, but was withdrawn from most markets in the late 1970s due to a high risk of lactic acidosis, which was fatal in 50% of cases.

Phenformin was discovered in 1957 by Ungar, Freedman and Seymour Shapiro, working for the US Vitamin Corporation. Clinical trials begun in 1958 showed it to be effective, but with gastrointestinal side effects.^[1]

Toxicity

Phenformin sales began to decline in the US from 1973 due to negative trial studies and reports of lactic acidosis. By October 1976, the FDA Endocrinology and Metabolism Advisory Committee recommended phenformin be removed from the market. The FDA began formal proceedings in May 1977, leading to its eventual withdrawal on November 15, 1978.^[2]

In 1977, 385,000 patients with early-stage diabetes were taking phenformin in the US. Ralph Nader's Health Research Group put the US government under pressure to ban the drug. Ciba-Geigy Corp resisted, claiming there was no satisfactory alternative for many patients. However, in July the FDA declared the drug an "imminent hazard to the public health" and gave doctors 90 days to switch to an alternative treatment (such as insulin, dietary restrictions or other drugs).^[3] As of 2008, phenformin was still legally available in Italy, Brazil, Uruguay, China, Poland, Greece and Portugal. Cases of phenformin-induced lactic acidosis continue to be reported worldwide.^[4] In Hong Kong, where phenformin is banned, cases of phenformin-induced lactic acidosis have occurred after taking Chinese proprietary medicines, claiming to be herbal, which were adulterated with phenformin.^[5] In the US, the FDA has recalled Chinese "herbal products" containing phenformin.^[6]

The related drug metformin is considerably safer than phenformin, with three cases of lactic acidosis per 100,000 patient-years compared to 64 cases per 100,000 patient-years, and those are mostly confined to patients with impaired renal function.^[7]

Cimetidine may reduce renal clearance of phenformin and increase lactic acidosis risk. There is also increased risk of lactic acidosis with alcohol, nephrotoxic drugs.

Chemistry and pharmacokinetics

Phenformin hydrochloride is a white crystalline powder, with a melting point of 175 to 178 °C; it is soluble at 1 in 8 parts of water and 1 in 15 of ethanol, and practically insoluble in chloroform and ether. Its dissociation constant (pKa) is 2.7, 11.8 (at 32 °C), and partition coefficient (log P in octanol/water) = –0.8. Phenformin is well absorbed after oral administration. The major metabolic reaction is aromatic hydroxylation to form 4–hydroxyphenformin, which is then conjugated with glucuronic acid. Up to about 50% of a dose is excreted in the urine in 24 h, about two–thirds in the form of unchanged drug and one–third as the hydroxy metabolite. Following a single oral dose of 50 mg to eight subjects, peak plasma concentrations of 0.08 to 0.18 mg/l (mean 0.13) were attained in about 3 h; plasma concentrations were higher in four subjects who were poor metabolisers of debrisoquine in comparison with the four extensive metabolisers. Following daily oral doses of 50 mg three times a day to 8 subjects, plasma concentrations of 0.10 to 0.24 mg/l (mean 0.18) were reported 2 h after a dose. Plasma half–life of phenformin is 10 to 15 h. Phenformin protein-binding in plasma is about 12 to 20%.^[8]

Dosage

When given orally for type 2 diabetes mellitus, the dosage is 200–400 mg, twice daily, for adults.

Anticancer properties

Phenformin, along with buformin and metformin, inhibits the growth and development of cancer. Respective studies were initiated by Vladimir Dilman (see f.e.^[9]^[10]^[11]^[12]^[13]^[14] The anticancer property of these drugs may be 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.^[15] Metformin reduces liver glucose production in diabetics and disrupts the Warburg effect in cancer by AMPK activation and inhibition of the mTor pathway.^[16]

References

↑ McKendry JB, Kuwayti K, Rado PP; Kuwayti; Rado (May 1959). "Clinical Experience with DBI (Phenformin) in the Management of Diabetes". Can Med Assoc J. 80 (10): 773–8. PMC 1831029. PMID 13652024.
↑ Tonascia, Susan; Meinert, Curtis L. (1986). Clinical trials: design, conduct, and analysis. Oxford [Oxfordshire]: Oxford University Press. pp. 53–54, 59. ISBN 0-19-503568-2.
↑ UPI (July 26, 1977). "Diabetic drug linked to deaths banned". Boca Raton News.
↑ Fimognari FL, Corsonello A, Pastorelli R, Antonelli Incalzi R; Corsonello; Pastorelli; Antonelli Incalzi (December 2008). "Older age and phenformin therapy: a dangerous association". Intern Emerg Med. 3 (4): 401–3. doi:10.1007/s11739-008-0154-y. PMID 18415028.
↑ Ching CK; Lai CK; Poon WT; et al. (February 2008). "Hazards posed by a banned drug--phenformin is still hanging around" (pdf). Hong Kong Med J. 14 (1): 50–4. PMID 18239244. Unknown parameter |author-separator= ignored (help)
↑ <Please add first missing authors to populate metadata.> (July 2001). "Herbs for health, but how safe are they?". Bulletin of the World Health Organization. Geneva. 79 (7): 691–692. doi:10.1590/S0042-96862001000700025. PMC 2566478. Unknown parameter |doi_brokendate= ignored (help)
↑ Crofford OB (August 1995). "Metformin". N. Engl. J. Med. 333 (9): 588–9. doi:10.1056/NEJM199508313330910. PMID 7623910.
↑ Phenformin in Analysis of Drugs and Poisons
↑ Dilman, VM; Berstein, LM; Zabezhinski, MA; Alexandrov, VA; Bobrov, JF; Pliss, GB (1978). "Inhibition of DMBA-induced carcinogenesis by phenformin in the mammary gland of rats". Arch Geschwulstforsch. 48 (1): 1–8.
↑ Caracia, Filippo; Chisari, Mariangela; Frasca, Giuseppina; Chiechio, Santina; Salomone, Salvatore; Pinto, Antonio; Angela Sortino, Maria; Bianchi, Alfredo (2003). "Effects of phenformin on the proliferation of human tumor cell lines". Life Sciences. 74 (5): 643–650. doi:10.1016/j.lfs.2003.07.015.
↑ Anisimov, Vladimir N. (2003). "Insulin/IGF-1 signaling pathway driving aging and cancer as a target for pharmacological intervention". Experimental Gerontology. 38 (10): 1041–1049. doi:10.1016/s0531-5565(03)00169-4.
↑ 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.

Template:Oral hypoglycemics

[McKendry1959-1] McKendry JB, Kuwayti K, Rado PP; Kuwayti; Rado (May 1959). "Clinical Experience with DBI (Phenformin) in the Management of Diabetes". Can Med Assoc J. 80 (10): 773–8. PMC 1831029. PMID 13652024.

[Tonascia1986-2] Tonascia, Susan; Meinert, Curtis L. (1986). Clinical trials: design, conduct, and analysis. Oxford [Oxfordshire]: Oxford University Press. pp. 53–54, 59. ISBN 0-19-503568-2.

[Boca-3] UPI (July 26, 1977). "Diabetic drug linked to deaths banned". Boca Raton News.

[Fimognari2008-4] Fimognari FL, Corsonello A, Pastorelli R, Antonelli Incalzi R; Corsonello; Pastorelli; Antonelli Incalzi (December 2008). "Older age and phenformin therapy: a dangerous association". Intern Emerg Med. 3 (4): 401–3. doi:10.1007/s11739-008-0154-y. PMID 18415028.

[Ching2008-5] Ching CK; Lai CK; Poon WT; et al. (February 2008). "Hazards posed by a banned drug--phenformin is still hanging around" (pdf). Hong Kong Med J. 14 (1): 50–4. PMID 18239244. Unknown parameter |author-separator= ignored (help)

[WHO-6] <Please add first missing authors to populate metadata.> (July 2001). "Herbs for health, but how safe are they?". Bulletin of the World Health Organization. Geneva. 79 (7): 691–692. doi:10.1590/S0042-96862001000700025. PMC 2566478. Unknown parameter |doi_brokendate= ignored (help)

[Crofford1995-7] Crofford OB (August 1995). "Metformin". N. Engl. J. Med. 333 (9): 588–9. doi:10.1056/NEJM199508313330910. PMID 7623910.

[8] Phenformin in Analysis of Drugs and Poisons

[9] Dilman, VM; Berstein, LM; Zabezhinski, MA; Alexandrov, VA; Bobrov, JF; Pliss, GB (1978). "Inhibition of DMBA-induced carcinogenesis by phenformin in the mammary gland of rats". Arch Geschwulstforsch. 48 (1): 1–8.

[10] Caracia, Filippo; Chisari, Mariangela; Frasca, Giuseppina; Chiechio, Santina; Salomone, Salvatore; Pinto, Antonio; Angela Sortino, Maria; Bianchi, Alfredo (2003). "Effects of phenformin on the proliferation of human tumor cell lines". Life Sciences. 74 (5): 643–650. doi:10.1016/j.lfs.2003.07.015.

[11] Anisimov, Vladimir N. (2003). "Insulin/IGF-1 signaling pathway driving aging and cancer as a target for pharmacological intervention". Experimental Gerontology. 38 (10): 1041–1049. doi:10.1016/s0531-5565(03)00169-4.

[12] 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.

[13] 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.

[14] 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.

[15] 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.

[16] 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.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]