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Coupling Computational and Experimental Techniques for the Design, Characterization, and Performance of Self-Assembled Dendrimers for Heparin and DNA Binding
Published in Costas Demetzos, Stergios Pispas, Natassa Pippa, Drug Delivery Nanosystems, 2019
Domenico Marson, Erik Laurini, Maurizio Fermeglia, Sabrina Pricl
To ensure the optimal level of heparin as an anticoagulant during medical operations, the quantification of this polyanion in blood is of paramount importance. In current practice, this is typically achieved via activated clotting time assays [2]. These measurements, however, suffer from several drawbacks, including (i) difficulty in determining the exact value of heparin levels, (ii) the amount of time required to complete the assays, and (iii) the impossibility of these tests to be carried out on a patient in a simple manner in situ. Moreover, once a surgical procedure in which heparin was used is concluded, there is an immediate need to neutralize its anticoagulant effect and allow blood clotting and recovery to begin. At the time being, the only Food and Drug Administration (FDA)-approved heparin antidote is protamine sulfate, a small, arginine-rich protein of shellfish origin. Protamine acts as a heparin neutralizer by forming a supermolecular complex (Fig. 8.1) driven by electrostatic interactions between the cationic arginine groups and the anionic heparin [3]. However, the binding is not selective for active or inactive heparin sequences. Furthermore, and most importantly, protamine can cause significant adverse effects, with major complications arising in 2.6% of cardiac surgeries, while up to 10% of patients treated with this protein experience different sorts of problems [4].
Sedation, analgesia and patient observation in interventional radiology
Published in William H. Bush, Karl N. Krecke, Bernard F. King, Michael A. Bettmann, Radiology Life Support (Rad-LS), 2017
Jeffrey E. Quam, Michael A. Bettmann
Heparin serves as a catalytic template for the thrombin-antithrombin reaction. It is a cofactor for antithrombin III, increasing the reaction rate 1000-fold.51 Heparin inhibits several additional activated coagulation factors. Parenteral heparin is degraded and disappears from the blood via first-order kinetics, and its effective half-life, while short (usually 1–2 h), is dependent on the dose administered. The anticoagulant effect typically disappears 2–8 h after discontinuation of heparin administration.52 If this short resolution time is considered excessive, heparin’s effects can be reversed with protamine. However, protamine has the potential side-effects of dyspnea, bradycardia, hypotension and, most importantly, anaphylaxis (particularly in diabetic patients who have used neutral protamine, Hagedorn (NPH) insulin). Protamine should therefore only be used in extreme circumstances, when waiting for heparin degradation is considered hazardous to the patient. Heparin allergies, which are relatively common, are another potential concern.
Drug-induced bronchospasm
Published in Philippe Camus, Edward C Rosenow, Drug-induced and Iatrogenic Respiratory Disease, 2010
K Suresh Babu, Jaymin Morjaria
Reactions to insulin therapy have occurred since the launch of animal insulin in 1922. With the initiation of recombinant human insulin, however, the incidence of insulin-induced allergic reactions has decreased. Anaphylactic reactions have been reported, though are rare, and IgE antibodies have been demonstrated,41 sometimes causing acute pulmonary hypertension. Reactions to protamine-containing insulins may be caused by the protamine component in the insulin preparation and not the insulin itself. Protamine sulphate is a low-molecular-weight polycationic protein that is used to reverse the anticoagulant properties of heparin, and it is also complexed to insulin to delay absorption. Dykewicz et al. reported on two patients with diabetes who had anaphylaxis in response to neutral protamine Hagedorn insulin and to protamine, indicating that protamine-specific IgE antibodies were responsible for the anaphylactic reactions.42 Inhaled insulin (Exubera), initially approved for the management of diabetes and then withdrawn from the market, had respiratory adverse events reported in approximately 11.6 per cent.43 It is not entirely certain, but the reactions might be due to the increased immunogenicity of inhaled insulin arising from the structural changes in insulin during manufacture of the powder, or due to differences in immune responses related to different routes of drug delivery, storage conditions, or pre-sensitization with subcutaneous insulin used previously; and pulmonary insulin may have an increased antibody response. This suggests that site of delivery and susceptibility of the recipient may significantly affect immune responses.44,45
Preparation of protamine-adsorbed calcium phosphate powders and their antibacterial property
Published in Journal of Asian Ceramic Societies, 2022
Daisuke Koizumi, Kitaru Suzuki, Hirogo Minamisawa, Rie Togawa, Kosuke Yasui, Keishi Iohara, Michiyo Honda, Mamoru Aizawa
Protamine, a cationic protein that is rich in arginine residues, has a molecular weight of approximately 5 kDa and an isoelectric point of 12–13. This protein, which is also known as salmine and clupeine, is bound to DNA in the sperm cells of fish, birds, and mammals. Protamine exhibits a broad spectrum of antibacterial activity against gram-positive and gram-negative bacteria, and has been used as a food preservative [13–16]. Although the antimicrobial mechanisms of protamine vary among species and have not been comprehensively elucidated, two mechanisms have been proposed to date [17]: i) electrostatic interactions between positively charged protamine and negatively charged extracellular epithelium to release K+, ATP, and intracellular enzymes; and ii) targeting of the cell membrane and inhibition of the energy transmission and nutrient uptake functions. In addition, protamine can regulate the transcription of bone sialoprotein, which can form HAp crystals [18]. Moreover, synthetic chemical antibiotics face an alarming issue involving resistant bacteria. However, the issue of resistant bacteria is believed to be less severe for antimicrobial peptides, such as protamine, because of their antimicrobial mechanism involving action on the biological membranes of the pathogens, which are dynamic fluids [19].
Comparison of mechanical cardiopulmonary support strategies during lung transplantation
Published in Expert Review of Medical Devices, 2020
Noah Weingarten, Dean Schraufnagel, Gilman Plitt, Anthony Zaki, Kamal S. Ayyat, Haytham Elgharably
CPB’s disadvantages relate to inflammation and coagulopathy. CPB induces a systemic inflammatory response when blood interacts with the circuit’s nonendothelial surface thereby activating the coagulation cascade. This activation in turn leads to the elaboration of a broad set of inflammatory mediators [27–29]. Leukocyte-depleting filters have been added to CPB circuits to decrease systemic inflammation, but their clinical benefit has not been definitively proven [30]. CPB induces coagulopathy by subjecting blood to non-laminar flow in an oxygenator, causing blood stasis in its venous reservoir, hemodiluting clotting factors via the infusion of priming fluids, and inducing fibrinolysis and platelet consumption [31–34]. To prevent life-threatening clotting, CPB requires high dose heparinization protocols that aim to maintain activated clotting times greater than 400 seconds [35]. Protamine, which is used to reverse heparin, has been linked to a paradoxical anticoagulant effect at excessive doses, as well as anaphylaxis, pulmonary edema, and pulmonary hypertension [34,36]. Following successful reversal of heparin with protamine, patients may be subject to a heparin rebound effect that increases risk of postoperative bleeding [34,36]. Whether prolonged time on CPB exacerbates these risks during LT is unknown, though evidence suggests that prolonged time on CPB is associated with various worse clinical outcomes in patients undergoing other surgeries like coronary artery bypass grafting [37].
A male germ cell assay and supporting somatic cells: its application for the detection of phase specificity of genotoxins in vitro
Published in Journal of Toxicology and Environmental Health, Part B, 2020
Khaled Habas, Martin H. Brinkworth, Diana Anderson
During spermiogenesis, haploid spermatids undertake several changes in the composition and compactness of chromatin (Steger 1999). In the round spermatid, the bond among deoxynucleic acid (DNA)-histone is replaced via transition proteins, while in elongated spermatids, the transition protein is replaced via protamine. Changes from histone to protamine initiate spermatozoa chromatin condensation (Steger et al. 2001). The process begins with an alteration of histone induced via transition protein 1 and 2 and ultimately exchanged via protamine (Ward, Kimura, and Yanagimachi 1999). Changes in transition proteins produced by protamine occur in the stage of elongating spermatid, and in humans, 85% histone is replaced by protamine (Steger 1999). The content of protamine is essential for the final stage in maturation of the sperm nucleus (Loir and Lanneau 1984). Any failure or arrest during these spermatogenic processes is one of the major causes of male factor infertility.