BEMNIFOSBUVIR HAS LOW POTENTIAL TO INHIBIT P-gp, BCRP, AND OATP1B1 MEDIATED TRANSPORT

Background: Bemnifosbuvir (BEM, AT-527) is a guanosine nucleotide prodrug candidate for the treatment of COVID-19 and chronic HCV. BEM was identified in vitro as an inhibitor of drug transporters P-glycoprotein, breast cancer resistant protein (BCRP) and organic anion transporting polypeptide 1B1 (OATP1B1). Ph 1 studies in healthy participants were conducted to assess the clinical implications of these results using digoxin (DIG) and rosuvastatin (ROSU) as P-gp and BCRP/ OATP1B1 index drugs, respectively. Method(s): Both studies employed a similar design with 2 groups of 14 healthy participants: Day 1/period 1, all participants received a single dose of DIG 0.25mg or ROSU 10mg alone. In period 2, participants received DIG 0.25mg or ROSU 10mg with BEM 1100mg, simultaneously (n=14) or staggered by 2h (n=14). Serial plasma samples were collected and quantitated for DIG or ROSU concentrations. Result(s): A single dose of BEM 1100mg simultaneously administered slightly increased the Cmax of DIG (78%), yet had no effect on its AUC, consistent with the transient nature of BEM plasma PK. When dosed staggered, BEM did not affect the PK of DIG. A single dose (simultaneous or staggered) of BEM 1100mg slightly increased the plasma exposure of ROSU (20%-40%). There was no effect on vital signs, ECG, and no SAEs or drug discontinuations. Conclusion(s): A single high dose of BEM 1100mg only slightly increased the plasma exposure of the P-gp and BCRP/OATP1B1 index drugs DIG and ROSU. BEM has low potential to exhibit clinical meaningful inhibition of these transporters. No dose adjustment will be needed for drugs that are sensitive substrates of P-gp or BCRP/OAT1B1 when co-administered with BEM, staggered dosing may lessen any DDI risk.

Intentional Taxus Baccata Ingestion Presenting with Cardiogenic Shock and Ventricular Tachycardia

Background The prevalence of anxiety and depression has increased following the COVID pandemic. Young women are disproportionally at risk of suicidal behaviors. Ingestion of Taxus baccata (English Yew) may lead to cardiotoxicity and death. Intoxication is known to be resistant to standard treatments with no effective antidotes. Case A 20-year-old female with a history of major depressive disorder presented to our emergency department unresponsive in pulseless ventricular tachycardia (VT) (figure 1A). She underwent CPR and achieved ROSC, however, was persistently hypotensive despite multiple pressors and was subsequently placed on VA ECMO. Review of a home journal revealed a plan to ingest 50 grams of Yew with suicidal intent. Decision-making Taxoids have been reported to have similar properties to digoxin and therefore digoxin-specific FAB antibodies were administered. She was also started on amiodarone and lidocaine for management of VT. After 3 hours she converted into sinus rhythm and had no further episodes of VT. Her clinical course was complicated by severe LV dysfunction and dilation while on VA-ECMO necessitating placement of an LV impella. By day three, all mechanical support was weaned off and she had normalization of her EF. Patient was discharged to an inpatient psychiatry facility on day 7 of hospitalization. Conclusion Ingestion of English Yew with suicidal intent is rare but may cause cardiogenic shock and VT requiring aggressive hemodynamic support until the toxin is metabolized. [Formula presented]Copyright © 2023 American College of Cardiology Foundation

Recent progress in microfluidic biosensors with different driving forces

Microfluidic biosensors integrating fluid control, target recognition, as well as signal transduction and output, have been widely used in the field of disease diagnosis, drug screening, food safety and environmental monitoring in the past two decades. As the central part and technical characteristics of microfluidic biosensors, the fluid control is not only associated with accuracy and convenience of the sensors, but also affects the material selection and working mode of the sensors. This review summarizes the fluid driving forces for microfluidic biosensors, including gravity, capillary force, centrifugal force, pressure, light, sound, electrical, and magnetic forces. Then, the recent advances in microfluidic biosensors for the detection of viruses, cells, nucleic acids, proteins and small molecules are discussed. Finally, we propose the current challenges and future perspectives of microfluidic biosensors. We hope this review can provide readers with a new perspective to understand the technical characteristics and application potential of microfluidic biosensors.Copyright © 2022 Elsevier B.V.

Case report of congenital disorder of glycosylation type Ia combined with dilated cardiomyopathy.

Clinical data and follow-up of a case of congenital disorder of glycosylation type Ia (CDG-Ia) combined with dilated cardiomyopathy admitted to the Department of Cardiology, Children's Hospital of Nanjing Medical University were analyzed retrospectively.The 5-year-old female patient was admitted in December 2016 due to recu-rrent shortness of breath for 2 months.Clinical symptoms and signs included repeated attacks of shortness of breath, physical retardation, malnutrition, binocular esotropia, multiple episodes of hypoglycemia, hepatosplenomegaly, hypotonia and other multi-system damages.Cardiac echocardiography suggested the feature of dilated cardiomyopathy, including the significant enlargement of the left ventricle, and decreased systolic function.Genetic testing revealed a compound heterozygous mutation in the PMM2 gene, and as a result, the patient was diagnosed as CDG-Ia.The patient's condition improved after symptomatic treatments such as Cedilanid, Dopamine, Dobutamine, Furosemide, as well as support treatments like myocardium nutrition, blood sugar maintenance, liver protection, etc.After discharge, the patient was given oral Digoxin, Betaloc, Captopril and diuretics, and hypoglycemia-controlling agents.The patient was followed up every 3-6 months.After more than 2 years of follow-up, the heart function and heart enlargement gradually returned to normal.During the Corona Virus Disease 2019 outbreak, self-withdrawal continued for 2 months.Re-examinations showed decreased cardiac function and enlarged left ventricle again.Medications were resumed again, and the patient was followed up closely.This case report suggested that CDG-Ia may be associated with dilated cardiomyopathy, and the cardiac phenotype may be improved by symptomatic supportive treatment.Copyright © 2021 by the Chinese Medical Association.

Medications safety for special population case studies: Pediatrics

Medication errors are among the most common medical errors, and studies have shown that the pediatric population is particularly vulnerable. Errors can occur at any stage of the medication process. We tried to build various cases, which highlighted different aspects of drug safety in pediatrics. The case studies focused on vancomycin infusion, supportive treatment in COVID-19-related multisystem inflammatory illness, side effect of antitubercular treatment drugs, management of respiratory failure, low cardiac functioning, acyclovir nephrotoxicity, stress ulcer, cyclophosphamide-induced hemorrhagic cystitis in rhabdomyosarcoma, blood pressure after aortic coarctation elective surgery, and use of paracetamol instead of NSAIDs in pediatrics. These cases would be useful in both as a diagnostic tool and as a way of monitoring certain conditions. © 2023 Elsevier Inc. All rights reserved.

Minimal recovery of drug from extracorporeal treatment in a case of phenytoin toxicity associated with coma and hypothermia

Background: The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup provides a weak conditional recommendation in support of hemodialysis (HD) for select patients with severe phenytoin poisoning. Despite this recommendation, the HD clearance of phenytoin is poorly studied. We present a patient who developed phenytoin toxicity that was treated with hemodialysis and report on the efficacy of phenytoin removal during HD. Case report: An 87-year-old man with epilepsy who was maintained on a stable dose of 300mg phenytoin extended-release daily was admitted to the hospital for treatment of Coronavirus Disease 2019 and congestive heart failure. On hospital day 14, the patient had a gradual onset of depressed mental status with hypothermia (nadir 35 degrees Celsius). At this time, he had a rising total blood phenytoin concentration (peak 49.3 mcg/mL [therapeutic 10-20mcg/mL] with an albumin of 3.8 g/dL [normal 3.4-5.4 g/dL]). The patient's other medications included furosemide, aspirin, atorvastatin, digoxin, doxycycline, metoprolol tartrate, and warfarin;he was also receiving albumin and crystalloid for hypovolemia (albumin nadir on hospital day 14: 2.5 g/dL). Free phenytoin concentrations were not available. Alternate etiologies of hypothermia (endocrine, infectious) were excluded. The Poison Control Center was consulted and recommended HD because of the concern for prolonged coma, as per EXTRIP guidelines. The patient received three sessions of HD over a period of 6 days at 2.5-3 h per session using an F160 Optiflux membrane filter (Fresenius Medical Care, Waltham, MA, USA), with a blood flow rate of 350mL/min and a dialysate flow rate of 700mL/min. After the first session of HD (2.5 h) on hospital day 21, his hypothermia resolved and his phenytoin concentration fell from 39.2mcg/mL to 34.2 mcg/mL with only mild improvement in his mental status. After 6 days (hospital day 27), his phenytoin concentration decreased to 19.5 mcg/mL and his mental status normalized. Effluent from the first HD session had phenytoin concentrations below the limit of detection (0.50mcg/mL). Thus, no greater than 52mg of phenytoin was removed during a 2.5-h session of hemodialysis. Discussion(s): The reason for the sudden increase in blood phenytoin concentrations in this patient is unclear in the absence of drug-drug interactions or dosing changes to the phenytoin. Although uncommonly reported, patients with phenytoin toxicity can experience hypothermia. In this case, the patient's hypothermia resolved during HD, although it is unclear if this was related to changes in phenytoin concentration or (more likely) direct extracorporeal warming via the HD machine. If the patient's phenytoin clearance from the first session were extrapolated to subsequent sessions an estimated maximum of 166.4mg of phenytoin would be removed in 8 total hours of HD, which is far less than previously reported phenytoin clearances on the order of grams. This difference may be related to the use of high cutoff dialysis membranes in prior studies, which are not routinely used. Conclusion(s): Although HD rapidly resolved this patient's hypothermia, a minimal amount of phenytoin was recovered in the patient's dialysate. Prior studies suggesting consequential clearance and efficacy of phenytoin removal by extracorporeal treatment may not apply to routine HD methods. Further studies on the utility of extracorporeal treatment for phenytoin toxicity are needed.

THE BIG IMPACT OF SMALL CHANGES IN NARROW THERAPEUTIC INDEX DRUGS

CASE: An 84-year-old woman with atrial fibrillation on Digoxin presented with acute onset of confusion associated with a week history of abdominal pain, vomiting, and poor fluid intake. A few days prior, Amiodarone was added to her drug regimen which included Lasix. Additionally, she received the COVID-19 booster vaccine which led to a viral-like syndrome resulting in dehydration. The patient was afebrile, normotensive, but bradycardic. EKG showed a prolonged PR interval and scooped ST segments. Labs showed hyperkalemia, pre-renal acute kidney injury (AKI), and a Digoxin level of 4.3 ng/mL (therapeutic range: 0.8-2.0 ng/mL). Digoxin and Lasix were held and Digoxin antidote, Digibind, was administered with normalizing heart rate, potassium, and clinical improvement. IMPACT/DISCUSSION: Digoxin is used to slow conduction in atrial fibrillation and increase cardiac contractility in heart failure. It inhibits the membrane sodium-potassium-adenosine triphosphatase pump (Na/K ATPase), resulting in increased cytosolic calcium and subsequent cardiac contractility and automaticity. In turn, this can also cause premature ventricular contractions and tachycardia. In the carotid sinus, increased baroreceptor firing and subsequent increased vagal tone occurs which can cause bradycardia, atrioventricular blocks, hypotension, and GI symptoms. In skeletal muscle, hyperkalemia can result due to the abundance of Na/K ATPase pumps. Digoxin has a narrow therapeutic index with serum levels easily affected by many commonly prescribed drugs by way of decreasing renal clearance, inhibiting P-glycoprotein, and inducing secondary electrolyte disturbances. That said, drug dosing should be individualized with close monitoring to avoid potentially life-threatening effects that may result with even mildly increased digoxin levels. Acute toxicity manifests as non-specific GI, and neurologic symptoms (confusion, lethargy, visual changes), hyperkalemia, and brady or tachy-arrhythmias. Treatment is with digoxin specific fragment antigen binding (Fab) antibody, Digibind, which binds digoxin, inactivating it within 6-8 hours. Postadministration, digoxin serum testing cannot distinguish free verse bound drug;therefore, drug levels remain elevated for days to weeks until the FabDigoxin complex is excreted. In the case above, the viral-like-syndrome after the booster vaccine with subsequent AKI secondary to dehydration likely precipitated Digoxin toxicity. Accompanying drug interactions of diuretics causing dehydration and hypokalemia, P-glycoprotein inhibitors (Amiodarone, Verapamil, Diltiazem, Quinidine), and ACE inhibitors can further worsen renal clearance and culminate in Digoxin toxicity. CONCLUSION: Given Digoxin's narrow therapeutic index, small clinical changes such as post COVID-19 vaccine flu-like symptoms, dehydration, and medication changes can manifest drug toxicity. Therefore, attentive monitoring of accompanying comorbidities and drug interactions is imperative at preventing catastrophic toxic effects.

Use of Intravenous Digoxin on General Inpatient Wards

Aim: We investigated the use of intravenous digoxin for atrial fibrillation on ISLHD’s Wollongong Hospital’s general wards. The primary aim was to inform the design of a new drug guideline. Methods: All results for e-meds use of intravenous digoxin in 2020 for ISLHD were accessed. They were filtered to Wollongong Hospital. Whilst the emergency department and intensive care unit were excluded as critical care areas, other key units with cardiac monitoring capacity (Coronary Care Unit, Neuro-high Intensity Unit and COVID-19 ward) were included. Results: 45 patients received intravenous digoxin on inpatients’ wards in Wollongong Hospital in 2020. The average age was 77 years, with 28 (62%) having known AF. 23 patients (51%) were on cardiac monitoring. 5 patients (11%) were haemodynamically unstable. 10 patients (22%) were not prescribed rate control when intravenous digoxin was initiated, and 4 patients (9%) were not taking their rate control due to swallowing issues or hypotension. 31 patients (69%) had a rapid response and cardiology was involved in 22 (49%) of the patients. Only one patient had a documented bradyarrhythmia. Conclusion: The above data informed a new drug guideline for intravenous digoxin on general wards. It specifically addressed low rates of cardiology involvement and earlier involvement in uncontrolled AF. It also included an emphasis on the utilisation of cardiac monitoring for haemodynamically unstable patients requiring intravenous digoxin.

Evolution of Therapeutic Drug Monitoring requests in a tertiary University Hospital in the last 16 years

Introduction: TDM has been widely used in clinical practice for many years and has application in various groups of drugs,mainly in drugs with pharmacokinetic variability, concentration related therapeutic and adverse effects, narrow therapeutic index, defined therapeutic concentration range and desired therapeutic effect difficult to monitor. Objectives: The aim of this study is to assess the evolution of TDM application throughout the years and its usefulness and necessity nowadays in a tertiary University Hospital. Methods: Data of Therapeutic Drug Monitoring requests were collected for the years 2005, 2010, 2015, 2019, 2020 and 2021 from the records of the Laboratory of Pharmacology General University Hospital of Alexandroupolis. Drugs monitored included digoxin, valproic acid, carbamazepine, phenytoin, phenobarbital, cyclosporine, tacrolimus, amikacin, gentamycin, vancomycin, serum benzodiazepines, methotrexate, cortisol, acetaminophen, salicylate, theophylline, tobramycin and primidone. More specifically, the data collected were the drug's level measurement and the clinic that requested the specific drug order. Results: A total of 1357 drug level measurement records were found for 2005, 1442 for 2010, 766 for 2015, 520 for 2019, 442 for 2020 and 622 for 2021. During these years the most frequent drug requested for TDM was digoxin (2005), cyclosporine (2010, 2019), valproic acid (2015, 2020), and tacrolimus (2021). In regards to the drugs requested, digoxin was predominantly requested by Cardiology and Pathology, cyclosporine and tacrolimus by Nephrology and valproic acid by Psychiatry. Furthermore, the percentage of non optimal therapeutic levels that required dose adjustments were calculated and will be presented. Conclusion: TDM retains a degree of its value as shown by the number of incidents requiring dose modifications. In addition, the presented results obtained from 2005 to 2021 show that there is a notable decrease in the number of requests for TDM per year. This can be imputed to several reasons such as the replacement of specific drugs with new therapeutic regimens and the evolution of therapeutic drug protocols in several diseases. Another major factor was the measures taken against the Covid-19 pandemic in the last two years which resulted to a substantial decrease of routine health examinations and scheduled appointments in the Hospital.

A BRIEF SYNOPSIS OF MONOCLONAL ANTIBODY FOR THE TREATMENT OF VARIOUS GROUPS OF DISEASES.

Monoclonal antibodies (mAbs) are increasingly being prescribed to patients and investigated in the field of medicine and research. This class of medication is unique due to its ability to be engineered into targeting a specific receptor. Numerous studies and reviews have reported the efficacy, potency, and clinical usage of mAbs in the treatment of a variety of diseases ranging from autoimmune disorders to malignant cancers. However, very few publications classify and provide a brief synopsis of mAbs that includes their pharmacological profiles. mechanisms of action, uses, and side effects in a concise manner. Therefore, this review aims to classify the current mAbs drugs used in clinical practice according to system diseases by providing a brief summary for each of them. For example, regarding cardiovascular disorders, mAbs such as Abciximab, Bevacizumab, and Digoxin Immune Fab will be reviewed. Denosumab, used to treat musculoskeletal disorders, will be also discussed. In addition, mAbs such as Adalimumab, Eculizumab, Natalizumab used in autoimmune disorders and Alemtuzumab, Trastuzumab, Cetuximab, and Rituximab that are prescribed for tumors will be reviewed. Finally, we shall discuss two mAbs that are IL-6 antagonists, Tocilizumab and Siltuximab, which are in ongoing clinical trials as potential treatments of COVID-19. The mAbs have profound benefits against chronic and malignant conditions, and the overall purpose of this review is to illustrate the basic pharmacological profiles of mAbs that physicians may find useful in establishing their management protocols.

Technical Note: Negative Interference of Ashwagandha, an Indian Ayurveda Medicine Indicated for Preventing COVID-19, in IL-6 Immunoassay.

OBJECTIVE: Ashwagandha, an Indian Ayurvedic medicine is indicated to prevent COVID-19 infection. Because IL-6 and C-reactive protein are widely measured to determine risk of cytokine storm in hospitalized COVID-19 patients, we studied potential interference of ashwagandha on these two assays. Previous studies indicated that ashwagandha may interfere with digoxin assay, so we also studied potential interference with digoxin assay. MATERIALS AND METHODS: We obtained one ashwagandha product from India (liquid extract) and one product from US (Herb Pharma; liquid extract). We prepared two serum pool each for IL-6, C-reactive protein and digoxin by combining appropriate left-over specimens submitted to our hospital laboratory for such tests. Then aliquots of each pools were supplemented with 10, 25 or 50 µL of ashwagandha extract followed by re-analysis for appropriate analyte and comparing values with original pool. RESULTS: We observed negative interference of ashwagandha with IL-6 assay only (Indian product showed more negative interference) but C-reactive protein assay and digoxin assay were not affected. Negative interference of ashwagandha in IL-6 assay has not been reported before. CONCLUSION: We conclude ashwagandha caused negative interference in IL-6 assay.

Cardiac Glycosides as Autophagy Modulators.

Drug repositioning is one of the leading strategies in modern therapeutic research. Instead of searching for completely novel substances and demanding studies of their biological effects, much attention has been paid to the evaluation of commonly used drugs, which could be utilized for more distinct indications than they have been approved for. Since treatment approaches for cancer, one of the most extensively studied diseases, have still been very limited, great effort has been made to find or repurpose novel anticancer therapeutics. One of these are cardiac glycosides, substances commonly used to treat congestive heart failure or various arrhythmias. Recently, the antitumor properties of cardiac glycosides have been discovered and, therefore, these compounds are being considered for anticancer therapy. Their mechanism of antitumor action seems to be rather complex and not fully uncovered yet, however, autophagy has been confirmed to play a key role in this process. In this review article, we report on the up-to-date knowledge of the anticancer activity of cardiac glycosides with special attention paid to autophagy induction, the molecular mechanisms of this process, and the potential employment of this phenomenon in clinical practice.

Repurposing Cardiac Glycosides: Drugs for Heart Failure Surmounting Viruses.

Drug repositioning is a successful approach in medicinal research. It significantly simplifies the long-term process of clinical drug evaluation, since the drug being tested has already been approved for another condition. One example of drug repositioning involves cardiac glycosides (CGs), which have, for a long time, been used in heart medicine. Moreover, it has been known for decades that CGs also have great potential in cancer treatment and, thus, many clinical trials now evaluate their anticancer potential. Interestingly, heart failure and cancer are not the only conditions for which CGs could be effectively used. In recent years, the antiviral potential of CGs has been extensively studied, and with the ongoing SARS-CoV-2 pandemic, this interest in CGs has increased even more. Therefore, here, we present CGs as potent and promising antiviral compounds, which can interfere with almost any steps of the viral life cycle, except for the viral attachment to a host cell. In this review article, we summarize the reported data on this hot topic and discuss the mechanisms of antiviral action of CGs, with reference to the particular viral life cycle phase they interfere with.

Classical Drug Digitoxin Inhibits Influenza Cytokine Storm, With Implications for Covid-19 Therapy.

BACKGROUND/AIM: Influenza viruses, corona viruses and related pneumotropic viruses cause sickness and death partly by inducing cytokine storm, a hyper-proinflammatory host response by immune cells and cytokines in the host airway. Based on our in vivo experience with digitoxin as an inhibitor of TNFα-driven NFĸB signaling for cytokine expression in prostate cancer in rats and in cystic fibrosis in humans, we hypothesize that this drug will also block a virally-activated cytokine storm. Materials Methods: Digitoxin was administered intraperitoneally to cotton rats, followed by intranasal infection with 107TCID50/100 g of cotton rat with influenza strain A/Wuhan/H3N2/359/95. Daily digitoxin treatment continued until harvest on day 4 of the experiment. RESULTS: The cardiac glycoside digitoxin significantly and differentially suppressed levels of the cytokines TNFα, GRO/KC, MIP2, MCP1, and IFNγ, in the cotton rat lung in the presence of influenza virus. CONCLUSION: Since cytokine storm is a host response, we suggest that digitoxin may have a therapeutic potential not only for influenza and but also for coronavirus infections.