Analgesics during Pregnancy
“Bert” Bertis Britt Little in 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.
Lupus Anticoagulants: Characteristics, Methods of Laboratory Detection and Some Clinical Associations
E. Nigel Harris, Thomas Exner, Graham R. V. Hughes, Ronald A. Asherson in Phospholipid-Binding Antibodies, 2020
Carreras et al.85 using rat aortic rings and human LA plasmas reported that LA-containing immunoglobulins could suppress the formation of prostacyclin, normally a powerful platelet aggregation inhibitor. Prostacyclin is formed by normal endothelium in response to thrombin stimulation and prevents platelets from adhering to and contributing to clotting in blood vessels distant from an injury. This process is membrane phospholipid dependent. The hypothesis that LA bind the phospholipid normally converted to prostacyclin, thereby compromising this antithrombotic pathway seemed most plausible.85 However, several investigators attempting to repeat these studies with homologous test systems have failed or else have obtained highly variable results.86 (This is discussed in more detail in a later chapter.) Other studies suggest that LA may activate platelets.
Source of Prostaglandins and their Influence on Bone Resorption and Formation
Wilson Harvey, Alan Bennett in Prostaglandins in Bone Resorption, 2020
Prostacyclin is also a major product of blood vessels22 originating in the endothelial cells.23 Although the proportion of PGI2 synthesized varies, it can be as high as 95% of the total cyclooxygenase products in bovine aorta endothelial cells.21 In view of its rapid conversion to 6-keto-PGF,a, a relatively poor resorber of bone compared to the parent compound, the contribution of endothelial cell PGI2 to bone resorption is uncertain. In order to stimulate resorbing cells on bone, the PGI2 would have to diffuse through the blood vessel wall and surrounding connective tissue. One can therefore envisage this occurring only when there is very close apposition of the blood vessels to the bone. Thrombin and trypsin24 and later bradykinin25 were found to stimulate PGI2 and PGE2 synthesis, respectively, in cultured endothelial cells, indicating the responsiveness of these cells to proteinases which would be present in damaged and inflamed tissue.
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).
Gustav Born: pioneer in imaging platelet and leukocyte biology
Published in Platelets, 2018
Simon J. Cleary, Clive P. Page
Born was also active in public engagement and was not afraid to challenge dogma. Both of these attributes are displayed in an excellent documentary which covers platelets, cardiovascular disease, and the discovery of prostacyclin by researchers at the Wellcome Research Laboratories. This video closes with distinct views of varying optimism posed by Born and Sir John Vane (Figure 3), a friend of Born’s from their time at Oxford University and the Royal College of Surgeons who would go on to win the Nobel Prize in Physiology or Medicine, and who would later appoint Born as an Emeritus Research Professor at his William Harvey Research Institute following Born’s retirement as Professor of Pharmacology at King’s College London. Vane says: We think that perhaps there will be a utility of prostacyclin after a heart attack
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].