Notre ambition a été de traduire le texte attribué à Galien intitulé Sur la thériaque à Pison où il reprend la recette de la thériaque d’Andromaque. Il a composé ce traité à l’attention de son ami Pison à qui il entreprend d’enseigner les différentes étapes de la composition à la réalisation de cet antidote si réputé dans l’Antiquité. Après un exposé détaillé et très instructif sur les préalables théoriques nécessaires en pharmacologie, Galien dresse la liste des ingrédients qui entrent dans la composition de la thériaque. Il s’attarde notamment sur l’explication des raisons de l’efficacité de la chair de vipère. En effet, la raison essentielle qui explique la capacité de la thériaque à lutter contre les effets nocifs des venins est la sympathie de la chair de vipère avec les venins. Quant à son efficience pour les nombreuses maladies, Galien l’explique par la présence des facultés diverses des simples qui entrent dans la composition du médicament. Après lui avoir donné la liste des ingrédients et mis en garde contre les différentes sources d’altération des médicaments, Galien dresse une longue liste des vertus thérapeutiques et curatives de la thériaque qui, selon lui, justifient largement la grande renommée dont elle jouissait auprès des empereurs romains notamment et plus largement auprès de tous ceux qui connaissaient son action. Nous avons tenté dans notre thèse de rendre ce texte plus accessible à un public pas toujours helléniste. Nous avons essayé dans la mesure du possible de rester fidèles aux idées de Galien dans notre traduction. Dans la dernière partie de cette thèse, nous avons aussi apporté commentaires et éclaircissements aux passages qui méritent selon nous une attention particulière. / Our aim has been to translate the text attributed to Galen: “On theriac to Piso” in which he takes again the recipe of Andromac’s theriac. He has dedicated this treaty to Piso to whom he teaches the different steps, from composition to realization, of this antidote that was very famous during the antiquity. After detailed and very instructive out settings of the necessary theoretical preconditions in pharmacology, Galen draws up the list of the ingredients that compose the theriac. He dwells on explicating the reasons which cause the efficiency of viper’s flesh. In fact, the main reason that explains theriac’s capacity in fighting against bad effects of the venoms is the sympathy between these one and viper’s flesh. As for the antidote’s effectiveness against many illnesses, Galen explains it by the presence of various powers of the simples that are among the ingredients which compose the medicine. After having given him the list of the ingredients and warned him of the different sources that can spoil the medicines, Galen draws on a long list of theriac’s therapeutical and curative properties which justify the fact that it was well known by people who knew its action, in particular by roman emperors. In our thesis, we tried to make this text more accessible for an audience that is not always Hellenist. So, we tried as far as possible to translate faithfully Galen’s speeches. In the thesis’ last part, we have formulated some comments and explanations on passages to which a particular attention must be paid.

<p>Stroke is the leading cause of morbidity and the third leading cause of death in the United States. Over 80% of strokes are ischemic in nature, produced by a thrombus occluding the cerebral circulation. Currently, there is only one pharmacologic treatment FDA approved for ischemic stroke; recombinant tissue-type plasminogen activator (rtPA). Unfortunately, thrombolysis with rtPA is underutilized, as it must be administered within three hours of symptom onset and it is not uncommon for treatment to result in intracranial hemorrhage. For these reasons, safe and effective treatments of stroke are a medical necessity. </p><p>Aptamers are an attractive emerging class of therapeutic agents that offer additional safety because their activity can be reversed with administration of a complimentary oligonucleotide. Accordingly, I hypothesized that aptamers could be used to treat acute ischemic stroke. First, an antithrombotic aptamer previously generated against coagulation factor IXa was used in a murine model of middle cerebral artery occlusion. Upon factor IXa aptamer administration following stroke, neurological function and inflammatory profiles were improved. Moreover, mice previously treated with the aptamer, followed by induction of subarachnoid hemorrhage, had severe mortality levels and hemorrhage grades that were mitigated by administration of the aptamer's matched antidote.</p><p>Second, I generated aptamers against the antifibrinolytic protein plasminogen activator inhibitor-1 (PAI-1), under the hypothesis that aptamer inhibition of PAI-1 would result in a reversible thrombolytic agent. However, after further testing, the aptamers were not found to disrupt the interaction between PAI-1 and its target proteases. Instead, the aptamers were shown to prevent PAI-1 binding to vitronectin, which translated to restoration of breast cancer cell adhesion in an environment of PAI-1 mediated detachment. </p><p>Therefore, aptamer inhibition of factor IXa has demonstrated efficacy in improving outcome following stroke, and should life-threatening hemorrhage arise, an antidote specific to the interventional agent is able to decrease not only hemorrhage grade, but also mortality. This may result in a safer stroke therapy, while a novel aptamer generated against PAI-1 may have application as an antimetastatic agent, which could be used as adjuvant therapy to traditional breast cancer treatment.</p> / Dissertation

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Les héparines regroupant les héparines standards (HNF), les héparines de bas poids moléculaire(HBPM), et le fondaparinux, sont des médicaments anticoagulants. Ils potentialisent l’antithrombine (AT) : un inhibiteur physiologique de la coagulation. Leur utilisation en thérapeutique est associée à un risque hémorragique majeur. Actuellement, le sulfate de protamine est le seul antidote disponible vis-à-vis des HNF. Il est partiellement efficace vis-à-vis des HBPM, et n’a aucun effet contre le fondaparinux, qui n’a pas d’antidote jusqu’à présent. C’est dans ce contexte que nous proposons des AT modifiées inactives, mais capables de se lier aux molécules d’héparines. Ces AT déplaceraient les molécules d’héparines de l’AT plasmatique, et neutraliseraient leur effet anticoagulant. Pour produire de telles AT, nous avons choisi une approche recombinante et une approche chimique. Dans la première approche, nous avons exprimé le variant AT-N135Q-Pro394. Ce variant possède une activité anti-Xa ou anti-IIa inférieure à 0,02% en présence de dérivés hépariniques, et une affinité à l’héparine 3 fois meilleure, comparée à l’AT plasmatique. En revanche, dans l’approche chimique, nous avons modifié l’AT plasmatique par la 2,3-butanedione (AT-BD), un réactif chimique de caractérisation des arginines. Contrairement au variant, cette AT-BD a une perte d’activité anticoagulante modérée, puis une affinité à l’héparine 20 fois meilleure, comparée à l’AT plasmatique. Malgré ces différences de propriétés biochimiques, ces 2 AT modifiées neutralisent d’une façon similaire les héparines in vitro et sur un modèle murin. Par ailleurs, à l’inverse du sulfate de protamine, nos antidotes n’ont pas d’activité anticoagulante propre sur un test de céphaline activée. Ainsi, ce travail de thèse a permis non seulement de proposer les premiers et les seuls antidotes spécifiques au fondaparinux décrits, mais aussi des antidotes alternatifs pour tous les anticoagulants hépariniques. / Unfractionnated heparin (UFH), low molecular weight heparins (LMWH), and fondaparinux are used therapeutically as anticoagulants. They potentiate antithrombin (AT): a physiological inhibitor of coagulation. Their therapeutic use is associated with a major risk of bleeding. Currently, protamine sulfate is the only antidote available for UFH. It is partially effective for LMWH, and has no effect against fondaparinux, which has no antidote. So, we propose modified inactive AT, but able to bind heparin molecules as antidote of these heparins. These molecules would compete with plasmatic AT for binding to heparins, and neutralize their anticoagulant effect. To produce that AT, we realized a genetic approach and a chemical approach. In the first approach, we expressed the variant AT-N135Q-Pro394 that had an anti-Xa or anti-IIa activity below 0.02% in the presence of heparins, and heparin affinity three times higher, compared to the plasmatic AT. In the chemical approach, we modified the plasmatic AT by 2,3-butanedione (AT-BD), a chemical reagent for arginin’s characterization. The AT-BD had a moderate loss of anticoagulant activity, and a heparin affinity 20 times higher, compared to the plasmatic AT. Despite these differences in biochemical properties, these two modified AT neutralize similarly heparins in vitro and in a mouse model. Moreover, unlike protamine sulfate, our antidotes had not an intrinsic anticoagulant effect in activated partial thromboplastin test. Thus, this PhD-work offers the first and the only specific antidote described to fondaparinux, and it can be used too alternatively for all anticoagulant heparins.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

La toxicité des antidépresseurs inhibiteurs de recapture de la sérotonine (IRS) dont le citalopram est le représentant le plus sélectif, est réputée faible. Or les IRS ont été rendus responsables de syndromes sérotoninergiques, de convulsions, d’anomalies électrocardiographiques, voire de troubles respiratoires et de décès. L’implication de cette classe pharmacologique au cours des intoxications médicamenteuses volontaires (IMV) apparait peu documentée par des données récentes en France. Ainsi, la morbidité des IMV impliquant un IRS aux urgences (SAU) et les symptômes les plus fréquemment observés à la suite d’une exposition toxique aux IRS sont peu décrits. De même, les mécanismes toxiques impliqués dans les décès ne sont clairs. Objectifs : Nous avons mené ces travaux dans le but de : 1- mieux connaitre l’épidémiologie des IMV dans un SAU et y préciser l’implication des IRS ; 2- explorer une éventuelle sur-morbidité liée aux IRS dans les IMV polymédicamenteuses ; 3-comprendre les mécanismes de décès induits par de fortes doses de citalopram et les moyens de les prévenir. Méthodes: Nous avons conduit une étude observationnelle des IMV admises au SAU durant 4 ans, avec appariement des patients ayant ingéré un IRS versus des patients intoxiqués non exposés à un IRS. Nous avons également mené une étude expérimentale chez le rat Sprague-Dawley pour connaitre la dose létale médiane (MLD) du citalopram et explorer la toxicité neurologique, respiratoire et systémique impliquée dans le décès consécutif à l’administration de citalopram. Des dosages de sérotonine plasmatiques et plaquettaires ont été effectués afin de caractériser le rôle de la toxicité sérotoninergique. Résultats : Les IRS étaient impliqués dans 16% des IMV au SAU, soit en 2e position après les benzodiazépines. L’attribution des symptômes observés aux effets sérotoninergiques était rarement faite (dans environ un cas sur cinq) par les médecins urgentistes en charge des patients. La survenue d’un syndrome sérotoninergique et de convulsions était plus fréquente dans le groupe de patients intoxiqués par IRS que chez les témoins appariés. Un allongement du QT a été noté chez un patient et aucune toxicité respiratoire n’a été décelée. Le recours à la ventilation mécanique était plus important du fait de troubles de la conscience, sans augmentation pour autant du nombre d’admission en réanimation en comparaison aux témoins. L’étude expérimentale nous a permis de montrer que les décès induits par le citalopram étaient toujours précédés de convulsions, et que la prévalence des convulsions étaient dose-dépendante, significativement plus fréquente pour les fortes doses de citalopram (80 et 120% de la MLD) comparativement aux autres groupes (60% de la MLD et témoins). De même, le citalopram induisait une baisse dose-dépendante de la sérotonine plaquettaire et une élévation dose-dépendante de la sérotonine plasmatique. L’incidence du syndrome sérotoninergique était, par contre, comparable. Le citalopram n’induisait ni hypoxémie, ni hypercapnie, ni hyperlactatémie ; mais il était responsable d’un allongement du temps inspiratoire et d’un « braking expiratoire » mimant un phénomène adaptatif à l’hypoxémie. Par ailleurs, le prétraitement par diazépam ou cyproheptadine des rats intoxiqués avec une dose létale de citalopram prévenait les convulsions et le décès. Conclusions : La toxicité des IRS et du citalopram en particulier, semble essentiellement neurologique, tant chez l’homme que chez l’animal. Le syndrome sérotoninergique et les convulsions devraient être rassemblés en marqueurs de la toxicité sérotoninergique. Il est nécessaire de sensibiliser les médecins urgentistes à cette toxicité, en utilisant les critères de Hunter, plus simples et probablement plus spécifique. La place des antidotes restent à définir, mais, selon notre modèle expérimental, ils pourraient être efficaces pour réduire cette toxicité spécifique. / Toxicity of the serotonin-reuptake inhibitors (SRI) including citalopram, the most selective one, is considered as relatively low. However SRI may be responsible for serotonin syndrome, seizures, electrocardiographic abnormalities, respiratory failure, and even death. Implication of SRI in deliberate drug poisonings has not been assessed by recent data in France. Morbidity of SRI-related poisonings as well as the most common resulting presentations in the emergency department (ED) remains poorly described. Moreover, mechanisms of SRI-attributed death remain unclear. Objectives: We conducted these clinical and experimental studies: 1-to better understand the epidemiology of drug poisonings in one ED in Paris area and analyze SRI involvement; 2- to investigate a possible over-morbidity related to SRI in multidrug poisonings and describe the most common SRI-related complications; 3- to understand mechanisms of death induced by elevated doses of citalopram and its possible prevention. Methods: We conducted an observational study during 4 years in an ED matching patients who ingested at least one IRS with patients who did not. We also conducted an experimental study in the Sprague-Dawley rat to determine the median lethal dose (MLD) of citalopram and investigate citalopram-related neurological, respiratory, and systemic toxicity as well as mechanisms of citalopram-induced death. Platelet and plasma serotonin were measured to ensure the serotoninergic mechanism. Results: SRI were involved in 16% of the drug poisonings admitted to the ED, ranking at the second place after the benzodiazepines. Attribution of the observed signs and symptoms to the serotonin toxicity was rarely performed by the emergency physicians in charge, in only one out of five cases. Onset of serotonin syndrome and seizures were more frequent in SRI-exposed patients than in their matched controls. QT prolongation was observed in one patient while no direct respiratory toxicity was reported. Mechanical ventilation was more frequently used in SRI-exposed patients due to impaired consciousness, despite no resulting increased admission rate to the intensive care unit in comparison to the controls. Based on our rat study, citalopram-induced death always occurred after seizures which were dose-dependent, with a greater prevalence at the two highest doses of citalopram (80 and 120% of the MLD) than in the other groups (60% of control and the MLD). Citalopram-induced decrease in platelet serotonin and increase in plasma serotonin were dose-dependent. However, incidence of serotonin syndrome appears similar in all the groups. Citalopram did not induce hypoxemia, hypercapnia or hyperlactacidemia, but resulted in a slight prolongation in the inspiratory time and an "expiratory braking" that could be attributed to an adaptive phenomenon to hypoxemia. Pretreatment with diazepam and cyproheptadine prevented rats treated with lethal-doses of citalopram from seizures and death. Conclusions: SRI and citalopram in particular are mainly responsible for neurological toxicity, both in humans and rats. Serotonin syndrome and seizures should be grouped as markers of serotonin toxicity. Emergency physicians should become more aware of this specific toxicity. Using the simpler and probably more specific Hunter criteria may be useful in the ED. The exact indications of antidotes remain to be defined, but our experimental model seems to support their effectiveness to prevent IRS-related specific serotonin toxicity.

<p>Thrombosis, or pathological blood clot formation, is intimately associated with cardiovascular disease and is the leading cause of morbidity and mortality in the western world. Antithrombotics are commonly prescribed as prophylactic medications or as rapid onset anticoagulants in acute care clinical settings. Although a number of antithrombotics are clinically available, their use is limited by immunogenicity, toxicity, and inability to be controlled with an antidote in the event of hemorrhage. Therefore, new antithrombotics that are effective, yet can be rapidly controlled are urgently needed. </p><p>Aptamers are oligonucleotides that form complex secondary and tertiary structures based on intramolecular base pairing and nucleic acid folding that allows them to bind to molecular targets with high affinity and specificity. Aptamers can be isolated that bind to proteins, such as clotting proteins, and modulate protein function. However, unlike most currently used antithrombotics, aptamers can be directly controlled with an antidote and therefore represent a safer class of therapeutic agents. </p><p>To generate a novel anticoagulant, we developed an aptamer-antidote pair against prothrombin. Prothrombin is a blood protein that plays an essential role in clot formation. I truncated, optimized, and studied the mechanism of an aptamer that can bind to prothrombin and inhibit prothrombin function, thereby severely impeding clot formation. Moreover, to increase the safety profile of this anticoagulant aptamer, I developed an antidote that can quickly reverse aptamer function and restore normal clotting. This aptamer and antidote pair is the first antidote reversible anticoagulant that targets prothrombin and may prove to be a valuable clinical anticoagulant.</p><p>A number of anticoagulants are in development, and a wide debate regarding the optimal protein target for anticoagulation is underway. We have previously generated anticoagulant aptamers to human coagulation factor VII, factor IX, factor X, and prothrombin. I compared the effects of these four anticoagulant aptamers to determine their impact on thrombin generation and clot formation. Each aptamer exerts its own unique effect on thrombin generation/clot formation, depending on the role that its protein target plays in coagulation. These studies provide valuable data regarding target validation and the anticoagulant effects of different therapeutic aptamers.</p><p>Robust anticoagulation is required during acute clinical surgical procedures to treat thrombosis. Currently used anticoagulants have several untoward side effects and most are not antidote controllable. I tested the effects of combining two anticoagulant aptamers to assess potential drug synergy. Several combinations of two anticoagulant aptamers were synergistic and severely impaired blood clot formation. One specific pair of aptamers that targeted factor X (FX) and prothrombin in combination was extremely potent and could keep blood fluid in an ex vivo model of extracorporeal circulation. Additionally, this pair of aptamers could be functionally modulated with two different types of antidotes. In conjunction with antidote reversal, this strategy of combining aptamer anticoagulants may prove useful in a variety of highly prothrombotic acute clinical settings. </p><p>Finally, to explore the potential of aptamers to regulate platelet function, I isolated and characterized an aptamer toward platelet glycoprotein VI. Glycoprotein VI is a platelet surface receptor that plays a key role in platelet activation and platelet plug formation. I isolated several aptamers that bind to glycoprotein VI, and show that the lead aptamer binds to platelets with high affinity and causes platelet activation and aggregation. This aptamer could potentially be further developed for topical administration to manage bleeding, or for biomarker detection of soluble glycoprotein VI in patient plasma.</p> / Dissertation

Les neurotoxiques organophosphorés (NOPs) sont des inhibiteurs irréversibles de l’acétylcholinestérase, une enzyme jouant un rôle clé dans la transmission de l’influx nerveux. Une intoxication par ces substances provoque de graves symptômes pouvant aboutir au décès des sujets empoisonnés. Bien qu’interdits par une convention internationale ratifiée par 190 pays, le contexte géopolitique actuel ravive la hantise d’une menace chimique contre des populations civiles, renouvelant l’intérêt de développer de nouveaux remèdes contre une intoxication aux NOP. A l’heure actuelle, les antidotes utilisés contre ces intoxications sont les mono- et bis- pyridinium aldoximes portant une ou deux charge(s) positive(s) permanente(s), qui présentent de nombreuses limitations, dont leur très faible capacité à traverser la barrière hémato-encéphalique et à réactiver efficacement les AChEs inhibées par les NOP dans le système nerveux central (SNC). Par ailleurs, leur efficacité est très dépendante de la nature du NOP utilisé, et il n’existe pas, aujourd’hui, de réactivateur universel. Dans ce contexte, le développement de nouveaux réactivateurs efficaces est un réel défi. Au cours de cette thèse, l’optimisation de la synthèse de cinq réactivateurs non chargés incorporant une amine cyclique en tant que ligand du site périphérique et la 3-hydroxypyridine aldoxime en tant que fonction réactivatrice a été développée pour évaluation in vivo. Dans cette continuité, vingt-et-un réactivateurs non chargés inédits comportant un ligand aminé du site périphérique de l’enzyme associée à la même fonction réactivatrice 3-hydroxypyridine aldoxime ont été conçus, synthétisés et testés sur l’AChE humaine inhibée par différents NOPs mais aussi sur les récepteurs nicotiniques. Certains d’entre eux ont été testés in vivo sur la souris. Parmi les réactivateurs synthétisés, certains possèdent des efficacités de réactivation identiques, voire meilleures que les oximes de référence utilisées de nos jours tout en ayant un effet antagoniste des récepteurs nicotiniques ouvrant ainsi la voie aux réactivateurs dits « Multi-cibles ». Avec comme objectif de traverser la barrière hémato-encéphalique en utilisant les transporteurs GLUTs présents sur les cellules endothéliales constituant cette barrière, quatre réactivateurs incorporant un motif carbohydrate ont été resynthétisés et évalués in vivo et in vitro. Enfin, de nouvelles fonctions réactivatrices constituées d’un motif thiadiazole-aldoxime et naphtaldoxime ont été étudiées ouvrant la voie à de nouvelles familles de réactivateurs et, pour la dernière fonction, remettant en cause le cahier des charges utilisé jusqu’alors pour la conception de nouveaux réactivateurs. / Organophosphorus nerve agents (OPNA) are irreversibly acetylcholinesterase (AChE) inhibitors, a key enzyme in the central nervos system playing a pivotal role in neurotransmission. OPNA poisoning induces to serious symptoms that can lead to death by respiratory failure. Despite an international convention prohibiting the use of chemical weapons, the current geopolitical context is reviving the fear of a chemical threat against civilian populations, and has renewed the interest of developing new remedies for OPNA poisoning. Nowadays, medical countermeasure used against OPNA intoxications are based on mono- and bis-pyridinium aldoximes carrying one or two permanent positive charge(s), which present many limitations, including their very low capacity to cross the blood-brain barrier and to reactivate effectively ChEs nhibited by NOPs in the central nervous system (CNS). Moreover, their effectiveness is highly dependent on the nature of the NOP used, therefore, there is no universal reactivator. In this context, the development of new effective reactivators is a real challenge. In this PhD, an optimized synthetic access to five uncharged reactivators incorporating a cyclic amine as peripheral site ligand and 3-hydroxypyridine aldoxime as reactivating function was developed for in vivo evaluation. Following up on this, twenty-one new uncharged reactivators bearing unprecedented cyclic amines as peripheral site ligand associated with our reactivating function were designed, synthetized and evaluated for reactivation on human AChE inhibited by several NOPs but also in vivo on mice and as antagonists on nicotinic receptors in vitro. Among these reactivators, some have identical or better reactivation efficiencies than the reference oximes used today while having a nicotinic receptor antagonist effect ; thus, paving the way for « Multi-target » reactivators. Aiming at an active BBB crossing using the GLUTs receptors, four reactivators including a carbohydrate moiety have been resynthetized and biologically evaluated. Last but not least, new reactivator functions consisting of a thiadazole-aldoxime and naphtaldoxime moieties have been studied, paving the way to new families of uncharged reactivators and, especially for the last function, calling into question design specifications of new reactivators.

Based upon experimental evidence from the 1970’s we proposed that a reduced form of hydroxocobalamin should be capable of producing carbon dioxide (CO2) from carbon monoxide (CO) in blood, and that this conversion should be detectable. Using resonance raman spectroscopy we demonstrated that a mixture of hydroxocobalamin and ascorbic acid could create the reduced form of hydroxocobalamin. We used a closed-loop circulation system with a hollow-fiber membrane oxygenator to produce carboxyhemoglobin. Using sensitive gas monitoring equipment to the gas-out port of the oxygenator we analyzed the CO and CO2 concentrations coming from the oxygenator. The mixture of hydroxocobalamin and ascorbic acid caused a 5-fold increase in the CO2 concentration of the gas-out flow, in comparison to baseline and negative controls. These findings offer initial support for the potential use of a mixture of hydroxocobalamin and ascorbic acid as an injectable antidote for carbon monoxide poisoning.

Thrombosis is initiated by platelets and leads to cardio-, cerebro-, and peripheral vascular disease, the leading causes of morbidity and mortality in the western world. Antiplatelet drugs have improved clinical outcomes for thrombosis patients. However, their expanded use is limited by hemorrhage at high concentrations and sub-therapeutic activity at lower doses. Thus, development of new antiplatelet agents with improved safety and efficacy is a medical priority. VWF is a multimeric plasma glycoprotein that plays a critical role in platelet-mediated thrombus formation and presents an attractive target for antiplatelet therapy. To this end, I have isolated and characterized aptamer molecules that bind to VWF with high affinity and have shown that some of these aptamer molecules could inhibit platelet activation/aggregation in vitro and in vivo. Furthermore, I designed antidote molecules that can reverse the effects of the aptamer molecules, restoring platelet function quickly and effectively. This project has yielded the first antidote controlled antiplatelet agent and may lead to significant improvements in thrombosis therapy. Thrombin is a plasma protein that plays a critical role in thrombosis. Currently, available antithrombin agents are efficacious in preventing coagulation but do not significantly affect platelet activation and aggregation, both essential components of thrombus formation. Therefore, I tested two aptamer molecules that bind to mutually exclusive exosites on thrombin and, when used together, synergistically inhibit both coagulation and platelet activation. I demonstrated that this method could potentially lead to the development of effective antithrombotic therapies. With an ever-increasing number of people taking multiple medications, the need to safely administer drugs and limit unintended side effects has never been greater. Antidote control remains the most direct means to counteract acute side effects of drugs but unfortunately it has been challenging and cost prohibitive to generate antidotes for most therapeutic agents. Therefore, I described the development of a set of antidote molecules that are capable of counteracting the effects of an entire class of therapeutic agents, i.e. aptamers, including those that I generated against VWF. I demonstrated that protein and polymer-based molecules that capture oligonucleotides can reverse the activity of aptamers in vitro and in vivo. / Dissertation