Buformin

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.{{cite journal | vauthors = Jacker HJ | title = [New Pharmacologic Products. 2. Buformin For Oral Therapy Of Diabetes] | journal = Pharmazeutische Praxis | volume = 10 | pages = 247–249 | year = 1964 | pmid = 14328846 }}{{cite book | vauthors = Clarke EG, Berle J | title = Isolation and identification of drugs in pharmaceuticals, body fluids and post-mortem material | volume = 1 | publisher = Pharmaceutical Press, Pharmaceutical Society of Great Britain. Dept. of Pharmaceutical Sciences. | date = 1974 | page = 226 }} Toxicity: guinea pig LD50 subcutaneous 18 mg/kg; mouse LD50 intraperitoneal 140 mg/kg and 300 mg/kg oral.{{cite journal | vauthors = Shroff JR, Bandurco V, Desai R, Kobrin S, Cervoni P | title = Chemistry and hypoglycemic activity of benzimidoylpyrazoles | journal = Journal of Medicinal Chemistry | volume = 24 | issue = 12 | pages = 1521–1525 | date = December 1981 | pmid = 7310831 | doi = 10.1021/jm00144a031 }} The log octanol-water partition coefficient (log P) 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.United States National Library of Medicine ChemLDplus advanced database

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.{{cite book | vauthors = Ravina E, Kubinyi H | title = The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. | publisher = Wiley | date = 2011 | page = 215 }} Biguanides may antagonize the action of glucagon, thus reducing fasting glucose levels.{{cite journal | vauthors = Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ | title = Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP | journal = Nature | volume = 494 | issue = 7436 | pages = 256–260 | date = February 2013 | pmid = 23292513 | pmc = 3573218 | doi = 10.1038/nature11808 | bibcode = 2013Natur.494..256M }}

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.{{cite journal | vauthors = Beckmann R | title = The fate of biguanides in man | journal = Annals of the New York Academy of Sciences | volume = 148 | issue = 3 | pages = 820–832 | date = March 1968 | pmid = 5241479 | doi = 10.1111/j.1749-6632.1968.tb27755.x | s2cid = 11875897 | bibcode = 1968NYASA.148..820B }} 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.{{cite journal | vauthors = Beckmann R, Lintz W, Schmidt-Böthelt E | title = Evaluation of a sustained release form of the oral antidiabetic butylbiguanide (Silubin retard) | journal = European Journal of Clinical Pharmacology | volume = 3 | issue = 4 | pages = 221–228 | date = September 1971 | pmid = 5151304 | doi = 10.1007/bf00565010 | s2cid = 39654704 }} 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.{{cite journal | vauthors = Marchetti P, Giannarelli R, di Carlo A, Navalesi R | title = Pharmacokinetic optimisation of oral hypoglycaemic therapy | journal = Clinical Pharmacokinetics | volume = 21 | issue = 4 | pages = 308–317 | date = October 1991 | pmid = 1760902 | doi = 10.2165/00003088-199121040-00006 | s2cid = 11701663 }}{{cite journal | vauthors = Gutsche H, Blumenbach L, Losert W, Wiemann H | title = [Concentration of 14C-1-butylbiguanide in plasma of diabetic patients and its elimination after administration of a new Galenical formulation (author's transl)] | journal = Arzneimittel-Forschung | volume = 26 | issue = 6 | pages = 1227–1229 | year = 1976 | pmid = 989423 }}{{cite journal | vauthors = Ritzl F, Feinendegen LE, Lintz W, Tisljar U | title = [Distribution and excretion of 14c-butylbiguanide in man (author's transl)] | journal = Arzneimittel-Forschung | volume = 28 | issue = 7 | pages = 1184–1186 | year = 1978 | pmid = 582707 }}

The daily dose of buformin is 150–300 mg by mouth.{{cite book | vauthors = Kuschinsky G, Lüllmann H | title = Textbook of pharmacology. | publisher = Academic Press | page = 225 | date = 1973 }} Buformin has also been available in a sustained release preparation, Silubin Retard, which is still sold in Romania.

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 conditions 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.

File:Dibetos50.jpgBuformin 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,{{cite journal | vauthors = Hankó B, Tukarcs E, Kumli P, Vincze Z | title = Antidiabetic drug utilization in hungary | journal = Pharmacy World & Science | volume = 27 | issue = 3 | pages = 263–265 | date = June 2005 | pmid = 16096899 | doi = 10.1007/s11096-004-5804-1 | s2cid = 9083315 }}{{cite journal | vauthors = Hankó BZ, Reszegi CA, Kumli P, Vincze Z | title = [Practice of antidiabetic therapy in Hungary] | language = Hungarian | journal = Acta Pharmaceutica Hungarica | volume = 75 | issue = 2 | pages = 77–86 | date = 2005 | pmid = 16318232 | doi = | url = }}{{cite book | vauthors = Schlesser JL | title = Drugs available abroad. | publisher = Gale Research Inc.; Derwent Publications, Ltd | date = 1990 | page = 28 }}{{cite journal | vauthors = Verdonck LF, Sangster B, van Heijst AN, de Groot G, Maes RA | title = Buformin concentrations in a case of fatal lactic acidosis | journal = Diabetologia | volume = 20 | issue = 1 | pages = 45–46 | year = 1981 | pmid = 7202882 | doi = 10.1007/BF01789112 | doi-access = free }} Taiwan{{cite journal | vauthors = Chou CH, Cheng CL, Huang CC | title = A validated HPLC method with ultraviolet detection for the determination of buformin in plasma | journal = Biomedical Chromatography | volume = 18 | issue = 4 | pages = 254–258 | date = May 2004 | pmid = 15162388 | doi = 10.1002/bmc.312 }} and Japan (sold by Nichi-Iko Pharmaceutical Co., Ltd as "DIBETOS" tablets, each containing 50 mg buformin hydrochloride).{{cite journal | vauthors = Wurita A, Hasegawa K, Nozawa H, Yamagishi I, Minakata K, Watanabe K, Suzuki O | title = Postmortem distribution/redistribution of buformin in body fluids and solid tissues in an autopsy case using liquid chromatography-tandem mass spectrometry with QuEChERS extraction method | journal = Forensic Science International | volume = 314 | pages = 110376 | date = September 2020 | pmid = 32615395 | doi = 10.1016/j.forsciint.2020.110376 | s2cid = 220328342 }} 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.{{cite journal | vauthors = Wittmann P, Haslbeck M, Bachmann W, Mehnert H | title = [Lactic acidosis in diabetics on biguanides (author's transl)] | language = German | journal = Deutsche Medizinische Wochenschrift | volume = 102 | issue = 1 | pages = 5–10 | date = January 1977 | pmid = 11984 | doi = 10.1055/s-0028-1104832 | s2cid = 260117450 }}{{cite journal | vauthors = Berger W, Mehnert-Aner S, Mülly K, Heierli C, Ritz R | title = [10 cases of lactic acidosis during biguanide therapy (buformin and phenformin)] | journal = Schweizerische Medizinische Wochenschrift | volume = 106 | issue = 50 | pages = 1830–1834 | date = December 1976 | pmid = 1013709 }}{{cite journal | vauthors = Deppermann D, Heidland A, Ritz E, Hörl W | title = [Lactic acidosis--a possible complication in buformin-treated diabetics (author's transl)] | journal = Klinische Wochenschrift | volume = 56 | issue = 17 | pages = 843–853 | date = September 1978 | pmid = 713413 | doi = 10.1007/BF01479834 | s2cid = 39728557 }}

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.{{cite journal | vauthors = Luft D, Schmülling RM, Eggstein M | title = Lactic acidosis in biguanide-treated diabetics: a review of 330 cases | journal = Diabetologia | volume = 14 | issue = 2 | pages = 75–87 | date = February 1978 | pmid = 344119 | doi = 10.1007/bf01263444 | doi-access = free }}

Buformin, along with phenformin and metformin, inhibits the growth and development of cancer.{{cite journal | vauthors = Saito S, Furuno A, Sakurai J, Sakamoto A, Park HR, Shin-Ya K, Tsuruo T, Tomida A | display-authors = 6 | title = Chemical genomics identifies the unfolded protein response as a target for selective cancer cell killing during glucose deprivation | journal = Cancer Research | volume = 69 | issue = 10 | pages = 4225–4234 | date = May 2009 | pmid = 19435925 | doi = 10.1158/0008-5472.can-08-2689 | doi-access = free }}{{cite journal | vauthors = Anisimov VN | title = Insulin/IGF-1 signaling pathway driving aging and cancer as a target for pharmacological intervention | journal = Experimental Gerontology | volume = 38 | issue = 10 | pages = 1041–1049 | date = October 2003 | pmid = 14580857 | doi = 10.1016/s0531-5565(03)00169-4 | s2cid = 27811309 }}{{cite journal | vauthors = Alexandrov VA, Anisimov VN, Belous NM, Vasilyeva IA, Mazon VB | title = The inhibition of the transplacental blastomogenic effect of nitrosomethylurea by postnatal administration of buformin to rats | journal = Carcinogenesis | volume = 1 | issue = 12 | pages = 975–978 | year = 1980 | pmid = 11272113 | doi = 10.1093/carcin/1.12.975 }}{{cite journal | vauthors = Anisimov VN, Ostroumova MN, Dil'man VM | title = [Inhibition of the blastomogenic effect of 7,12-dimethylbenz(a)anthracene in female rats by buformin, diphenin, a polypeptide pineal extract and L-DOPA] | journal = Biulleten' Eksperimental'noi Biologii I Meditsiny | volume = 89 | issue = 6 | pages = 723–725 | date = June 1980 | pmid = 6772259 | doi = 10.1007/bf00836263 | s2cid = 46058518 }}{{cite journal | vauthors = Anisimov VN, Berstein LM, Popovich IG, Zabezhinski MA, Egormin PA, Tyndyk ML, Anikin IV, Semenchenko AV, Yashin AI | display-authors = 6 | title = Central and peripheral effects of insulin/IGF-1 signaling in aging and cancer: antidiabetic drugs as geroprotectors and anticarcinogens | journal = Annals of the New York Academy of Sciences | volume = 1057 | issue = 1 | pages = 220–234 | date = December 2005 | pmid = 16399897 | doi = 10.1196/annals.1356.017 | s2cid = 5744858 | bibcode = 2005NYASA1057..220A }} 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.{{cite journal | vauthors = Vander Heiden MG, Cantley LC, Thompson CB | title = Understanding the Warburg effect: the metabolic requirements of cell proliferation | journal = Science | volume = 324 | issue = 5930 | pages = 1029–1033 | date = May 2009 | pmid = 19460998 | pmc = 2849637 | doi = 10.1126/science.1160809 | bibcode = 2009Sci...324.1029V }} Metformin reduces liver glucose production in diabetics and disrupts the Warburg effect in cancer by AMPK activation and inhibition of the mTor pathway.{{cite journal | vauthors = Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC | display-authors = 6 | title = The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin | journal = Science | volume = 310 | issue = 5754 | pages = 1642–1646 | date = December 2005 | pmid = 16308421 | pmc = 3074427 | doi = 10.1126/science.1120781 | bibcode = 2005Sci...310.1642S }} Buformin decreased cancer incidence, multiplicity, and burden in chemically induced rat mammary cancer, whereas metformin and phenformin had no statistically significant effect on the carcinogenic process relative to the control group.{{cite journal | vauthors = Zhu Z, Jiang W, Thompson MD, Echeverria D, McGinley JN, Thompson HJ | title = Effects of metformin, buformin, and phenformin on the post-initiation stage of chemically induced mammary carcinogenesis in the rat | journal = Cancer Prevention Research | volume = 8 | issue = 6 | pages = 518–527 | date = June 2015 | pmid = 25804611 | pmc = 4452421 | doi = 10.1158/1940-6207.CAPR-14-0121 }} Buformin also exhibits anti-proliferative and anti-invasive effects in endometrial cancer cells,{{cite journal | vauthors = Kilgore J, Jackson AL, Clark LH, Guo H, Zhang L, Jones HM, Gilliam TP, Gehrig PA, Zhou C, Bae-Jump VL | display-authors = 6 | title = Buformin exhibits anti-proliferative and anti-invasive effects in endometrial cancer cells | journal = American Journal of Translational Research | volume = 8 | issue = 6 | pages = 2705–2715 | year = 2016 | pmid = 27398153 | pmc = 4931164 }} lung cancer cells{{cite journal | vauthors = Yakisich JS, Azad N, Kaushik V, Iyer AK | title = The Biguanides Metformin and Buformin in Combination with 2-Deoxy-glucose or WZB-117 Inhibit the Viability of Highly Resistant Human Lung Cancer Cells | journal = Stem Cells International | volume = 2019 | pages = 6254269 | year = 2019 | pmid = 30918522 | pmc = 6409035 | doi = 10.1155/2019/6254269 | doi-access = free }} and cervical cancer cells.{{cite journal | vauthors = Li J, Chen L, Liu Q, Tang M, Wang Y, Yu J | title = Buformin suppresses proliferation and invasion via AMPK/S6 pathway in cervical cancer and synergizes with paclitaxel | journal = Cancer Biology & Therapy | volume = 19 | issue = 6 | pages = 507–517 | date = June 2018 | pmid = 29400636 | pmc = 5927663 | doi = 10.1080/15384047.2018.1433504 }}

Biguanides were first noted to be active against influenza in the 1940s.{{cite journal | vauthors = Bailey CJ | title = Metformin: historical overview | journal = Diabetologia | volume = 60 | issue = 9 | pages = 1566–1576 | date = September 2017 | pmid = 28776081 | doi = 10.1007/s00125-017-4318-z | s2cid = 2088719 | doi-access = free }} Further studies confirmed their antiviral activity in vitro.{{cite journal | vauthors = Weinberg ED | title = Antimicrobial activities of biguanides | journal = Annals of the New York Academy of Sciences | volume = 148 | issue = 3 | pages = 587–600 | date = March 1968 | pmid = 4872309 | doi = 10.1111/j.1749-6632.1968.tb27733.x | s2cid = 19580586 | bibcode = 1968NYASA.148..587W }} Buformin, especially, was potently antiviral against vaccinia and influenza.{{cite journal | vauthors = Fara GM, Lugaro G, Galli MG, Giannattasio G | title = Antiviral activity of selected biguanide derivatives | journal = Pharmacological Research Communications | volume = 6 | issue = 2 | pages = 117–126 | date = April 1974 | pmid = 4373765 | doi = 10.1016/s0031-6989(74)80019-6 }}{{cite journal | vauthors = Denys A, Bocian J | title = [Effect of Silubin-retard (1-butyl-biguanide hydrochloride) on the course of influenza-virus infection in mice] | language = pl | journal = Polski Tygodnik Lekarski | volume = 25 | issue = 9 | pages = 332–334 | date = March 1970 | pmid = 5447272 }}{{cite journal | vauthors = Babiński S, Giermaziak H | title = [Influenza epidemic in 1971 in diabetics treated with 1-butyl-biguanidine hydrochloride (Silubin retard) and 1-phenylethyl-biguanidine hydrochloride (Phenformin)] | language = pl | journal = Polski Tygodnik Lekarski | volume = 28 | issue = 46 | pages = 1815–1817 | date = November 1973 | pmid = 4771858 }} Buformin is a metabolic antiviral that inhibits the mTOR pathway used by influenza {{cite journal | vauthors = Lehrer S | title = Inhaled biguanides and mTOR inhibition for influenza and coronavirus (Review) | journal = World Academy of Sciences Journal | volume = 2 | issue = 3 | date = May 2020 | pmid = 32313883 | pmc = 7170270 | doi = 10.3892/wasj.2020.42 }} and Middle East respiratory syndrome-related coronavirus.{{cite journal | vauthors = Kindrachuk J, Ork B, Hart BJ, Mazur S, Holbrook MR, Frieman MB, Traynor D, Johnson RF, Dyall J, Kuhn JH, Olinger GG, Hensley LE, Jahrling PB | display-authors = 6 | title = Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis | journal = Antimicrobial Agents and Chemotherapy | volume = 59 | issue = 2 | pages = 1088–1099 | date = February 2015 | pmid = 25487801 | pmc = 4335870 | doi = 10.1128/AAC.03659-14 }}

Buformin was synthesized as an oral antidiabetic in 1957.{{cite patent | inventor = Shapiro SL, Freedman L | assign1 = US Vitamin and Pharmaceutical Corp | title = Salts Of N-Amylbiguanide. | country = US | number = 2961377 | fdate = 5 August 1957 | gdate = 1960 }}

File:Buformin synthesis.png).]]

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

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{{oral hypoglycemics}}

Category:Withdrawn drugs

Category:Biguanides

Category:Butyl compounds