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1.
Annu Rev Med ; 75: 337-351, 2024 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-37582490

RESUMEN

Carbon monoxide (CO) poisoning leads to 50,000-100,000 emergency room visits and 1,500-2,000 deaths each year in the United States alone. Even with treatment, survivors often suffer from long-term cardiac and neurocognitive deficits, highlighting a clear unmet medical need for novel therapeutic strategies that reduce morbidity and mortality associated with CO poisoning. This review examines the prevalence and impact of CO poisoning and pathophysiology in humans and highlights recent advances in therapeutic strategies that accelerate CO clearance and mitigate toxicity. We focus on recent developments of high-affinity molecules that take advantage of the uniquely strong interaction between CO and heme to selectively bind and sequester CO in preclinical models. These scavengers, which employ heme-binding scaffolds ranging from organic small molecules to hemoproteins derived from humans and potentially even microorganisms, show promise as field-deployable antidotes that may rapidly accelerate CO clearance and improve outcomes for survivors of acute CO poisoning.


Asunto(s)
Intoxicación por Monóxido de Carbono , Humanos , Estados Unidos , Intoxicación por Monóxido de Carbono/terapia , Intoxicación por Monóxido de Carbono/epidemiología , Hemo
2.
Circulation ; 148(16): e149-e184, 2023 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-37721023

RESUMEN

In this focused update, the American Heart Association provides updated guidance for resuscitation of patients with cardiac arrest, respiratory arrest, and refractory shock due to poisoning. Based on structured evidence reviews, guidelines are provided for the treatment of critical poisoning from benzodiazepines, ß-adrenergic receptor antagonists (also known as ß-blockers), L-type calcium channel antagonists (commonly called calcium channel blockers), cocaine, cyanide, digoxin and related cardiac glycosides, local anesthetics, methemoglobinemia, opioids, organophosphates and carbamates, sodium channel antagonists (also called sodium channel blockers), and sympathomimetics. Recommendations are also provided for the use of venoarterial extracorporeal membrane oxygenation. These guidelines discuss the role of atropine, benzodiazepines, calcium, digoxin-specific immune antibody fragments, electrical pacing, flumazenil, glucagon, hemodialysis, hydroxocobalamin, hyperbaric oxygen, insulin, intravenous lipid emulsion, lidocaine, methylene blue, naloxone, pralidoxime, sodium bicarbonate, sodium nitrite, sodium thiosulfate, vasodilators, and vasopressors for the management of specific critical poisonings.


Asunto(s)
Reanimación Cardiopulmonar , Paro Cardíaco , Humanos , Antagonistas Adrenérgicos beta , American Heart Association , Benzodiazepinas , Digoxina , Paro Cardíaco/inducido químicamente , Paro Cardíaco/terapia , Estados Unidos
3.
Appl Environ Microbiol ; : e0012124, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38980046

RESUMEN

Naja atra, the Chinese cobra, is a major cause of snake envenomation in Asia, causing hundreds of thousands of clinical incidents annually. The current treatment, horse serum-derived antivenom, has unpredictable side effects and presents manufacturing challenges. This study focused on developing new-generation snake venom antidotes by using microbial phage display technology to derive nanobodies from an alpaca immunized with attenuated N. atra venom. Following confirmation of the immune response in the alpaca, we amplified VHH genes from isolated peripheral blood mononuclear cells and constructed a phage display VHH library of 1.0 × 107 transformants. After four rounds of biopanning, the enriched phages exhibited increased binding activity to N. atra venom. Four nanobody clones with high binding affinities were selected: aNAH1, aNAH6, aNAH7, and aNAH9. Specificity testing against venom from various snake species, including two Southeast Asian cobra species, revealed nanobodies specific to the genus Naja. An in vivo mouse venom neutralization assay demonstrated that all nanobodies prolonged mouse survival and aNAH6 protected 66.6% of the mice from the lethal dosage. These findings highlight the potential of phage display-derived nanobodies as valuable antidotes for N. atra venom, laying the groundwork for future applications in snakebite treatment.IMPORTANCEChinese cobra venom bites present a formidable medical challenge, and current serum treatments face unresolved issues. Our research applied microbial phage display technology to obtain a new, effective, and cost-efficient treatment approach. Despite interest among scientists in utilizing this technology to screen alpaca antibodies against toxins, the available literature is limited. This study makes a significant contribution by introducing neutralizing antibodies that are specifically tailored to Chinese cobra venom. We provide a comprehensive and unbiased account of the antibody construction process, accompanied by thorough testing of various nanobodies and an assessment of cross-reactivity with diverse snake venoms. These nanobodies represent a promising avenue for targeted antivenom development that bridges microbiology and biotechnology to address critical health needs.

4.
Br J Clin Pharmacol ; 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38926082

RESUMEN

Bleeding events are common in patients prescribed anticoagulants and can have devastating consequences. Several specific and nonspecific agents have been developed to reverse the effects of anticoagulant drugs or toxins. Vitamin K, as the oldest of these antidotes, specifically counteracts the effects of pharmaceuticals and rodenticides designed to deplete stores of vitamin K-dependent factors. In cases of life-threatening bleeding, the addition of prothrombin complex concentrates (PCCs) allows for the immediate replacement of coagulation factors. While the use of PCCs has been extended to the non-specific reversal of the effects of newer direct oral anticoagulants, the specific agents idarucizumab, targeting dabigatran and andexanet-α, binding factor Xa inhibitors, have recently been developed and are being preferentially recommended by most guidelines. However, despite having rapid effects on correcting coagulopathy, there is to date a lack of robust evidence establishing the clear superiority of direct oral anticoagulant-specific reversal agents over PCCs in terms of haemostatic efficacy, safety or mortality. For andexanet-α, a potential signal of increased thromboembolic risks, comparatively high costs and low availability might also limit its use, even though emerging evidence appears to bolster its role in intracranial haemorrhage. Protamine is the specific agent for the reversal of unfractionated heparin anticoagulation used mainly in cardiovascular surgery. It is much less effective for low molecular weight heparin fragments and is usually reserved for cases with life-threatening bleeding.

5.
Ann Pharmacother ; : 10600280241232660, 2024 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-38389166

RESUMEN

BACKGROUND: Sugammadex rapidly reverses the nondepolarizing neuromuscular blocking agents (NMBAs) rocuronium and vecuronium. The role of sugammadex is not well-defined outside of the postoperative setting. OBJECTIVE: This study aims to describe sugammadex use outside the postoperative setting for the reversal of nondepolarizing NMBAs. METHODS: This was a single-center, retrospective cohort study conducted in patients who received sugammadex outside of the postoperative setting at an academic medical center between June 2016 and November 2022. The primary outcome was the effect of sugammadex use for rocuronium reversal, defined as any increase in train-of-four (TOF) after sugammadex administration and/or progress note documentation if TOF was unavailable. Secondary outcomes included adverse events and documentation of contraceptive counseling in patients taking hormonal contraceptives with child-bearing ability. RESULTS: A total of 14 383 patients received sugammadex during the study period. Of those patients, 39 (0.3%) were outside of the postoperative setting for the reversal of rocuronium and included in the study. Twenty-nine (74%) patients had an increase in TOF after sugammadex administration and/or progress note documentation if TOF was unavailable. Ten (26%) patients lacked documentation regarding the effect of sugammadex. No adverse reactions were reported. Three (8%) patients included in the study were of child-bearing ability, and 1 of the 3 patients was counseled on using an alternative method of contraception following sugammadex administration. CONCLUSION AND RELEVANCE: There is a paucity of literature for the use of sugammadex outside of the postoperative setting. This study found that while the use of sugammadex was rare, overall, it was safe and well-tolerated.

6.
Arch Toxicol ; 2024 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-39004640

RESUMEN

The risk of the use of toxic chemicals for unlawful acts has been a matter of concern for different governments and multilateral agencies. The Organisation for the Prohibition of Chemical Weapons (OPCW), which oversees the implementation of the Chemical Weapons Convention (CWC), considering recent events employing chemical warfare agents as means of assassination, has recently included in the CWC "Annex on Chemicals" some organophosphorus compounds that are regarded as acting in a similar fashion to the classical G- and V-series of nerve agents, inhibiting the pivotal enzyme acetylcholinesterase. Therefore, knowledge of the activity of the pyridinium oximes, the sole class of clinically available acetylcholinesterase reactivators to date, is plainly justified. In this paper, continuing our research efforts in medicinal chemistry on this class of toxic chemicals, we synthesized an A-230 nerve agent surrogate and applied a modified Ellman's assay to evaluate its ability to inhibit our enzymatic model, acetylcholinesterase from Electrophorus eel, and if the clinically available antidotes are able to rescue the enzyme activity for the purpose of relating the findings to the previously disclosed in silico data for the authentic nerve agent and other studies with similar A-series surrogates. Our experimental data indicates that pralidoxime is the most efficient compound for reactivating acetylcholinesterase inhibited by A-230 surrogate, which is the opposite of the in silico data previously disclosed.

7.
Am J Emerg Med ; 80: 226.e1-226.e3, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38702220

RESUMEN

A 53-year-old male patient presented to a regional hospital Emergency Department approximately 2 h post an intentional ingestion of Coopers Instant Wetting Powder Sheep Dip (66% arsenic trioxide, 23% sulphur and 0.42% rotenone), mixed in 600 mL water, as a suicide attempt. On arrival to the Emergency Department, the patient had nausea, vomiting and diarrhoea. Seven hours post ingestion, hypotension developed (BP 90/60 mmHg) and intravenous fluids were commenced. He later developed QTc prolongation. He was treated with 2,3-Dimercapto-1-propanesulfonic acid (DMPS) and N-acetylcysteine and improved without development of neurology. Further investigation of NAC efficacy in humans in the setting of acute arsenic poisoning is required and the optimal duration of treatment and dosing needs to be established. This case highlights an uncommon poisoning which presented to the Emergency Department, the acute symptoms of arsenic toxicity and considerations for management.


Asunto(s)
Acetilcisteína , Intoxicación por Arsénico , Arsenicales , Intento de Suicidio , Masculino , Humanos , Persona de Mediana Edad , Acetilcisteína/uso terapéutico , Trióxido de Arsénico/envenenamiento , Óxidos/envenenamiento , Antídotos/uso terapéutico , Unitiol/uso terapéutico
8.
J Oncol Pharm Pract ; 30(1): 67-77, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37032471

RESUMEN

INTRODUCTION: Extravasation is a potentially severe complication of intravenous administration of antineoplastic drugs. The limited data makes it difficult to develop an optimal management scheme. The objective of this study is to describe the clinical practice in the extravasation management of antineoplastic agents in Spanish centers. METHODS: An online survey was distributed to oncology pharmacists using the email distribution list of the Spanish Society of Hospital Pharmacists. Respondents were surveyed on the standard operational protocol (SOP) of extravasation, tissue damage risk classification, and specific measures of extravasation management. RESULTS: A total of 68 surveys were completed. A specific extravasation SOP was available in 82.4% centers. The pharmacist participates in the authorship (100%) and actively collaborates in extravasation management (76.5%). A tissue damage risk classification based on the three categories was mostly adopted (48.2%) and 73.2% applied specific criteria based on concentration and/or extravasated volume. Extravasation management was mainly performed with the application of physical measures and/or antidotes (91.2%). High variability in the choices of pharmacological and/or physical measures recommended is outstanding. CONCLUSION: The results of this study highlight the involvement of Spanish pharmacists in extravasation management, the application of physical measures and/or pharmacological measures as the method of choice in extravasation management, as well as the existing discrepancies in tissue damage risk classification and management recommendations.


Asunto(s)
Antídotos , Antineoplásicos , Extravasación de Materiales Terapéuticos y Diagnósticos , Humanos , Antídotos/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Infusiones Intravenosas
9.
Br J Clin Pharmacol ; 89(1): 34-38, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-34957591

RESUMEN

Paracetamol poisoning continues to be a worldwide problem and, despite the availability of an effective antidote, acetylcysteine (NAC), the optimal way to use this antidote, particularly following very large doses of paracetamol, has not been established. Recent case series have shown an increased toxicity from high doses of paracetamol, even in those receiving prompt NAC therapy, particularly in patients above the 300 mg/L nomogram treatment line. Clinical trial evidence supporting shorter NAC dosing now allows the possibility for intensifying treatment without the risk of very high rates of ADRs. New biomarkers also show the possibility of early identification of patients at risk of liver injury who might also benefit from increased intensity treatment. This article discusses these data and proposes a logical therapy for increasing NAC dosing which now requires clinical trial testing.


Asunto(s)
Analgésicos no Narcóticos , Enfermedad Hepática Inducida por Sustancias y Drogas , Sobredosis de Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Acetilcisteína/uso terapéutico , Acetaminofén , Antídotos/uso terapéutico , Sobredosis de Droga/tratamiento farmacológico
10.
Biometals ; 36(5): 1125-1140, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37222858

RESUMEN

The similarities between thallium and potassium have suggested the use of calcium polystyrene sulfonate (CPS), an oral ion exchange resin, as a potential agent against thallium intoxication. Therefore, the study was an attempt to evaluate the efficacy of CPS and Prussian blue when given alone or in combination against thallium toxicity. The effect on binding capacity was investigated in terms of contact time, amount of CPS, influence of pH, simulated physiological solutions and interference of potassium ions. Also, rats were given single dose of thallium chloride (20 mg kg-1) and the treatment with PB and CPS was given for 28 days as CPS 30 g kg-1, orally, twice a day, PB 3 g kg-1, orally, twice a day and their combination. The effect of antidotal treatment was evaluated by calculating the thallium levels in various organs, blood, urine and feces. The results of the in vitro study indicated exceedingly quick binding in the combination of CPS and PB as compared to PB alone. Also, it was found that the binding capacity at pH 2.0 was considerably increased for PB with CPS (184.656 mg g-1) as compared to PB (37.771 mg g-1). Furthermore, statistically significant results were obtained in the in vivo study as after 7th day, thallium levels in blood of rats treated with combination were reduced by 64% as compared to control group and 52% as compared to alone PB treated group. Also, Tl retention in liver, kidney, stomach, colon and small intestine of combination treated rats was significantly reduced to 46%, 28%, 41%, 32% and 33% respectively, as compared to alone PB treated group. These findings demonstrate this as a good antidotal option against thallium intoxication.


Asunto(s)
Antídotos , Talio , Ratas , Animales , Talio/metabolismo , Antídotos/farmacología , Antídotos/uso terapéutico , Ferrocianuros/farmacología , Ferrocianuros/uso terapéutico
11.
J Thromb Thrombolysis ; 56(2): 315-322, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37289371

RESUMEN

Given the paucity of comparative efficacy data and the difference in cost between andexanet-alfa and prothrombin complex concentrates (PCC), debates continue regarding optimal cost-effective therapy for patients who present with major bleeding associated with oral factor Xa inhibitors. Available literature comparing the cost-effectiveness of the reversal agents is limited, and the large difference in price between therapy options has led many health systems to exclude andexanet-alfa from their formularies. To evaluate the clinical outcomes and cost of PCC compared to andexanet-alfa for patients with factor Xa inhibitor associated bleeds. We performed a quasi-experimental, single health system study of patients treated with PCC or andexanet-alfa from March 2014 to April 2021. Deterioration-free discharge, thrombotic events, length of stay, discharge disposition, and cost were reported. 170 patients were included in the PCC group and 170 patients were included in the andexanet-alfa group. Deterioration-free discharge was achieved in 66.5% of PCC-treated patients compared to 69.4% in the andexanet alfa-treated patients. 31.8% of PCC-treated patients were discharged home compared to 30.6% in the andexanet alfa-treated patients. The cost per deterioration-free discharge was $20,773.62 versus $5230.32 in the andexanet alfa and 4 F-PCC group, respectively. Among patients that experienced a bleed while taking a factor Xa inhibitor, there was no difference in clinical outcomes for patients treated with andexanet-alfa compared to PCC. Although there was no difference in the clinical outcomes, there was a significant difference in cost with andexanet-alfa costing approximately four times as much as PCC per deterioration-free discharge.


Asunto(s)
Inhibidores del Factor Xa , Humanos , Anticoagulantes/uso terapéutico , Antitrombina III , Factor Xa/farmacología , Inhibidores del Factor Xa/efectos adversos , Fibrinolíticos/uso terapéutico , Hemorragia/inducido químicamente , Hemorragia/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico
12.
Chemistry ; 28(40): e202200678, 2022 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-35420233

RESUMEN

Reactivators are vital for the treatment of organophosphorus nerve agent (OPNA) intoxication but new alternatives are needed due to their limited clinical applicability. The toxicity of OPNAs stems from covalent inhibition of the essential enzyme acetylcholinesterase (AChE), which reactivators relieve via a chemical reaction with the inactivated enzyme. Here, we present new strategies and tools for developing reactivators. We discover suitable inhibitor scaffolds by using an activity-independent competition assay to study non-covalent interactions with OPNA-AChEs and transform these inhibitors into broad-spectrum reactivators. Moreover, we identify determinants of reactivation efficiency by analysing reactivation and pre-reactivation kinetics together with structural data. Our results show that new OPNA reactivators can be discovered rationally by exploiting detailed knowledge of the reactivation mechanism of OPNA-inhibited AChE.


Asunto(s)
Reactivadores de la Colinesterasa , Agentes Nerviosos , Acetilcolinesterasa/química , Antídotos , Inhibidores de la Colinesterasa/farmacología , Reactivadores de la Colinesterasa/química , Compuestos Organofosforados , Oximas/química
13.
Bioorg Med Chem Lett ; 64: 128696, 2022 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-35318165

RESUMEN

Arsenicals belong to the class of chemical warfare agents known as vesicants, which are highly reactive, toxic and cause robust inflammatory response. Cutaneous exposure to arsenicals causes a wide range of systemic organ damage, beginning with cutaneous injuries, and later manifest multi-organ damage and death. Thus, the development of suitable antidotes that can effectively block injury following exposure to these agents is of great importance. Bromodomain 4 (BRD4), a member of the bromodomain and extra terminal domain (BET) family, plays crucial role in regulating transcription of inflammatory, proliferation and cell cycle genes. In this context, the development of potent small molecule inhibitors of BRD4 could serve as potential antidotes for arsenicals. Herein, we describe the synthesis and biological evaluation of a series of compounds.


Asunto(s)
Arsenicales , Antiinflamatorios/química , Antídotos/farmacología , Arsenicales/farmacología , Arsenicales/uso terapéutico , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo
14.
Am J Emerg Med ; 55: 38-44, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35272069

RESUMEN

BACKGROUND: Existing research recommends either andexanet alfa (AA) or four-factor prothrombin complex concentrate (4F-PCC) as an antidote for major bleeding events due to apixaban or rivaroxaban. Currently, there is limited published research that directly compares the risks and benefits of the two agents in patients with oral factor Xa inhibitor related traumatic and spontaneous intracerebral hemorrhages. Additional head-to-head data is needed to support favoring either AA or 4F-PCC when it comes to efficacy, safety, and cost. METHODS: A retrospective chart review was conducted to assess patients admitted to a multi-center healthcare system and a stand-alone teaching hospital in central Florida from June 2016 to December 2020. Patients included in the study were at least 18 years of age, taking apixaban or rivaroxaban prior to admission, had radiographical evidence of an intracranial hemorrhage, and received either AA or 4F-PCC as a reversal agent. The primary outcome analyzed was the level of excellent hemostasis achieved, based on a standardized rating system for effective hemostasis defined by the International Society of Thrombosis and Hemostasis (ISTH), after administration of AA or 4F-PCC. Secondary outcomes analyzed included changes in the initial hemorrhage volume as reported on computed tomography (CT) scan and at 12 to 24 h post treatment, rate of thromboembolic events, rate of inpatient mortality, and total cost of treatment after AA or 4F-PCC administration. RESULTS: A total of 109 patients were included in the study with 47 in the AA group (43.1%) and 62 in the 4F-PCC group (56.9%). There were no statistically significant differences between AA and 4F-PCC in terms of the primary and secondary outcomes with the exception of total cost of treatment. The level of excellent hemostasis achieved after reversal administration of AA was seen in 27 patients (71.1%) and 41 patients (70.7%) after 4F-PCC administration (p = 1, p adjusted = 0.654 after controlling for age, ICH score, regional mass effect, and midline shift). There was no statistically significant difference in the median percentage change in hemorrhagic volume from baseline to 12-24 h after reversal treatment (0 [-0.17--0.24] vs. 0 [-0.021-0.29], p = 0.439, adjusted p = 0.601) in the AA and 4F-PCC groups, respectively. The total incidence of thromboembolic events (4 [8.5%] vs. 6 [9.7%], p = 1, adjusted p = 0.973) and rate of inpatient mortality was similar between the two groups (16 [34.0%] vs. 13 [21.0%], p = 0.134, adjusted p = 0.283). A statistically significant difference was observed with the total cost of reversal treatment: $23,602 for treatment with AA and $6692 for treatment with 4F-PCC. CONCLUSIONS: No statistically significant differences were identified in primary or secondary outcomes between the two agents with the exception of total treatment cost. There is insufficient evidence based on this study to recommend AA over 4F-PCC for patients with intracranial hemorrhages associated with the use of apixaban or rivaroxaban.


Asunto(s)
Rivaroxabán , Tromboembolia , Anticoagulantes/efectos adversos , Factores de Coagulación Sanguínea/farmacología , Factores de Coagulación Sanguínea/uso terapéutico , Hemorragia Cerebral , Factor Xa , Inhibidores del Factor Xa/efectos adversos , Humanos , Hemorragias Intracraneales/inducido químicamente , Hemorragias Intracraneales/tratamiento farmacológico , Pirazoles , Piridonas , Proteínas Recombinantes , Estudios Retrospectivos , Rivaroxabán/efectos adversos
15.
J Biol Chem ; 295(19): 6357-6371, 2020 05 08.
Artículo en Inglés | MEDLINE | ID: mdl-32205448

RESUMEN

Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC-treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 µm) and nitric oxide (100 µm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 µm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning.


Asunto(s)
Intoxicación por Monóxido de Carbono/metabolismo , Monóxido de Carbono/toxicidad , Mitocondrias Cardíacas/metabolismo , Mitocondrias Hepáticas/metabolismo , Neuroglobina/metabolismo , Animales , Intoxicación por Monóxido de Carbono/patología , Carboxihemoglobina/metabolismo , Humanos , Masculino , Ratones , Mitocondrias Cardíacas/patología , Mitocondrias Hepáticas/patología , Óxido Nítrico/metabolismo , Óxido Nítrico/farmacología , Consumo de Oxígeno/efectos de los fármacos , Ratas
16.
Ann Pharmacother ; 55(12): 1455-1466, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-33843267

RESUMEN

BACKGROUND: The clinical use of factor VIII inhibitor bypassing activity (FEIBA) for factor Xa (FXa) inhibitor reversal is derived from small studies with notable variation in patient eligibility for use, dosage regimens, concurrent supportive care, and outcome measures. Consequently, additional effectiveness and safety data are warranted to expand the literature evaluating FEIBA for FXa inhibitor reversal. OBJECTIVE: This study sought to determine the incidence of observed effective hemostasis within 24 hours of post-FEIBA® administration as well as in-hospital and 30-day post-discharge incidences of thromboembolic event (TEE) and mortality between apixaban and rivaroxaban in the intracranial hemorrhage (ICH) and non-ICH populations. METHODS: This case series evaluated patients between January 1, 2014 through July 1, 2019 who received at least one FEIBA® dose for apixaban or rivaroxaban reversal secondary to acute ICH or non-ICH. Patient demographics, FEIBA® dosages, adjunct treatments, effectiveness, and safety outcomes were retrospectively collected from electronic medical record review. Modified hemostasis outcomes, adapted from criteria previously published by Sarode et al., TEE, and mortality between apixaban and rivaroxaban in the ICH and non-ICH populations were evaluated. RESULTS: Among the 104 patients evaluated, 62 received apixaban and 42 rivaroxaban. Thirty apixaban and 25 rivaroxaban users experienced ICH, whereas 32 apixaban and 17 rivaroxaban users experienced non-ICH. Among the combined ICH and non-ICH populations, effective hemostasis occurred in 89%, TEE in 8%, and mortality in 13%. No statistically significant differences were observed within ICH and non-ICH populations receiving apixaban or rivaroxaban regarding effective hemostasis, TEE, or mortality. CONCLUSION AND RELEVANCE: The combined ICH and non-ICH overall rates of effective hemostasis, TEE, and mortality were comparable to preexisting studies of FEIBA for factor Xa inhibitor reversal. The limitations inherent to the study design warrant a randomized controlled trial with an active comparator to confirm these observations.


Asunto(s)
Cuidados Posteriores , Rivaroxabán , Factores de Coagulación Sanguínea , Hemorragia , Humanos , Alta del Paciente , Pirazoles , Piridonas , Estudios Retrospectivos , Rivaroxabán/efectos adversos
17.
Ann Pharmacother ; 55(2): 261-264, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32667214

RESUMEN

The recent shortage of protamine prompted an investigation of alternatives for reversal of unfractionated heparin. Heparin is an anticoagulant utilized in the hospital setting. Available options for anticoagulation include direct oral anticoagulants, vitamin K antagonists, thrombin inhibitors, low-molecular-weight heparins, and heparin. Protamine is the approved reversal agent for heparin with few alternatives under investigation. Although andexanet was designed as an antidote for apixaban and rivaroxaban, in vitro studies show that in a dose-dependent technique, andexanet had near full reversal of heparin, reversed anti-factor Xa activity, and neutralized anticoagulant effects of activated partial thromboplastin time and thrombin time induced by heparin.


Asunto(s)
Coagulación Sanguínea/efectos de los fármacos , Factor Xa/uso terapéutico , Antagonistas de Heparina/uso terapéutico , Protaminas/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Anticoagulantes/efectos adversos , Pruebas de Coagulación Sanguínea , Factor Xa/administración & dosificación , Factor Xa/efectos adversos , Hemorragia/inducido químicamente , Hemorragia/prevención & control , Heparina/efectos adversos , Antagonistas de Heparina/administración & dosificación , Antagonistas de Heparina/efectos adversos , Antagonistas de Heparina/farmacología , Humanos , Protaminas/administración & dosificación , Protaminas/efectos adversos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos
18.
Ann Pharmacother ; 55(8): 980-987, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33305592

RESUMEN

BACKGROUND: The ideal dose and specific prothrombin complex concentrate (PCC) for warfarin reversal is unknown. OBJECTIVE: To evaluate the reduction in international normalized ratio (INR) of 3 different PCC dosing regimens: fixed-dose activated 4-factor PCC (aPCC), fixed-dose 4-factor PCC (4PCC), and standard-dose 4PCC. METHODS: This was a multicenter retrospective cohort review. Patients >18 years of age who received PCC for warfarin reversal between January 1, 2017, and December 31, 2017, were screened for inclusion. Patients were excluded if they did not receive the correct PCC dosing regimen, received PCC for nonwarfarin bleeding, had a baseline INR less than 2, or received a massive transfusion protocol. Two institutions utilized aPCC dosed at 500 IU for INR <5 and 1000 IU for INR ≥5. Two institutions utilized fixed-dose 4PCC at 1500 to 2000 units depending on patient factors. Two institutions utilized 4PCC package insert dosing. The primary outcome was achievement of post-PCC target INR ≤1.4. Secondary outcomes included percentage change in INR, lowest 24-hour INR, and mortality. RESULTS: A total of 154 patients were included (fixed-dose aPCC: n = 29; fixed-dose 4PCC: n = 53; standard-dose 4PCC: n = 72). There was no statistical difference between groups in achieving the primary outcome (58.6% vs 69.8% vs 79.2%, respectively; P = 0.103) or any secondary outcomes. CONCLUSION AND RELEVANCE: There was no difference in the ability to achieve a post-PCC INR of ≤1.4 between 3 different PCC regimens for warfarin reversal. Additional research is warranted to determine the ideal dose and PCC agent for warfarin reversal.


Asunto(s)
Anticoagulantes , Warfarina , Anticoagulantes/efectos adversos , Factores de Coagulación Sanguínea , Humanos , Relación Normalizada Internacional , Estudios Retrospectivos , Warfarina/efectos adversos
19.
J Enzyme Inhib Med Chem ; 36(1): 1370-1377, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34148470

RESUMEN

Organophosphorus poisoning caused by some pesticides and nerve agents is a life-threating condition that must be swiftly addressed to avoid casualties. Despite the availability of medical countermeasures, the clinically available compounds lack a broad spectrum, are not effective towards all organophosphorus toxins, and have poor pharmacokinetics properties to allow them crossing the blood-brain barrier, hampering cholinesterase reactivation at the central nervous system. In this work, we designed and synthesised novel isatin derivatives, linked to a pyridinium 4-oxime moiety by an alkyl chain with improved calculated properties, and tested their reactivation potency against paraoxon- and NEMP-inhibited acetylcholinesterase in comparison to the standard antidote pralidoxime. Our results showed that these compounds displayed comparable in vitro reactivation also pointed by the in silico studies, suggesting that they are promising compounds to tackle organophosphorus poisoning.


Asunto(s)
Acetilcolinesterasa/efectos de los fármacos , Reactivadores de la Colinesterasa/farmacología , Isatina/farmacología , Piridinas/farmacología , Simulación por Computador , Técnicas In Vitro
20.
Supramol Chem ; 33(3): 53-62, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34305377

RESUMEN

We report the design and synthesis of the acyclic cucurbit[n]uril-ß-cyclodextrin chimeric host H1. The goal of the study is to deepen the cavity of the receptor to allow ß-CD complexation of moieties on the guest (especially fentanyl) that protrude from the cavity of the primary acyclic CB[n] binding site to enhance binding affinity and deliver new supramolecular antidotes for fentanyl intoxication. 1H NMR spectroscopy was used to deduce the geometry of the complexes between H1 and H2 and the guest panel (G1 - G8 and fentanyl) whereas isothermal titration calorimetry was used to determine the thermodynamic parameters of complexation. Hosts H1 and H2 retain the essential molecular recognition features of CB[n] receptors, but chimeric host H1 binds slightly stronger toward the guest panel than H2 for reasons that remain unclear. Compared to tetraanionic hosts M1 and M2, the dianionic hosts H1 and H2 are less potent receptors which reflects the importance of electrostatic (ion-ion and ion-dipole) interactions in this series of hosts. The work highlights the challenges inherent in the optimization of binding affinity of hosts as potential supramolecular antidotes.

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