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Analgesics during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
The main use of aspirin has been as an analgesic, antipyretic, or anti-inflammatory agent. Salicylates were used clinically for over 120 years and are one of the most commonly used nonnarcotic analgesics. Aspirin has been widely used in pregnancy in the past, but acetaminophen has supplanted ASA as the most frequently used analgesic in pregnancy. Prospective study of 1529 pregnant women in 1974 and 1975, reported an estimated 50 percent of the women took aspirin sometime during pregnancy, but less than 5 percent took the drug daily. Salicylates are prostaglandin synthetase inhibitors, and non-selectively inhibit cyclooxygenase (COX) enzymes 1 and 2. COX-1 inhibition blocks normal production of protective esophageal and gastric mucosa, increasing the risk for gastrointestinal bleeds and associated complications. COX-1 suppression blocks synthesis of prostacyclin and thromboxane A (vasoactive prostaglandins). Prostacyclin is a strong vasodilator that is a platelet aggregation inhibitor. Thromboxane A is a potent vasoconstrictor that stimulates platelet aggregation (Bhagwat et al., 1985; Ellis et al., 1976). Prostaglandin E and prostaglandins are also inhibited. COX-2 suppression possesses analgesic activity associated with blocking prostaglandins linked with inflammation.
Effects of Antithrombotic and Results of Drug Screening
Published in Josef Hladovec, Antithrombotic Drugs in Thrombosis Models, 2020
Several eicosanoids were investigated in the author’s laboratory in the endothelemia test.444 Prostacyclin was effective against a citrate-induced endothelemia increase in rats at extremely low doses (10-3 ng/kg i.v.) (Figure 28). However, with the dose of 10-2 ng/kg this effect disappeared to show a second peak around 102 ng/kg and to vanish again at much higher doses. The agent alone, i.e., without the citrate challenge had no effect, but at a relatively high dose level of 10 ng/kg it had an unfavorable, destabilizing activity. Arachidonic acid likewise had a complicated dose-to-effect relation (Figure 29). Positively effective doses corresponded to those of prostacyclin, but adverse effects prevailed at doses around 102 ng/kg. Similar complicated dose-effect curves of exogenous arachidonic acid to platelet aggregating activity and TXB2 production were observed in a higher concentration range by Tanoue et al.392 This indicates the existence of a finely tuned balance of endogenous eicosanoid regulators, and all exogenous interventions may bring about a series of counter regulations influencing unfavorably and unpredictably the intended effect often resulting in an opposite response. The effective intervention is possible only with relatively high pharmacological doses exceeding by several orders of magnitude the levels of endogenous mediators.
Gene Therapy for Acute Diseases of the Lungs
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
The prostanoids prostacyclin and prostaglandin E2 (PGE2) have physiologic effects that could prevent or reverse acute lung injury and its consequent pathophysiology. Prostacyclin is a pulmonary vasodilator and prevents platelet activation. PGE2 can inhibit neutrophil aggregation, prevent induction of proinflammatory cytokines, and prevent airway constriction. Studies in animal models of acute lung injury show that exogenous delivery of pharmacologic amounts of these anti-inflammatory prostanoids can ameliorate lung injury and dysfunction (18).
Effect of quercetin on the pharmacokinetics of selexipag and its active metabolite in beagles
Published in Pharmaceutical Biology, 2022
Shun-bin Luo, Er-min Gu, Yu-ao Chen, Shi-chen Zhou, Chen Fan, Ren-ai Xu
Characterised by a gradual increase in pulmonary vascular resistance and pulmonary artery pressure, Pulmonary Arterial Hypertension (PAH) is a progressive, debilitating and chronic life-threatening disease (Sardana et al. 2016; Bruderer et al. 2017; Bhadru et al. 2019; Highland et al. 2019; Ilyin et al. 2019; Klose et al. 2019, 2021; Yazıcı & Güngör 2019; A Xe Lsen et al. 2021; Genecand et al. 2021). PAH may cause right ventricular dysfunction and potential failure and the average survival time of patients is only 2.8 years if not treated (Gnerre et al. 2018; Highland et al. 2019). There is strong evidence to support early intervention and the achievement of all treatment objectives with monotherapy or combination therapy has been critical to date (Ilyin et al. 2019). Prostacyclin, produced by prostaglandin H2 (PGH2) endothelial cells via prostacyclin synthase, is a potent vasodilator with anti-proliferative, anti-thrombotic, and anti-inflammatory effects (Bhadru et al. 2019). The role of prostacyclin or prostacyclin receptor (IP receptor) agonists in the treatment of PAH is reasonable because PAH is associated with vasoconstriction, proliferation, and thrombosis (Gnerre et al. 2018).
An appraisal of vascular endothelial growth factor (VEGF): the dynamic molecule of wound healing and its current clinical applications
Published in Growth Factors, 2022
Aakansha Giri Goswami, Somprakas Basu, Farhanul Huda, Jayanti Pant, Amrita Ghosh Kar, Tuhina Banerjee, Vijay Kumar Shukla
Several stimuli such as hypoxia, hypoglycemia, low pH, mechanical stress, estrogens, inflammatory cells, and their products and particularly VEGF can initiate angiogenesis in wounds (Kajdaniuk et al. 2011). VEGF induces endothelial nitric oxide synthase (eNOS) and cyclooxygenase through VEGFR-2, which in turn releases nitric oxide (NO) and prostacyclin respectively (Murohara et al. 1998). Both NO and prostacyclin are strong vasodilators. Moreover, prostacyclin inhibits activated platelet aggregation, thus forming negative feedback on thrombus formation and platelet release reaction. NO also increases vascular permeability through the formation of vesico-vacuolar organelle (VVO) in EC (Kohn et al. 1992). VVO comprises of multiple intercommunicating vacuoles, which form a fenestration spanning from the luminal to abluminal surfaces and transports plasma proteins, plasminogen, fibrin, fibronectin, and other macromolecules to the ECM. Some movement of plasma proteins also takes place through the leaky intercellular junctions, which results from VEGF and NO mediated degradation and relocation of junctional proteins such as VE-cadherin, claudins, occludins, and connexins (Kevil et al. 1998). Excessive extravazation of macromolecules is prevented by angiopoietin-1 (Ang-1), a pro-angiogenic factor released from EC, through activation of its receptor Tie-2. This probably acts as negative feedback and restricts tissue edema (Thurston et al. 2000). The extravasated macromolecules form a scaffold in the ECM on which the EC migration takes place (Kevil et al. 1998).
Epoprostenol for the treatment of pulmonary arterial hypertension
Published in Expert Review of Clinical Pharmacology, 2021
María José Cristo Ropero, Alejandro Cruz-Utrilla, María Pilar Escribano-Subias
Prostanoids can be divided into prostaglandins (PGD2, PGE2, PGI2 or prostacyclin, and PGF2) and thromboxane. They act on G-protein-coupled prostanoid IP receptors. Within the pulmonary vasculature, these receptors could be categorized as relaxant (IP, DP1, EP2, EP4) and contractile receptors (EP1, EP3, FP, and TP). Prostacyclin synthase produces prostacyclin within vascular endothelial cells. Epoprostenol acts as a synthetic analog of prostaglandin I2 in endothelial cells with a vasodilatory effect. The receptor’s activation in other cells produces anti-inflammatory, antiaggregating, and antiproliferative effects (Figure 1). Also, smooth muscle cell proliferation is slowed via transformation of ATP to AMP and an increase in protein kinase A activity. Two main metabolites of have been identified as follows: 6-keto-prostacyclin F1α, the more suitable marker of plasma concentrations of the drug and formed by hydration; and 6,15-diketo-13,14-dihydro-prostacyclin F1α, produced by enzymatic degradation. This drug has a short elimination half-life (3–6 minutes) in the human blood stream [42].