Drugs and Therapeutics
James Sherifi in General Practice Under the NHS, 2023
Metformin reduces insulin resistance by facilitating the cellular uptake of glucose. Unlike the other commonly used glycaemic drugs of the time, the sulfonylureas, it did not cause hypoglycaemia or weight gain. In fact, it had few adverse effects, the most common being diarrhoea. Metformin has since found other medical indications, its anti-androgenic properties leading to its unlicensed use in treating hirsutism and polycystic ovarian syndrome. Chlorpropamide—1958Diabetes Chlorpropamide26, a first-generation sulphonylurea, acts by stimulating pancreatic beta-cells to produce insulin. Therefore, by definition, it is ineffective when these cells are totally depleted, as in Type 1 Diabetes Mellitus (T1DM). It was an excellent drug at reducing blood glucose but had one major drawback, a long half-life that could, albeit infrequently, lead to profound hypoglycaemia and coma. It was a not uncommon cause, often overlooked by clinicians, of comatose patients being admitted to hospital. Chlorpropamide was the mainstay of treatment for Type 2 Diabetes Mellitus (T2DM) until the 1980s when second-generation sulphonylureas replaced it. Glibenclamide and gliclazide were no more potent but had a shorter half-life and, thus, were less likely to cause hypoglycaemia.
Biochemical and Pharmacological Rationales in Radiotracer Design
Lelio G. Colombetti in Principles of Radiopharmacology, 2019
The sulfonylurea hypoglycemic agents exert their effect primarily by stimulating the release of insulin from the beta cells of the pancreas.77 Therefore, a radioiodinated analog of the hypoglycemic agent chlorpropamide (Figure 7) was synthesized as a potential agent for imaging the pancreas.78 While initial studies in the dog did not show selective uptake in the pancreas as compared to other tissues, autoradiographic studies of the dog pancreas showed that the radioactivity was associated with the islet cells.79 These cells comprise only 1 to 4°7o of total pancreas weight,80 so that even high concentrations in these cells might not lead to selective concentration of the radiodiagnostic in the whole organ. Subsequently this agent was tested in hamsters with functional islet cell tumors, but no selective tumor uptake was demonstrated.81
Hyptis suaveolens (L.) Poit.: A REVIEW OF ITS ETHNOBOTANY, PHYTOCHEMICAL, AND PHARMACOLOGICAL PROFILE
V. R. Mohan, A. Doss, P. S. Tresina in Ethnomedicinal Plants with Therapeutic Properties, 2019
Diabetes mellitus is a leading metabolic disorder worldwide, caused by inherited or acquired deficiency in production of insulin in β cells of pancreas, or by the desensitization of insulin receptors for insulin. Such a deficiency results in the increased concentration of glucose in the blood which results in secondary complications affecting eyes, kidneys, nerves, and arteries (Ismail, 2009). Studies on the evaluation of antidiabetic activity of the aerial parts of H. suaveolens have been reported (Danmalam et al., 2009; Nayak et al., 2013). Aqueous, methanol and ethanol extracts of the plant was used to monitor the effect on alloxan-induced diabetic rats. The blood glucose concentration was assayed at time intervals, using chlorpropamide as standard. Results showed that there was significant (p = 0.05) reduction in the blood glucose concentration indicating that H. suaveolens possesses antidiabetic activity, which might be related to the presence of tannins, terpenoids, and flavonoids. Acute toxicity studies on the methanol extract of the plant also indicated that it can be considered as relatively safe (Danmalam et al., 2009), having obtained an LD50 of 2154.1 mg/kg body weight in rats.
Home management of pediatric sulfonylurea ingestions
Published in Clinical Toxicology, 2022
Courtney Temple, Ruby Hoang, Shana Kusin
Accidental pediatric sulfonylurea ingestions have raised concerns regarding both delayed and prolonged hypoglycemia. This class of medications frequently appears on “one pill can kill” lists, leading many health care providers to adopt a one-size-fits-all approach to even small, exploratory pediatric ingestions, a practice shored up by some cautionary tales in the medical literature. An early retrospective study that included pediatric and adult patients found that patients with sulfonylurea overdose and known time of ingestion had variable onset of hypoglycemia (up to 21 h with glyburide and 48 h with chlorpropamide) [11]. A prospective poison center study of pediatric sulfonylurea exposures later found that one third of patients developed hypoglycemia, on average 5.3 h after ingestion, but with some cases delayed by as much as 21 h [12]. Both of these series focused on all overdoses, and not specifically on single pill exposures.
Metabolic profiling of coumarins by the combination of UPLC-MS-based metabolomics and multiple mass defect filter
Published in Xenobiotica, 2020
Yao Xiao, Yi-Kun Wang, Xue-Rong Xiao, Qi Zhao, Jian-Feng Huang, Wei-Feng Zhu, Fei Li
Chromatographic analysis of coumarins metabolites was performed on an Agilent 1290 infinity UPLC system (Agilent Technologies, Santa Clara, CA, USA) equipped with a XDB-C18 column (2.1 × 100 mm, 1.8 µM, Agilent). Column temperature was maintained at 45 °C throughout the run. The flow rate was 0.3 mL/min with a gradient ranging from 2% to 98% acetonitrile containing 0.01% formic acid in 16 min run. The mass signals of ions were collected in both positive and negative mode by the electrospray ionization QTOFMS (Agilent 6500, Santa Clara, CA, USA). Nitrogen was applied as both drying gas (9 L/min) and collision gas. The drying gas temperature was set at 350 °C and nebulizer pressure was kept at 35 psi. Capillary voltage was set at 3.5 kV. The MS/MS of three coumarins metabolites was performed in the targeted mode by collision energy of 15 eV. Relative quantitation of metabolites was determined based on the abundance of peak area normalized by the internal standard (chlorpropamide).
Evaluation system for cell-permeable CYP3A4 inhibitory activity using 1α,25-dihydroxy-vitamin D3-induced intestinal cell lines
Published in Xenobiotica, 2021
Toshiya Ueno, Saori Takahashi, Tomoya Nakamura, Yasuhiro Tanaka, Hisako Hori, Kenta Mizoi, Takuo Ogihara
Metabolic activity of CYP3A4 was measured with reference to previous reports (Mizoi et al.2020b) as follows. The metabolic activity was quantitated in terms of the amounts of remaining MDZ and generated 1′-OH MDZ, which were determined using an LCMS-8040 triple quadrupole liquid chromatography mass spectrometer (LC-MS/MS) (Shimadzu, Kyoto, Japan) coupled with an LC-20A system (Shimadzu, Kyoto, Japan). Separation was performed on a CAPCEL PAK Type MG III-H (C18, 3 µm 2.0 mmID × 100 mm, Osaka Soda, Osaka, Japan). The mobile phases consisted of 0.1% formic acid in water: 0.1% formic acid in acetonitrile in a ratio of 50:50. The electrospray mass spectrometer was operated in the positive ion mode for MDZ and 1′-OH MDZ, and in the negative ion mode for chlorpropamide. Multiple reaction monitoring (MRM) was conducted at m/z 326.05 > 291.10 for MDZ, at m/z 342.00 > 323.95 for 1′-OH MDZ and at m/z 274.90 > 190.05 for chlorpropamide. Collision energy was −23 V for MDZ, −24 V for 1′-OH MDZ, and 24 V for chlorpropamide. Chlorpropamide was used as an internal standard for analytical LC-MS/MS. The operating parameters of LC-MS/MS were as follows: block heater temperature 400 °C, nebuliser gas flow rate 3 L/min, drying gas flow rate 15 L/min.
Related Knowledge Centers
- Beta Cell
- Pancreas
- Sulfonylurea
- Type 2 Diabetes
- Insulin
- Hypoglycemia
- Drug
- Gliclazide
- Tolbutamide
- Old Age