Disulfiram: A repurposed drug in preclinical and clinical development for the treatment of infectious diseases

This article reviews preclinical and clinical studies on the repurposed use of disulfiram (Antabuse) as an antimicrobial agent. Preclinical research covered on the alcohol sobriety aid include uses as an anti-MRSA agent, a carbapenamase inhibitor, antifungal drug for candidiasis, and a treatment for parasitic diseases due to protozoa (e.g., giardiasis, leishmaniasis, malaria) and helminthes (e.g., schistosomiasis, trichuriasis). Past, current, and pending clinical studies on disulfiram as a post-Lyme disease syndrome (PTLDS) therapy, an HIV latency reversal agent, and an intervention for COVID-19 infections are also reviewed.

Successful Anesthetic Management of Myotonic Dystrophy Type I Using Sugammadex: A Case Report

Myotonic dystrophy (DM) is an uncommon inherited disease. Anesthesia for DM patients is tough due to its potency of cardiogenic and pulmonary problems, but a series of studies have shown how to manage and avoid complications and situations. We describe a case of a 33-year-old male patient who was scheduled for an elective excision & biopsy on the left axillae for hidradenitis suppurativa with DM type I. Anesthesia was induced and maintained with propofol, remifentanil, and rocuronium. Sugammadex is used as a reversal agent of neuromuscular blockade. He didn’t show myotonia during surgery and emergence. He also didn’t show postoperative pulmonary complications.

The Safety of Benzodiazepines and Opioids in the Geriatric Population: An Analysis of Patient Safety Events Reported by Hospitals and Ambulatory Surgical Facilities

Benzodiazepines may increase the risk of cognitive impairment, delirium, falls, fractures, and motor vehicle crashes in patients 65 years and older. The concomitant use of benzodiazepines and opioids may also be inappropriate for older adults due to the increased risk of overdose. We searched the Pennsylvania Patient Safety Reporting System (PA-PSRS) for reports of patient safety events related to the concomitant use of benzodiazepines and opioids in older adults in order to gain a better understanding of the potential risks of using these medications in combination. We identified 80 reports in which a patient may have experienced an adverse drug reaction (ADR) to the combined use of a benzodiazepine and an opioid pain medication. Reports were reviewed to determine the ADR(s) experienced by the patient. Changes in mental status were most common, occurring in more than two-thirds of reports (68.8%; 55 of 80), followed by respiratory reactions (51.3%; 41 of 80) and cardiovascular reactions (25.0%; 20 of 80). In over two-thirds of reports (70.0%; 56 of 80), the patient received a reversal agent, either flumazenil (10.7%; 6 of 56) or naloxone (35.7%; 20 of 56), or both (53.6%; 30 of 56). The inappropriate use of benzodiazepines and opioid pain medications in combination among patients 65 years and older is a growing problem, and an increased awareness may be the first step for providers to begin addressing it.

Bentracimab for Ticagrelor Reversal in Patients Undergoing Urgent Surgery

Ticagrelor is a reversible oral P2Y12 platelet inhibitor used in patients with many forms of heart and vascular disease. Because patients receiving ticagrelor may bleed or need emergent surgery, bentracimab was studied as a ticagrelor reversal agent. In this study in 150 patients, treatment had a significant salutary impact on laboratory measured platelet function. Adjudicated hemostasis was achieved in over 90% of patients, most of whom had cardiac surgery; thrombotic events occurred in just over 5% of treated patients.

Retrospective analysis of the effectiveness of a reduced dose of idarucizumab in dabigatran reversal

Background The recommended dose of idarucizumab, the specific reversal agent for dabigatran etexilate, is 5g. However, published data showed biochemical reversal after an initial 2.5g dose. Objectives This study aims to retrospectively compare the clinical effectiveness of 2.5g and 5g doses of idarucizumab used in dabigatran reversal in three hospitals in Auckland, New Zealand. Methods All patients receiving idarucizumab for dabigatran reversal between 1st April 2016 and 31st December 2018 were included. The primary outcome was the likelihood of receiving a second dose of idarucizumab during the same admission. Secondary outcomes included normalisation of coagulation profiles; and 30-day thrombotic, bleeding and mortality rates. Results Of 329 patients included, 206 received an upfront 2.5g dose and 123 received a 5g dose. The median age was 78 years and median creatinine clearance was 50mL/min. Most patients (62.6%) required idarucizumab for an urgent procedure, while 37.4% presented with bleeding. A 2.5g dose was not associated with an increased rate of receiving a second dose (OR 0.686, 95% CI 0.225-2.090). A similar proportion of patients in each group achieved a normal APTT (73.8% vs 80.0%, p=0.464) and dTCT (95.9% vs 91.4%, p=0.379) following idarucizumab infusion. There was no increase in the rate of death (OR 0.602, 95% CI 0.292-1.239), thrombosis (OR 0.386, 95% CI 0.107-1.396) or bleeding (OR 0.96, 95% CI 0.27-3.33) in the 2.5g dose group compared to the 5g dose group. Conclusions An initial 2.5g dose of idarucizumab appears effective for dabigatran reversal in the real-world setting.

Acute Stroke Treatment in an Anticoagulated Patient: When Is Thrombolysis an Option?

Purpose of Review Direct oral anticoagulants (DOACs: the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban and the direct thrombin inhibitor dabigatran) are the mainstay of stroke prevention in patients with non-valvular atrial fibrillation (AF). Nevertheless, there is a residual stroke risk of 1–2% per year despite DOAC therapy. Intravenous thrombolysis (IVT) reduces morbidity in patients with ischemic stroke and improves functional outcome. Prior DOAC therapy is a (relative) contraindication for IVT but emerging evidence supports its use in selected patients. Recent Findings Recent observational studies highlighted that IVT in patients on prior DOAC therapy seems feasible and did not yield major safety issues. Different selection criteria and approaches have been studied including selection by DOAC plasma levels, non-specific coagulation assays, time since last intake, and prior reversal agent use. The optimal selection process is however not clear and most studies comprised few patients. Summary IVT in patients taking DOAC is a clinically challenging scenario. Several approaches have been proposed without major safety issues but current evidence is weak. A patient-oriented approach balancing potential benefits of IVT (i.e., amount of salvageable penumbra) against expected bleeding risk including appropriate monitoring of anticoagulant activity seem justified.

Development and Implementation of an Opioid Risk-Reduction Strategy

Practice Problem: Accidental overdose is a continued concern for those who are prescribed opioids, and it is essential that healthcare members intensify prevention and response measures in order to prevent death or misuse from this medication. PICOT: The PICOT question that guided this project was: “In adult patients at an outpatient chronic pain management clinic (P), how does development and implementation of a safe opioid risk-reduction office policy (I), compared to usual practice (C), improve patient rates of naloxone availability and health literacy (O) over eight weeks (T)?” Evidence: The CDC’s Guideline for Prescribing Opioids for Chronic Pain, the Surgeon General’s Advisory on Naloxone and Opioid Overdose, and the U.S Department of Health and Human Services website were used to gather evidence-based components for information and practice changes. Intervention: This project created a safe opioid risk-reduction strategy in the form of a new office protocol that ensured naloxone was received with instruction on what to do in the event of an overdose or life-threatening respiratory reaction to opioids and other safety information. The providers assessed the change in knowledge by using the teach back method. Outcome: The results showed improvement in the availability of naloxone as a reversal agent as well as increased understanding of safe opioid storage, disposal, and drug interactions. Conclusion: The manuscript reports barriers, successes, and challenges discovered during the project. The recommendations can be applied to other outpatient clinic sites to enhance the safety of all patients who manage their chronic pain with the use of prescription opioids.

The HIV latency reversal agent HODHBt enhances NK Cell effector and memory-like functions by increasing IL-15 mediated-STAT activation

Elimination of latent HIV reservoirs is a critical endpoint to eradicate HIV. One therapeutic intervention against latent HIV is ‘shock and kill’. This strategy is based on the transcriptional activation of latent HIV with a Latency-Reversing Agent (LRA) with the consequent killing of the reactivated cell by either the cytopathic effect of HIV or the immune system. We have previously found that the small molecule 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) act as an LRA by increasing Signal Transducers and Activators of Transcription (STAT) activation mediated by IL-15 in cells isolated from aviremic participants. The IL-15 superagonist (N-803) is currently under clinical investigation to eliminate latent reservoirs. IL-15 and N-803 share similar mechanism of action by promoting the activation STATs and have shown some promise in pre-clinical models directed towards HIV eradication . In this work, we evaluated the ability of HODHBt to enhance IL-15 signaling in NK cells and the biological consequences associated with increased STAT activation in NK effector and memory-like functions. We showed that HODHBt increased IL-15-mediated STAT phosphorylation in NK cells, resulting in increased secretion of CXCL10 and IFN- g and expression of cytotoxic proteins including Granzyme B, Granzyme A, Perforin, Granulysin, FASL and TRAIL. This increased cytotoxic profile results in an increase cytotoxicity against different tumor cell lines and HIV-infected cells. HODHBt also improved the generation of cytokine-induced memory-like NK cells. Overall, our data demonstrate that enhancing the magnitude of IL-15 signaling with HODHBt favors NK cell cytotoxicity and memory-like generation, and targeting this pathway could be further explored for HIV cure interventions.