Anti-coagulation in acute coronary syndrome
K Sarat Chandra, AJ Swamy in Acute Coronary Syndromes, 2020
UFH is the most affordable, oldest and remains the most frequently used anti-coagulant in ACS. It binds with anti-thrombin III and inhibits factors IIa (thrombin) and Xa indirectly by activation of antithrombin. Heparin requires parenteral administration and is usually given via a continuous intravenous route. Clearance of heparin is extra-renal; hence, it is safe in renal dysfunction. Levels of heparin-binding proteins vary from person to person inside the blood circulation, which results in unpredictable and variable anti-coagulant responses of heparin. Because of intra- and inter-individual variability, monitoring of the anti-coagulation effect either by aPTT, activated clotting time (ACT) or anti-factor Xa level is essential to ensure a therapeutic response [2,3]. Activity of heparin may be reduced in the vicinity of platelet-rich thrombus by neutralisation of heparin by high concentration of PF4 released from activated platelets. Another important limitation is risk of heparin-induced thrombocytopenia (HIT), which can paradoxically increase thromboembolic risk (arterial or venous thrombosis) in the patient. It is a serious and potentially life-threatening complication in the setting of ACS. It has also been postulated that heparin discontinuation causes biological rebound generation of thrombin and increases prothrombotic state [4]. The most common side effect is bleeding, and the antidote protamine can be used in patients with serious bleeding. Typically, 1 mg of intravenous protamine can neutralise 100 units of heparin.
Role of Sperm DNA Damage in Male Infertility Assessment
Botros Rizk, Ashok Agarwal, Edmund S. Sabanegh in Male Infertility in Reproductive Medicine, 2019
Infertility has evolved as a global health problem affecting 15% of couples worldwide, with male factor contributing to 50% of all infertility cases [1]. Though conventional semen analysis (SA) is the fundamental practice for assessing male fertility status, it is a poor predictor of reproductive outcome [2]. With expanding knowledge on sperm cell biology and extensive research on sperm-testing techniques, sperm DNA damage has been recognized to play an imperative role in pathophysiology of male infertility [3]. Protamine bound to the sperm DNA enforces a compact state and ensures protection from damage during its transit through the female reproductive tract. The successful fertilization, healthy embryo development, implantation, and pregnancy are highly dependent on the integrity of sperm DNA [4]. Evaluation of sperm genome integrity has important clinical implications because spermatozoa with damaged DNA may have adverse consequences on the progeny due to the paternal transmission of defective genome [5].
Andrological causes of recurrent implantation failure
Efstratios M. Kolibianakis, Christos A. Venetis in Recurrent Implantation Failure, 2019
Thus far, only histones and protamines have been validated to be a part of nongenomic paternal contribution to the embryo. The replacement of most histones by protamines 1 and 2 during spermiogenesis facilitates a high order of chromatin packaging necessary for normal sperm function.32 A significant negative correlation between sperm motility and protamine-2 mRNA levels has been demonstrated.33 It has also been suggested that protamines are not only important for fertilization but may additionally have an impact on the correct initiation of gene expression in the early embryo.34 Moreover, incorrect histone to protamine exchange results in a prolonged presence of histones, which are known to exhibit a variety of epigenetic modifications that are transmitted through fertilization.35
An overview of rational design of mRNA-based therapeutics and vaccines
Published in Expert Opinion on Drug Discovery, 2021
Kenneth K.W. To, William C.S. Cho
The high molecular weight and negative charge of mRNA species prevent their penetration of cell membrane through diffusion and also results in electrostatic repulsion from the anionic cell membrane. While the physical methods (e.g. electroporation) are widely used for delivering DNA-based drugs into the cells, the use of physical methods for intracellular mRNA drug delivery is less reported [107]. Cell penetrating peptides, which are cationic in nature, have been used to facilitate mRNA delivery to intracellular target sites. Protamine is an ariginine-rich cationic peptide that can bind to mRNA and transport it to the cytoplasm [108]. Recently, an innovative mRNA delivery platform has been reported, which consists of poly(lactic acid) and cationic cell penetrating peptides as mRNA condensing agent [109]. This novel mRNA-delivering nano-complexes were taken up efficiently by dendritic cells and they induced strong protein expression and innate immune response [109].
Protamine stimulates platelet aggregation in vitro with activation of the fibrinogen receptor and alpha-granule release, but impairs secondary activation via ADP and thrombin receptors
Published in Platelets, 2021
Mattias Törnudd, Sofia Ramström, John-Peder Escobar Kvitting, Joakim Alfredsson, Richard Pihl, Sören Berg
Clinical use of protamine is associated with serious side effects [8]. Apart from allergic and anaphylactoid reactions, protamine can also severely increase pulmonary vasoconstriction with secondary right-sided acute heart failure and circulatory collapse [26,27]. The exact mechanism responsible for this reaction is not known but activation of platelets has been proposed, and a reduction in circulating platelets after protamine administration after CPB is seen [25,26]. Our data showing platelet activation by protamine could be compatible with this hypothesis. Although the concentrations of protamine used in this study are considerably higher than would be expected after total equilibration and binding to circulating heparin at the end of CPB, it is possible to speculate that platelets could be exposed to high concentrations of unbound free protamine during rapid or repeated injections of protamine which could correspond to the empirical knowledge that protamines negative impact on hemodynamics can be avoided by a slow injection.
Influence of protamine shell on nanoemulsions as a carrier for cyclosporine-A skin delivery
Published in Pharmaceutical Development and Technology, 2019
M. Javiera Alvarez-Figueroa, José María Abarca-Riquelme, José Vicente González-Aramundiz
Different materials have been used for the development of new nanosystems for drug and antigen delivery, among them, polyaminoacids and polypeptides are gaining much attention for their safe and biocompatible properties (González-Aramundiz et al. 2012). Protamine is one of these; it is a drug approved by the FDA for reverting the anticoagulant effect of heparin and as an excipient, it is used in the formulation of neutral protamine Hagedorn insulin (NPH) (Scheicher et al. 2015). This biomaterial comes from a family of arginine-rich polypeptides with a molecular weight of ∼4KDa and represents one of the three major groups of basic nuclear sperm proteins (Kasinsky et al. 2011). Recently, this excipient has been studied for the development of novel systems of nanometric size for delivery of genetic material and antigens (Dileep et al. 2005; González-Aramundiz et al. 2015). Therefore, studying the effect of a polymer coating of protamine on nanometric systems is a valid strategy to increase the penetration of active molecules through the skin.