China
Africa
Explore chapters and articles related to this topic
Methsuximide
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
MSM is readily absorbed and achieves peak plasma levels within 2 to 4 hours. It distributes evenly throughout the body and penetrates into the brain and fat tissue better than ESM (3). Because of its poor lipid solubility and absence of protein binding, MSM equilibrates with cerebral spinal fluid (B. J. Wilder, unpublished data). MSM is rapidly converted to N-desmethyl-methsuximide (NDM) or 2-methyI-2-phenyl succinimide within hours (3–6) with a mean half-life of 1.4 hours. Trough plasma concentrations of MSM are reported to be undetectable in fasting specimens (7). NDM is the major active metabolite of MSM; it achieves high, steady-state plasma levels and provides a major anticonvulsant effect. It has a mean half-life of 38 hours (range 37 to 48 hours)(4,8), although Browne et al. (7) have reported a longer elimination half-life (51.6 to 80.2 hours), probably because they placed their patients on maximal doses of MSM, which might have inhibited the biotransformation of NDM. A shift from first-order kinetics to zero-order kinetics could also be responsible for the longer half-life at higher plasma concentrations. N-Methyl-2-hydroxymethyl-2-phenylsuccinimide is another metabolite of MSM that was reportedly detected by analysis of gas chromatography-mass spectrometry of the serum of a patient with a fatal overdose of PRM and MSM.
High-Performance Liquid Chromatography
Published in Adorjan Aszalos, Modern Analysis of Antibiotics, 2020
Joel J. Kirschbaum, Adorjan Aszalos
A 5-μm octylsilane analytical column and precolumn were used to assay the various constituents of gentamycin in serum and urine after derivatization with o-phthalicdicarboxaldehyde, with a mobile phase of 0.1% tris (hydroxymethyl) aminomethane (adjusted to pH 4.3 with 1 M HCl) with acetonitrile (30:70) flowing at 1.5 ml/min. Fluorescence detection was used at 340 nmex/418 nmem [14]. Although similar results were found using a radioimmunoassay, the HPLC method is more specific.
Cholinergic Antagonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Vishal S. Gulecha, Manoj S. Mahajan, Aman Upaganlawar, Abdulla Sherikar, Chandrashekhar Upasani
It is a competitive antimuscarinic agent and a prodrug. It generates active metabolite known as 5-hydroxymethyl tolterodine, a hydrolytic product after metabolism by nonspecific esterases. Its bioavailability is about 52%, and it is bound to plasma protein mainly albumin and α1-AGP. The active metabolite is further biotransformed by hepatocytes by two cyto-chrome P450 (CYP) enzymes, that is, CYP2D6 and CYP3A4. Most of the administered fraction (about 70%) of fesoterodine is found in urine. The drug is contraindicated in urinary and gastric retention, narrow-angle glaucoma, and so on. It is one of the drugs for the treatment of overactive bladder with UI, urgency, and frequency (Game et al., 2018).
TGR5 agonists for diabetes treatment: a patent review and clinical advancements (2012-present)
Published in Expert Opinion on Therapeutic Patents, 2022
Rachana S. Bhimanwar, Amit Mittal
An application on modulators of TGR5/FXR was filed by BAR Pharmaceuticals in 2017 with a modified Cholane scaffold at C-17 of steroidal nuclei attached to side chains (general structure 3 in Figure 3). Novel series of compounds were synthesized with variation in the number of carbons in the C-17 side chain with different substituents like -CH2OH, -COOH, CH2OSO3H. A luciferase reporter gene assay was performed in transfected HEK-293 T cells to evaluate the modulating activities of all designed compounds. The four representative compounds 3a-3d modularize GPBAR1 approximately 70% compared to the 10 µM standard. The compound 3a with hydroxymethyl group at the C-17 side chain showed high selectivity for FXR (% efficacy – 488) and TGR5 (% efficacy – 108) in comparison with the activity of 10 μM Chenodeoxycholic acid, as a standard [28]. Compound 3b TGR5 (% efficacy – 80.9), compound 3 c TGR5 (% efficacy – 47.7), and compound 3d (% efficacy – 80.5) all demonstrate a smaller percentage efficacy toward TGR5.
Applications of fluorine to the construction of bioisosteric elements for the purposes of novel drug discovery
Published in Expert Opinion on Drug Discovery, 2021
As part of a program to identify compounds with superior potency and a better pharmacokinetic profile as an alternative clinical development candidate to nicotinic acid [178–181], Qin and coworkers have reported on the identification of a thiobarbituric acid (49) derivative identified from a high-throughput screen that showed moderate in vitro potency as a GPR109a agonist [182]. Sequential SAR investigations in order to improve the potency initially focused on the C-2 vector with the goal to identify a suitable replacement for the reactive, sensitive thiol-group in 49 (Figure 8). Most replacements tested led to a complete loss of activity, but the hydroxymethyl derivative (1100 nM, not shown) showed modest levels of activity, which was attenuated through formation of the corresponding ether (3393 nM, not shown). Installation of fluoroalkyl groups at the C-2 position presented an interesting profile with the trifluoromethyl group (50) showing similar activity to the hydroxymethyl variant (not shown), while the difluoro- (51) and monofluoro-methyl (52) analogues showed significant improvements in potency, which were superior even to the initial SH-based lead (49). Switching from the difluoromethyl to a fluorochloromethyl (2705 nM, not shown) led to a > 8-fold loss of potency. Despite being marginally better in terms of activity than the difluoromethyl derivative (51), the monofluoro-compound (52) was deprioritized owing to its potential to produce toxic α-fluoroacetic acid.
Effect of CYP2C9 genetic polymorphism and breviscapine on losartan pharmacokinetics in healthy subjects
Published in Xenobiotica, 2021
Hang-Xing Huang, He Wu, Yingying Zhao, Tao Zhou, Xin Ai, Yu Dong, Yan Zhang, Yong Lai
This study in which was conducted a randomised, open-label, two-phase crossover design (Figure 1) at the Affiliated Hospital of Dali University. During each phase, 12 subjects took breviscapine tablets of the same batch ((Lot No.20141201; Yunnan Plant Drug Co., Ltd. Kunming, China) or placebo (Starch 45%, Dextrin 30%, Sodium Hydroxymethyl Starch 3%, Microcrystalline Cellulose 20%, Talc 1%, Magnesium Stearate 1%) at a dose of 40 mg three times daily for 14 days consecutively, and four weeks as a washout period. All fasting participants received a single dose of 50 mg Losartan potassium tablets (Lot No.15061602; Yangtze River Pharmaceutical Co., Ltd., Jiangsu, China) along with 40 mg placebo or breviscapine tablets with 100 ml water at 8 AM on day 15 (Han et al.2009, Gao et al.2017). The doses of breviscapine and losartan were both clinical therapeutic doses. Blood samples were collected once before dosing, then at 0.17, 0.33, 0.5, 0.67, 1, 1.33, 1.67, 2, 2.5, 3, 4, 6, 8, 12, 24, and 36 h after administration, which were to analyse pharmacokinetic parameters of losartan potassium and its metabolites. The blood samples were then centrifuged at 3000 g within 1 h of collection, and the resulting samples should be stored at −80 °C until analysis. During the entire study period, the vital sign measurements of all subjects were closely observed by investigators. And the adverse events were performed by asking related questions about health as well as self-reporting by the subjects throughout the study.