| Revision as of 12:03, 5 December 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 463079324 of page Phenformin for the Chem/Drugbox validation project (updated: 'DrugBank'). |
Latest revision as of 07:12, 10 November 2024 edit 76.174.0.57 (talk) Navbox. |
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{{short description|Chemical compound}} |
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{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}} |
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{{Drugbox |
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{{Drugbox |
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| Verifiedfields = changed |
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| Watchedfields = changed |
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| verifiedrevid = 457458012 |
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| verifiedrevid = 464200205 |
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| IUPAC_name = 2-(''N''-phenethylcarbamimidoyl)guanidine |
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| IUPAC_name = 2-(''N''-phenethylcarbamimidoyl)guanidine |
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| image = Phenformin.svg |
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| image = Phenformin.svg |
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| width = 225 |
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<!--Clinical data--> |
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<!--Clinical data--> |
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| legal_UK = <!-- GSL / P / POM / CD --> |
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| legal_UK = <!-- GSL / P / POM / CD --> |
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| legal_US = <!-- OTC / Rx-only --> |
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| legal_US = <!-- OTC / Rx-only --> |
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| legal_status = |
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| legal_status = |
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| routes_of_administration = |
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| routes_of_administration = Oral |
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<!--Pharmacokinetic data--> |
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<!--Pharmacokinetic data--> |
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| metabolism = |
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| metabolism = |
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| elimination_half-life = |
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| elimination_half-life = |
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| excretion = |
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| excretion = |
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<!--Identifiers--> |
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<!--Identifiers--> |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 114-86-3 |
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| CAS_number = 114-86-3 |
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| ATC_suffix = BA01 |
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| ATC_suffix = BA01 |
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| PubChem = 8249 |
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| PubChem = 8249 |
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| DrugBank_Ref = {{drugbankcite|changed|drugbank}} |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = DB00914 |
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| DrugBank = DB00914 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = DD5K7529CE |
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| UNII = DD5K7529CE |
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| ChEBI_Ref = {{ebicite|changed|EBI}} |
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| ChEBI = 8064 |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D08351 |
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| KEGG = D08351 |
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<!--Chemical data--> |
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<!--Chemical data--> |
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| C=10 | H=15 | N=5 |
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| C=10 | H=15 | N=5 |
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| molecular_weight = 205.26 g/mol |
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| smiles = N(=C(/N=C(\N)N)N)\CCc1ccccc1 |
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| smiles = N(=C(/N=C(\N)N)N)\CCc1ccccc1 |
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| InChI = 1/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) |
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| InChIKey = ICFJFFQQTFMIBG-UHFFFAOYAA |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 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) |
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| StdInChI = 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) |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = ICFJFFQQTFMIBG-UHFFFAOYSA-N |
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| StdInChIKey = ICFJFFQQTFMIBG-UHFFFAOYSA-N |
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| melting_point = 175 |
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| melting_high = 178 |
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}} |
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}} |
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'''Phenformin''' is an ] from the ] 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 ], which was fatal in 50% of cases. |
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Phenformin was developed in 1957 by Ungar, Freedman and ], working for the U.S. Vitamin Corporation. Clinical trials begun in 1958 showed it to be effective, but with gastrointestinal side effects.<ref name=McKendry1959>{{cite journal | vauthors = McKendry JB, Kuwayti K, Rado PP | title = Clinical experience with DBI (phenformin) in the management of diabetes | journal = Canadian Medical Association Journal | volume = 80 | issue = 10 | pages = 773–778 | date = May 1959 | pmid = 13652024 | pmc = 1831029 }}</ref> |
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==Toxicity== |
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Phenformin sales began to decline in the U.S. from 1973 due to negative trial studies and reports of lactic acidosis. By October 1976, the U.S. Food and Drug Administration (FDA) Endocrinology and Metabolism Advisory Committee recommended phenformin be removed from the market. The FDA began formal proceedings in May 1977, leading to Phenformin's eventual withdrawal on November 15, 1978.<ref name=Tonascia1986>{{cite book | vauthors = Tonascia S, Meinert CL |title=Clinical trials: design, conduct, and analysis |publisher=Oxford University Press |location=Oxford |year=1986 |pages=53–54, 59 |isbn=978-0-19-503568-1}}</ref> |
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In 1977, 385,000 patients with early-stage diabetes were taking phenformin in the U.S.. ]'s Health Research Group put the U.S. government under pressure to ban the drug. Ciba-Geigy Corp resisted, claiming there was no satisfactory alternative for many patients. But 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).<ref name=Boca>{{cite news | work=Boca Raton News | date=July 26, 1977 | title=Diabetic drug linked to deaths banned | agency = UPI | url=https://news.google.com/newspapers?nid=1291&dat=19770726&id=mt4PAAAAIBAJ&pg=4457,3796314}}</ref> As of 2008, phenformin was still legally available in Italy, Brazil, Uruguay, China, Poland, Greece and Portugal and cases of phenformin-induced lactic acidosis continued to be reported worldwide.<ref name=Fimognari2008>{{cite journal | vauthors = Fimognari FL, Corsonello A, Pastorelli R, Antonelli Incalzi R | title = Older age and phenformin therapy: a dangerous association | journal = Internal and Emergency Medicine | volume = 3 | issue = 4 | pages = 401–403 | date = December 2008 | pmid = 18415028 | doi = 10.1007/s11739-008-0154-y | s2cid = 33747462 }}</ref> In Hong Kong, where phenformin is banned, cases of phenformin-induced lactic acidosis occurred after taking Chinese proprietary medicines, claiming to be herbal, which were adulterated with phenformin.<ref name=Ching2008>{{cite journal | vauthors = Ching CK, Lai CK, Poon WT, Wong EN, Yan WW, Chan AY, Mak TW | title = Hazards posed by a banned drug--phenformin is still hanging around | journal = Hong Kong Medical Journal = Xianggang Yi Xue Za Zhi | volume = 14 | issue = 1 | pages = 50–54 | date = February 2008 | pmid = 18239244 | url = http://www.hkmj.org/article_pdfs/hkm0802p50.pdf }}</ref> In the U.S., in 2001 the FDA recalled Chinese "herbal products" containing phenformin.<ref name=WHO>{{cite journal | vauthors = Speth PA, Linssen PC, Termond EF, Boezeman JB, Wessels HM, Haanen C | title = In vivo and in vitro pharmacokinetic differences between four structurally closely related anthracyclines in hematopoietic cell subtypes in humans | journal = Drug Metabolism and Disposition | volume = 17 | issue = 1 | pages = 98–105 | date = July 2001 | pmid = 2566478 }}</ref> |
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The related drug ] 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.<ref name=Crofford1995>{{cite journal | vauthors = Crofford OB | title = Metformin | journal = The New England Journal of Medicine | volume = 333 | issue = 9 | pages = 588–589 | date = August 1995 | pmid = 7623910 | doi = 10.1056/NEJM199508313330910 }}</ref> |
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==Chemistry and pharmacokinetics== |
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Phenformin hydrochloride is a white crystalline powder, with a melting point of 175–178 °C; it is soluble at 1 in 8 parts of water and 1 in 15 of ethanol, and practically insoluble in chloroform and ether.{{citation needed|date=March 2016}} Phenformin is less polar and more lipid soluble and exhibits a higher affinity for mitochondrial membranes than metformin.<ref name=2015revWeinberg/> Its dissociation constant (pKa) is 2.7, 11.8 (at 32 °C), and ] = –0.8.{{citation needed|date=March 2016}} |
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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 0.08–0.18 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 eight subjects, plasma concentrations of 0.10–0.24 mg/L (mean 0.18) were reported 2 h after a dose. Plasma half-life of phenformin is 10–15 h. Phenformin protein binding in plasma is about 12–20%.{{citation needed|date=March 2016}} |
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==Research== |
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Vladimir Dilman first proposed in 1971 that ] like ] and phenformin may have potential to treat cancer, prevent cancer, and to extend life, an idea that was subsequently supported by ''in vitro'' and animal studies, as well as an apparent reduction in the incidence of cancer in people taking metformin for diabetes.<ref name=2015revPryor/> |
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Laboratory studies attribute these apparent effects to inhibition of ], inhibition of ], with phenformin being a more potent inhibitor than metformin,<ref name=2015revWeinberg>{{cite journal | vauthors = Weinberg SE, Chandel NS | title = Targeting mitochondria metabolism for cancer therapy | journal = Nature Chemical Biology | volume = 11 | issue = 1 | pages = 9–15 | date = January 2015 | pmid = 25517383 | pmc = 4340667 | doi = 10.1038/nchembio.1712 }}</ref><ref name=2015revPryor>{{cite journal | vauthors = Pryor R, Cabreiro F | title = Repurposing metformin: an old drug with new tricks in its binding pockets | journal = The Biochemical Journal | volume = 471 | issue = 3 | pages = 307–322 | date = November 2015 | pmid = 26475449 | pmc = 4613459 | doi = 10.1042/BJ20150497 }}</ref> It appears that inhibition of complex I may cause diminished ] intermediate production and decreased mitochondrial ] production thus resulting in ] activation and lower ] activity.<ref name=2015revWeinberg/> |
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== See also == |
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* ] |
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== References == |
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{{Reflist}} |
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{{Oral hypoglycemics}} |
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{{Phenethylamines}} |
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] |
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] |
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] |