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Clinical Pharmacogenomics Of Human Cyp2d6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Phenformin, a biguanide antidiabetic agent, is a substrate of CYP2D6 (Oates et al. 1982; Shah et al. 1985). Risk factors for phenformin-induced lactic acidosis include renal, liver or cardiac disease, alcoholism, and the CYP2D6 PM phenotype (Krentz et al. 1994; Marchetti and Navalesi 1989). Increased phenformin plasma concentrations have been observed in patients with lactic acidosis (Marchetti and Navalesi 1989), and the AUC of phenformin is ~1.4-fold higher and lactate concentrations are greater in PMs after a single dose (Oates et al. 1983). However, there is weak evidence implicating the CYP2D6 phenotype as a cause or a primary risk factor (Oates et al. 1981; Wiholm et al. 1981) and the risk of developing lactic acidosis may be related more to other factors than to CYP2D6 PM status.
Use of oral hypoglycemic agents in pregnancy
Published in Moshe Hod, Lois G. Jovanovic, Gian Carlo Di Renzo, Alberto de Leiva, Oded Langer, Textbook of Diabetes and Pregnancy, 2018
Biguanides were recognized as early as 1920 but received clinical recognition in the United States only in the recent past. Phenformin, the primary drug in this group, was withdrawn from American and European markets because of the side effects of lactic acidosis. Its replacement, metformin, although used extensively in Europe, has only been recognized for use in the United States since 1995.27 Metformin is an oral antihyperglycemic agent that is chemically and pharmacologically unrelated to the sulfonylureas. Metformin is a second-generation biguanide that was reintroduced and distributed in the United States after biguanide phenformin was withdrawn from the market in the 1970s: both were introduced in 1957. Metformin has universally been shown to be effective in improving the glycemic profile in diabetic patients. Its mechanism of action is thought to include decreased hepatic glucose production and intestinal absorption of glucose and increased peripheral uptake of glucose and utilization. The two latter mechanisms result in improved insulin sensitivity, i.e., decreased insulin requirements.41–43 Importantly, metformin does not stimulate insulin secretion and, therefore, does not cause hypoglycemia either in diabetic or in control patients. The drug acts by causing the translocation of glucose transporters from the microsomal fraction to the plasma membrane of hepatic and muscle cells.43
Managing Diabetes without Weight Gain
Published in David Heber, Zhaoping Li, Primary Care Nutrition, 2017
French lilac, or goat’s rue (Galega officinalis), was used as a folk remedy for diabetes in southern and eastern Europe during medieval times (White and Campbell 2008). In the early twentieth century, the glucose-lowering compound in this plant, guanidine, was isolated and synthesized (Frank et al. 1926). It was named Synthalin in Germany and used to treat diabetes during the 1920s (Galloway 1988). These early drugs were toxic to the liver, and their use ended with the discovery of insulin. However, in the 1960s and 1970s, drugs modified to reduce toxicity included the biguanide drugs phenformin in the United States, metformin in France, and buformin in Germany (Alberti et al. 1997). Phenformin and buformin were associated with lactic acidosis, especially in elderly individuals with reduced renal function. Metformin, first introduced in 1959, was approved in the United States in the 1990s. Metformin is the most widely used glucose-lowering drug in the world (White and Campbell 2008).
Acid-base and electrolyte disturbances in patients with diabetes mellitus
Published in Acta Clinica Belgica, 2019
Lissa Pipeleers, Karl Martin Wissing, Robert Hilbrands
A severe side-effect of biguanides is the development of lactic acidosis, which has led to the withdrawal of two older biguanides (phenformin and buformin) from the market many years ago [9]. The risk of lactic acidosis is much lower with metformin, with an estimated incidence ranging from 1 to 16.7 cases per 100,000 patient years of treatment [13,14]. The significance of lactic acidosis as a side effect of metformin was even questioned by two systematic reviews in which the incidence of metformin-associated lactic acidosis (MALA) was not distinguishable from the background rate of lactic acidosis in the overall population with diabetes [15,16].
A dual-functional buformin-mimicking poly(amido amine) for efficient and safe gene delivery
Published in Journal of Drug Targeting, 2020
Mei Lu, Haonan Xing, Lin Cheng, Hui Liu, Lang Lang, Tianzhi Yang, Xiaoyun Zhao, Hui Xu, Pingtian Ding
Biguanides including metformin, phenformin and buformin have long been used in the treatment of type-2 diabetes. In addition to their antihyperglycemic effect, biguanides have been reported to be capable of reducing the risk of cancer and tumorigenesis through activation of AMPK and inhibition of mTOR pathways in multiple types of neoplasms [19–21]. Therefore, in the following section, cell viability and western-blot analysis were performed to explore whether buformin-mimicking side chains could endow CBA-Bu with antiproliferative effects on cancer cells through pathways similar to that of buformin.
Protective effects of phenformin on zebrafish embryonic neurodevelopmental toxicity induced by X-ray radiation
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Lu Gan, Menghuan Guo, Jing Si, Jinhua Zhang, Zhiyuan Liu, Jin Zhao, Fang Wang, Junfang Yan, Hongyan Li, Hong Zhang
Phenformin is a biguanide compound with hypoglycaemic actions for type-2 diabetes similar to those of metformin. Population-based and preclinical studies have demonstrated that biguanides also possess antitumor activity both in vitro and in vivo associated with AMPK pathway modulation. Yuan et al found that phenformin is much more potent than metformin in suppressing tumour growth due to greater lipophilicity and inhibitory activity against mitochondrial complex I and cellular ATP production [28–30]. However, there is yet no evidence for radioprotective effects of biguanides.