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Cardiovascular Drugs during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
Chlorthalidone (Hygroton, Thalitone), metolazone (Diulo, Zaroxolyn), and quinethazone (Hydromox) are not true thiazide diuretics from the standpoint of chemical structure, although their mode of action is very similar to the thiazide group. There is little available information regarding the use of chlorthalidone in women in the first trimester of pregnancy. Over 1300 women who used thiazide diuretics were included in the Collaborative Perinatal Project database, but only 20 used chlorthalidone during the first trimester (Heinonen et al., 1977). Although there was an increased frequency of congenital dislocation of the hip in this latter group, it is difficult if not impossible to draw valid conclusions from such numbers. Only one infant exposed to chlorthalidone in the first trimester was included in the Swedish Birth Defects Registry (Kallen, 2019). There were no reported significant differences in the frequency of birth offspring of mothers exposed to chlorthalidone after 15 weeks gestation, compared to controls (Tervila and Vartianen, 1971). Only eight pregnant women were exposed to quinethazone in the Collaborative Perinatal Project database, and none who received metolazone (Heinonen et al., 1977). No published reports are available on congenital anomalies in the offspring of women who took either of these two diuretics during pregnancy. Metolazone was not found to be teratogenic in one animal study (Nakajima et al., 1978), and no animal teratology studies are available for quinethazone. The Swedish Birth Defects Registry contained 372 infants whose mothers took thiazides during the first trimester (Kallen, 2019), and the frequency of birth defects were not increased in frequency.
Applications of carbonic anhydrases inhibitors in renal and central nervous system diseases
Published in Expert Opinion on Therapeutic Patents, 2018
Due to the wealth of tissues such as the kidney and the brain in many CAIs, the inhibition or activation of such isoforms leads to pharmacological applications. The diuretic effects of the CAIs are well known for decades and led to the development of diuretics belonging to several classes, such as acetazolamide, the thiazides and then high-ceiling diuretics, but also to a thorough understanding of the renal physiology [9,16]. Many drugs possessing diuretic effects and potent CA inhibitory activity against various mammalian CAIs are widely used clinically, among which are the thiazides, furosemide, quinethazone, metholazone, chlorthalidone, and indapamide, but their applications were dealt with extensively in a previous work [9]. Most of the recent work related to the renal applications of the CAs and their inhibitors deal mainly with aspects related to the reduction of drug toxicity by suing CAIs (e.g. methotrexate and lithium-induced nephrotoxicity seem to benefit from this association) as well as to the role of renal CAs as nitrous anhydrases, and their connection with the NO signaling pathway.
Advances in the structural annotation of human carbonic anhydrases and impact on future drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Alessio Nocentini, Claudiu T. Supuran
The first generation CAIs include sulfonamides 1–5: acetazolamide 1, methazolamide 2, ethoxzolamide 3, sulthiame 4 and dichlorophenamide 5 [2,14–22]. They are prevalently used as diuretics [14], antiglaucoma [2,15,16] or antiepileptic agents [2,17] but also for the management of idiopathic intracranial hypertension [20]. The second generation CAIs are constituted by dorzolamide 6 and brinzolamide 7, topically acting antiglaucoma agents [2–4,15,16]. For compounds, 8–15 the CA inhibitory properties were discovered after they were launched for other therapeutic applications [1,3,7,8], whereas 16 has been originally designed as a third-generation CAI, specific for the tumor-associated isoforms [23,24] (Figure 1). Some well-known pharmacological agents for the management of a variety of disorders are included among the CAIs mentioned above (8–15), such as the dopamine D2/D3-antagonist sulpiride 8 [25], the anticonvulsants topiramate 9 [26] and zonisamide 10 [27], the sweetener saccharine 11 [28], the COX-2 selective inhibitors celecoxib 12 [29] and valdecoxib 13 [30], the histamine H2-receptor antagonist famotidine 14 [31], the tyrosine kinase pan-inhibitor pazopanib 15 [32], as well as the indoleamine-2,3-dioxygenase inhibitor epacadostat 17, in Phase III clinical trials as an antitumor drug [33]. All of them are characterized by the presence of sulfonamide, sulfamate or sulfamide moieties, well-known for their affinity to bind the zinc(II) ion from the CA active site (see detailed discussion in the next section). On the other hand, the diuretic activity of acetazolamide 1 (and its congeners) led to the development of most diuretic agents used clinically nowadays (of types 18–24), which although possessing a variety of pharmacological effects which account for their diuretic activity [14,19] still possess significant CA inhibitory properties [34,35]. Indeed, the various thiazides 18a-e, quinethazone 19, metolazone 20, chlorthalidone 21, indapamide 22, furosemide 23 and bumetanide 24 (Figure 2) were demonstrated to possess significant CA inhibitory properties, which may explain some of their diuretic effects (in addition to their interference with various transporters from the kidney tubules [14]) but might be also exploited for other pharmacologic applications [34,35].