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Advances in Wet Granulation of Modern Drugs
Published in Dilip M. Parikh, Handbook of Pharmaceutical Granulation Technology, 2021
Bing Xun Tan, Wen Chin Foo, Keat Theng Chow, Rajeev Gokhale
Previously, the relatively lower operating temperatures of jacketed high-shear granulators (50–90 °C) meant that only low-melting binders (e.g., waxes, polyethylene glycol, and lipids) could be utilized. However, the advent of twin-screw granulators allowed the usage of polymeric binders, which require a higher temperature to function in melt granulation. Batra et al. demonstrated the use of a twin-screw granulator for melt granulation at 130 °C and 180 °C for several HPC, HPMC, PVP, and methacrylate-based polymers. At binder amounts of 10% w/w, granules containing either metformin hydrochloride or acetaminophen were successfully produced and resulted in tablets of >2 MPa tensile strength [44]. The use of twin-screw granulator technology also has advantages in improving the dissolution of some poorly soluble drugs due to the fine dispersion of the drug in the microenvironment of the binder. This drug solubility improvement was reported by Melkebeke et al. using PEG as a binder in formulation with surfactants and maltodextrin as the filler [45]. On the other hand, using insoluble polymeric binders such as ethylcellulose can modify and retard the release of highly soluble drugs such as imatinib mesylate in a high dose tablet formulation [46]. The use of fluid bed granulators for melt granulation had also been reported to be a viable alternative to high-shear granulator equipment albeit with differences in granule size distribution and morphology owing to the different mechanisms of granule growth [47].
The Discovery and Pharmacology of Tirilazad Mesylate
Published in John J. Lemasters, Constance Oliver, Cell Biology of Trauma, 2020
Tirilazad mesylate and other 21-aminosteroids exert physicochemical effects on the cell membrane. In egg lecithin/cholesterol monolayer experiments conducted by Hinzmann et al.,4 a very small amount of tirilazad mesylate (0.5 to 2 mol%) increases head group viscosity (reduces dynamic membrane fluidity) and expands the molecular area while decreasing the thickness of the bilayer. In lipid vesicle experiments, tirilazad mesylate reduces the diffusion of small molecules like acrylamide into the bilayer. The model from Figure 3 also predicts that lipid order in membranes or vesicles will decrease; this has been confirmed by van Ginkel et al.5 Other compounds that are not antioxidants but that can inhibit lipid peroxidation through physical effects on membranes have been reported.6 We believe that the physical effects exerted on membranes by tirilazad mesylate are partially responsible for the compound’s inhibition of lipid peroxidation. In addition, these physicochemical effects on membranes explain other activities of tirilazad mesylate such as inhibition of efflux glycoprotein mediated multiple drug resistance as reported by Abraham et al.7
Familial Gastrointestinal Stromal Tumor Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Imatinib mesylate is a tyrosine kinase inhibitor that proves effective for pre- or postoperative treatment of 80%–85% of GIST harboring KIT or PDGFRA (except PDGFRA exon 18 D842 V) mutations, and also for treatment of unresectable/metastatic disease [45,46]. With a tenfold more active favorable response than any agent examined for treatment of GIST, imatinib mesylate helps shrink tumor, converts patients from inoperable to operable, and dramatically reduces GIST metastases. Patients harboring KIT exons 8, 9, and 11 mutations are particularly susceptible to imatinib mesylate treatment, while those possessing KIT exon-13 and 17 mutations are somewhat resistant. For patients with KIT or PDGFRA mutations who have poor response to imatinib mesylate, alternative tyrosine kinase inhibitors (e.g., sunitinib, regorafenib, dasatinib, and crenolanib) may be considered. In fact, PDGFRA exon 18 mutation p.D842 V, commonly found in sporadic GIST but not in familial GIST, confers resistance to both imatinib and sunitinib, and therefore use of dasatinib and crenolanib is suggested [47–49].
Association between pharmacokinetics of lenvatinib in healthy subjects and genetic polymorphisms of ABCB1 3435C>T and ABCB1 2677G>T/A
Published in Xenobiotica, 2021
Haojing Song, Wanjun Bai, Xue Sun, Bo Qiu, Nini Guo, Caihui Guo, Yiting Hu, Zhanjun Dong
The pharmacokinetics of lenvatinib has been assessed in humans with both single and multiple dosing study. In the single dose administration study, lenvatinib mesylate was rapidly absorbed. Within the investigation period, the maximum concentration usually occurred (Tmax) between 1 and 4 h (Shumaker et al. 2014). For doses between 0.8 and 32 mg, the apparent oral clearance rate of lenvatinib ranged from 4.2 to 7.1 L/h, and the apparent terminal volume of distribution (uncorrected for bioavailability) ranged from 50.5 to 163 L. The contribution of renal excretion to oral clearance, based on mass balance, was minimal (1–2%). The terminal exponential half-life (t1/2) is 28 h. In both single and multiple dosing study, area under curve (AUC) of the plasma concentration vs time, and maximum plasma concentration (Cmax) of total (protein bound and unbound) lenvatinib increased proportionally with dose (Yamada et al. 2011; Boss et al. 2012). For doses ranging from 12 to 32 mg once daily, the mean accumulation index based on AUC ranged from 0.96 to 1.28.
Analysis of the influencing factors related to liver and cardiac iron overload in MDS patients detected by MRI in the real world
Published in Hematology, 2021
Chao Xiao, Yao Zhang, Jun-gong Zhao, Lu-xi Song, You-shan Zhao, Yan Jia, Juan Guo, Shuang Han, Zhao-wei Li, Cha Guo, Xiao Li, Chun-kang Chang
One hundred and five MDS patients in our department were studied. MDS diagnosis references to this literature [6]. Typing was in accordance with the 2016 WHO classification standards [7]. Iron overload diagnosis references to this literature [8]. In this study, liver T2*>6.3 ms was defined as normal, 1.4–6.3 ms as mild to moderate IO and <1.4 ms as severe IO. Cardiac T2*>20 ms as normal, 8–20 ms as mild to moderate IO and <8 ms as severe IO. A decrease in the liver T2* or cardiac T2* value indicates an increase in liver or cardiac iron content and vice versa. Patients with no blood transfusion were classified as group 1, monthly blood transfusion volume >800 ml as group 2 and monthly blood transfusion volume <800 ml as group 3. Among a total of 35 patients who received ICT treatment, 20 patients received the treatment of ICT for more than four courses. The usage is as follows: the deferoxamine mesylate dose was 20–60 mg kg−1 d−1, and the drug was continuously infused by a subcutaneous pump for 12 h.
Efficacy and safety of imatinib mesylate in systemic sclerosis. A systematic review and meta-analysis
Published in Expert Review of Clinical Immunology, 2020
Vasiliki Liakouli, Jacopo Ciaffi, Francesco Ursini, Piero Ruscitti, Riccardo Meliconi, Francesco Ciccia, Paola Cipriani, Roberto Giacomelli
Despite providing an updated overview on the effect of imatinib mesylate in SSc, our work has some limitations. Among the selected studies, five were phase II clinical trials, and one was a case series. No phase III trials were retrieved, and only two studies had a controlled design. The lack of a placebo group and the low number of included patients may be considered as major sources of bias along with different concomitant therapies and disease subsets. Concerning the analysis of FVC and DLCO, included studies were not all specifically designed to investigate the PFTs and did not specify the percentage of patients with ILD, thus impairing the generalization of the results and suggesting the need of further studies to fully elucidate this issue. In this context, the results of further studies are awaited to fully elucidate the therapeutic role of imatinib mesylate in SSc [ClinialTrial.gov, NCT00613171; NCT00479934; NCT00677092]. Finally, the application of simplified staging system constructed by Goh et al. could provide additional information about the efficacy of imatinib mesylate on ILD extension [5].