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Endocrine Disorders, Contraception, and Hormone Therapy during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
Clinical characteristics are polyuria, excessive thirst (polydipsia), and low urinary specific gravity. Diabetes insipidus may be idiopathic, autosomal dominant inheritance, or secondary to trauma or tumor. Fertility is not impaired and fetal outcomes are not adversely affected in patients with diabetes insipidus when the disease is successfully treated (Hime and Richardson, 1978; Jouppila and Vuopala, 1971). Therapy includes hormone replacement. The drug of choice in pregnancy is DDAVP (1-deamino-8-D-arginine vasopressin) given as a nasal spray. Other therapeutic regimens in patients with partial diabetes insipidus are not recommended for use during pregnancy (chlorpropamide, clofibrate, and carbamazepine). Note that DDAVP is not effective for the treatment of nephrogenic diabetes insipidus.
Drug Combinations
Published in Josef Hladovec, Antithrombotic Drugs in Thrombosis Models, 2020
Clofibrate was originally combined with androsterone (Atromid), but the effect of the androsterone component on platelet functions was questioned. Carson et al.76 suggested a synergistic effect on platelet stickiness. Some warnings have been issued against the combination of clofibrate with oral anticoagulants, but O’Reilly et al.77 did not find any increased bleeding tendency and no change in platelet and clotting system functions ex vivo.
Atherosclerosis
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Many drugs inhibit cholesterol synthesis, such as 2-phenylbutyric acid and derivatives.19,64,132,198,461,541,542,626,700 Application of this drug in clinical trials has resulted in toxic manifestations. Derivatives of this compound reduce acetyl-CoA formation. The currently employed clofibrate has some effect on cholesterol biosynthesis at the level of 3-hydroxy-3-methylglutaryl-CoA reductase.21 There are some other drugs blocking cholesterol synthesis at other steps. Benzmalacene (N-[l-methyl-2,3-bis(p-chlorophenyl)propyl]maleamic acid or 4-[2,3-bis(4-chlorophenyl)-l-methylpropyl]amino]-4-oxo-2-butenoic acid) inhibits the incorporation of mevalonic acid into cholesterol in rat liver homogenates. However, benzamalacene given to animals has a toxic effect and results in liver damage.207,304 This drug has been among the first compounds used clinically. It is structurally related to a series of nonsteroidal estrogens and estogen antagonists.
Optimal pH 8.5 to 9 for the hydrolysis of vixotrigine and other basic substrates of carboxylesterase-1 in human liver microsomes
Published in Xenobiotica, 2022
Joshua L. Johnson, Jiansheng Huang, Michael Rooney, Chungang Gu
Note that in Figure 5, different incubation times for individual substrates ranging from 0.25 h to 2 h were chosen to fit different hydrolysis rate of individual substrates for the investigation on pH effect in HLM. Vixotrigine has apparently the lowest rate of hydrolysis among all these CES1 substrates tested, thus, was incubated for the longest time 2 h. For all other substrates having higher turnover of carboxylic acid metabolite, a suitable incubation time was applied to ensure adequate parent drug remaining at the end of incubation, e.g. with approximately 30–70% parent drug remaining for clopidogrel, oseltamivir, benazepril, methylphenidate, and quinapril at pH 7.4. When the incubation time was too long and the depletion of parent drug was too much, the formation of carboxylic acid metabolites could be plateaued. As the consequence, a pH-dependence of hydrolysis would become less obvious even if it does exist. Note that clofibrate and fenofibrate are not suitable for LC-MS analysis due to their poor ionisation efficiency in electrospray ionisation (ref to Figure 2 for chemical structures), thus, only their hydrolysis metabolites were monitored by negative ion HRMS (Table 1). Nevertheless, a proper incubation time was chosen for clofibrate and fenofibrate so that the formation of their carboxylic acid metabolites was not plateaued.
The human organic cation transporter OCT1 and its role as a target for drug responses
Published in Drug Metabolism Reviews, 2019
Nicolas Brosseau, Dindial Ramotar
The lipid-lowering agent clofibrate is an agonist that binds to the transcription factor PPARa, which can then increase OCT1 gene expression and hence the activity of the encoded transporter (Nie et al. 2005; Wang L et al. 2012). Clofibrate binding to PPARa can increase the killing effect of imatinib on chronic myeloid leukemia cells. This effect is a result of clofibrate-induced expression of OCT1 that mediated imatinib uptake. It has been observed that patients with high OCT1 gene expression before treatment had better responses to imatinib and overall survival than those with lower levels of expression (Kajiwara et al. 2008; Wang L et al. 2008; Austin et al. 2015). It is therefore plausible that upregulation of OCT1 such as agonist binding to PPARa in cancer patients is expected to improve the uptake of cationic anticancer drugs.
Pharmacological treatment options for severe hypertriglyceridemia and familial chylomicronemia syndrome
Published in Expert Review of Clinical Pharmacology, 2018
Rabia Chaudhry, Adie Viljoen, Anthony S. Wierzbicki
Statins reduce TGs in proportion to their efficacy in reducing low-density lipoprotein cholesterol (LDL-C) and to baseline TG levels [55]. Data exist for statins reducing TGs in a dose- and efficacy-proportional manner based on a trial which recruited patients up to a maximum TG of 8 mmol/L [56]. Statins act to increase LDL receptor expression. The LDL receptor can bind two ligands – apoB100 and at lesser affinity apoE [57]. TG-rich particles have multiple apoE molecules and only one apoB100 and so are cleared preferentially despite their lower molecular affinity for the receptor. There is little evidence for statins in FCS though they are commonly prescribed. Fibrate-statin combination therapy is used in the treatment of LPLD based on their complementary mechanisms of action and in case series of type IV and V hyperlipidemia with reductions of up to 80% in TGs being achieved mostly through actions on VLDL turnover [58–60]. Combination therapy with clofibrate and lovastatin resulted in a 75% decrease in TGs and a 67% fall in total cholesterol in one study in type V hyperlipidemia [6]. There is some support from the general lipid trials for the anti-inflammatory secondary action of statins reducing rates of pancreatitis [61].