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Lipase-Mediated Biocatalysis as a Greener and Sustainable Choice for Pharmaceutical Processes
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Monika Sharma, Tanya Bajaj, Rohit Sharma
Ramatroban is a pharmacologically potent compound with 1-indolepropanoic acid structure. This drug acts as a thromboxane A2 (TxA2) antagonist and prostaglandin D2-induced eosinophil migration inhibitor improving nasal obstruction symptoms by lowering the levels of lipid mediators such as thromboxane A2 and leukotriene in the respiratory system (Ohkubo and Gotoh, 2003) and is therefore used to treat allergic rhinitis and asthma. Its (fij-enantiomer (Fig. 1.16) is 10 to 100 times more active than the βj-enantiomer and thus the chiral drug needs resolution (Sugimoto et al., 2003). As an intermediate step in the synthesis of drug, the enzymatic acetylation of f±J-2,3,4,9-Tetrahydro-1H-carbazol-3-ol was performed using various commercially available lipases including Burkholderia cepacia lipase, Candida antarctica lipase type A (CAL-A) and Candida antarctica lipase type B (CAL-B) using vinyl acetate as the acyl donor and tetrahydrofuran as the solvent (Busto et al., 2012).
Liposomes
Published in Sourav Bhattacharjee, Principles of Nanomedicine, 2019
Liposomes are known to trigger acute non-immunoglobulin E–mediated allergic/hypersensitivity reactions, known as CARPA, by means of activating the complement pathways [123]. An estimated 2%–45% of the patients receiving liposomal formulations develop CARPA, which unfortunately is true for formulations already approved (e.g., Doxil®, Ambisome®, and DaunoXome®) or currently undergoing clinical trials. The complement fractions that are responsible for these sensitivity reactions are usually the anaphylatoxins (C3a and C5a) or derivatives of C3 (e.g., C3d) [124]. These fractions stimulate the immune cells (e.g., basophils, mast cells, and macrophages) to release inflammatory vasodilators, for example, histamine, prostaglandins (prostaglandin D2), leukotrienes (LTB2, LTB4, LTC4, LTD4, and LTE4), platelet-activating factor, and thromboxane (TXA2). Release of such inflammatory mediators is particularly prompt after intravenous infusion and is thought to be due to coating of the liposomal vesicles with molecules like IgM, IgG, C3, C-reactive protein, and mannose binding lectin. Patients already suffering from cardiovascular ailments are more susceptible. Typical symptoms of CARPA are facial flushing and swelling, respiratory distress, and chills. The line of management includes reducing the rate of infusion and use of antiallergic medications (e.g., antihistaminic, corticosteroid, and adrenaline). In severe cases the administration of the liposomal preparation may need to be stopped completely.
Drug-induced bronchospasm
Published in Philippe Camus, Edward C Rosenow, Drug-induced and Iatrogenic Respiratory Disease, 2010
K Suresh Babu, Jaymin Morjaria
IgE-mediated drug reactions have been studied extensively and the pathophysiological processes that trigger these reactions have been well characterized. IgE and IgG antibodies are generated by B-lymphocytes in response to the exposure to a specific antigen. IgE molecules bind to high-affinity FcεRI receptors on the surface of tissue mast cells and circulating basophils,8 and antigen cross-linking of these molecules results in degranulation of mast cells, releasing both preformed (histamine, heparin, tryptase, chymase and tumour necrosis factor) and newly synthesized mediators over minutes (platelet-activating factor, prostaglandin D2, sulphidoleukotrienes, leukotriene (LT)-B4, LT-C3, LT-D4 and LT-E4) and over hours (interleukin (IL)-4, IL-5, IL-13 and granulocyte macrophage colony stimulating factor).9 This results in fluid influx (leading to upper airway obstruction), vasodilation (in combination with fluid extravastion from the vascular space causes distributive hypovolaemic shock), and smooth muscle contraction akin to asthma – causing lower airway obstruction due to bronchospasm, mucosal oedema and mucous plugging. Treatment should be targeted according to pathophysiology.
Genetic variants affecting chemical mediated skin immunotoxicity
Published in Journal of Toxicology and Environmental Health, Part B, 2022
Isisdoris Rodrigues de Souza, Patrícia Savio de Araujo-Souza, Daniela Morais Leme
Loss of FLG function is also related to an enhanced activation of group 2 innate lymphoid cells (ILC2) – cells associated with AD progression. ILC2 express MHC II on their cell surface and secrete IL-5 and IL-13 (effector type 2 cytokines) in response to epithelial cell-derived cytokines IL-25, IL-33 and/or thymic stromal lymphopoietin (TSLP). ILC2 also respond to mast cell mediators, such as prostaglandin D2 (PGD2), resulting in ILC2 migration, production of type 2 cytokines and upregulation of IL-33 and IL-25 receptor subunits expression (ST2 and IL-17RA) (Xue et al. 2014). ILC2-derived cytokines, such as IL-13, are necessary to activate and expand DCs, demonstrating the critical role of ILC2 in Th2 response (Rafei-Shamsabadi et al. 2019).