Digoxin-specific antibody fragments 38mg powder for solution for infusion vials

Oleander poisoning, resulting from the ingestion of Nerium oleander or Thevetia peruviana, is a serious toxicological issue in various parts of the world, particularly in regions where these plants grow abundantly and are easily accessible. Oleander contains potent cardiac glycosides, such as oleandrin and thevetin, which exert powerful effects on the cardiovascular system, leading to symptoms ranging from nausea and abdominal pain to severe arrhythmias and sudden cardiac death. This review summarizes the existing literature on the epidemiology, clinical features, pathophysiology, and challenges in treatment management associated with oleander poisoning. While supportive care, gastric decontamination, and the administration of digoxin-specific Fab antibody fragments (Digifab) are essential therapeutic measures, limited access to Digifab, delays in intervention, and insufficient supportive care practices remain significant complicating factors. Particular attention is given to findings from autopsy reports, which provide critical insights into the pathophysiological effects of oleander toxins and help bridge gaps in understanding fatal cases. This review acknowledges key limitations, particularly the scarcity of English-language publications, which restricts input from regions such as southern Asia and the Mediterranean-areas where oleander-related poisoning, especially in cases of intentional self-harm, is more prevalent. Additionally, this review highlights the socio-cultural dimensions of oleander ingestion, often linked to intentional self-poisoning, and emphasizes the need for enhanced preventive measures and public education. Future research efforts should prioritize addressing these gaps through autopsy-based studies and the development of more accessible and effective antidotes, which are essential to mitigate the global health burden of oleander-related mortality.

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The abundance of macrophages within the tumor microenvironment (TME) of lung cancer represents a noteworthy therapeutic target. Exploiting the phagocytic function of macrophages by blocking the "don't eat me" signal, CD47, has shown significant therapeutic potential. However, novel CD47-targeted combination strategies warrant further investigation. Through an analysis of data obtained from a screening model focused on the macrophage-mediated killing effect, two cardiac glycosides (CGs), ouabain and digoxin, are shown to increase the capacity of macrophages to kill cancer cells after combination with CD47 antibody. Compared with the control, the combination strategy reduced the tumor volume in different lung cancer models and increased the macrophage phagocytosis rate ≈5-fold. Mechanistically, in addition to Fc-FcγR interaction, CGs enhanced the expression of a pro-phagocytotic signal, calreticulin (CRT). Moreover, PERK inhibitor, ER-Golgi protein trafficking inhibitor, and siRNA-mediated knockdown of exocytosis protein exo70, abrogated both CGs-induced CRT upregulation and the ensuing enhancement of phagocytosis. These findings indicate that CGs drive CRT translocation originates from ER to Golgi apparatus, where it subsequently anchors to the cell surface via exo70-mediated exocytosis. Overall, this study offers compelling evidence that supports the clinical translation of an innovative combination regimen for the treatment of patients with lung cancer.

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Introduction: Digoxin is a cardiac glycoside used for rate control in atrial fibrillation and heart failure. Despite its efficacy, digoxin has a narrow therapeutic window and can cause severe side effects, including life-threatening arrhythmias. Literature and guidelines on management of digoxin toxicity remain inconsistent whether to include serum digoxin concentrations as a key criterium for diagnosing digoxin toxicity and determining the indication for digoxin-specific antibody fragments. This report presents a case of digoxin toxicity at therapeutic serum concentrations. Case report: A 76-year-old male presented with bradycardia, hyperkalemia, and acute kidney injury following gastrointestinal bleeding. Despite serum digoxin concentrations within the therapeutic range (1.4 ng/ml), the patient exhibited symptoms consistent with severe digoxin toxicity. Initial treatments, including calcium gluconate, insulin-glucose, and sodium bicarbonate, failed to resolve hyperkalemia and/or bradycardia. Administration of 40 mg digoxin-specific antibody fragments led to rapid normalization of potassium levels, improved heart rate, and hemodynamic stabilization, indicative for severe digoxin toxicity despite therapeutic serum concentrations. Discussion: This case demonstrates that digoxin toxicity can occur at serum concentrations in therapeutic range, emphasizing the importance of clinical features in diagnosing digoxin toxicity. Current guidelines vary on the role of serum digoxin concentrations in guiding the use of digoxin-specific antibody fragments, but this case underscores its efficacy in resolving symptoms related to digoxin toxicity, even at low serum concentrations.

Abstract licence: CC BY-NC-ND

Digoxin is a cardiac glycoside that has been used for several decades to treat heart failure and atrial fibrillation. Several doctors prescribe it to their patients, although it is not the first choice for either condition. In rare cases, intoxication can occur, leading to life-threatening cardiac arrhythmias. Here we report the case of an 84-year-old Caucasian woman who presented to the emergency department with dyspnoea, cough, and bilateral lower limb oedema. Eight days prior to her presentation, she had been prescribed methyldigoxin. As the patient had undiagnosed dementia and was taking medication without supervision, she ingested toxic amounts of the drug. Electrocardiogram showed the presence of arrhythmia, which resolved after using digoxin-specific Fab antibody fragments. In elderly patients, special care should be exercised when prescribing drugs with narrow therapeutic windows.

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Digoxin toxicity is a serious clinical concern, particularly in patients with chronic kidney disease (CKD), due to impaired renal clearance and the potential for both chronic tissue accumulation and acute overdose. Standard therapy with digoxin-specific antibody fragments (Fab) may be insufficient in cases with large tissue digoxin burdens and in patients with acute renal failure, as the delayed clearance of digoxin-Fab complexes can result in complex dissociation and rebound toxicity. We present a unique case of a 73-year-old woman with acute-on-chronic digoxin toxicity in the setting of acute renal failure who exhibited persistent toxicity symptoms despite Fab therapy. The patient underwent plasma exchange (PLEX) to remove lingering digoxin-Fab complexes and remaining free digoxin, resulting in successful clinical resolution and no disease recurrence. This case highlights the use of PLEX as a potential salvage therapy for patients with chronic digoxin toxicity and renal impairment who exhibit persistent toxicity symptoms despite treatment with Fab therapy.

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Preclinical neurological research relies predominantly on male animals, despite well-documented sex differences in neurological diseases, which ultimately may result in sex-dependent treatment efficiency. A key player in neurological disease treatment is the blood-brain barrier (BBB), the barrier property of brain capillaries, which tightly regulates molecular exchange between the blood and the brain. The BBB represents a major obstacle to brain drug delivery due to its tightness and presence of drug efflux pumps, with some studies suggesting that the BBB properties may differ between sexes. However, in vivo evidence is limited, and whether primary in vitro BBB models, commonly used to evaluate the permeability of novel drug candidates, display sex-dependent differences, lacks attention. With this study, we therefore aimed to investigate if a mouse in vitro model of the BBB displayed sex-dependent differences in BBB morphology and phenotype, and therefore whether sex should be considered a critical variable in its use. Primary mouse brain endothelial cells (PMBEC) were isolated from cortices of sexually mature C57Bl/6 mice. Transendothelial electrical resistance (TEER) measurements and transport of the paracellular marker [14C]-mannitol were used to evaluate monolayer tightness. Gene and protein expression of tight junction proteins, selected transporters and receptors as well as efflux transporters were assessed. P-glycoprotein (P-gp) function was evaluated in bidirectional [3H]-digoxin transport studies. Female- and male-derived PMBECs grew in monolayers, expressed the endothelial marker von Willebrand factor and showed elongated spindle-shaped morphology typical of endothelial cells. Female- and male derived PMBEC monolayers exhibited comparable barrier properties as reflected by TEER measurements and mannitol permeability. Tight junction mRNA and protein expression did not differ between sexes and displayed similar expression levels of key transporters. Lastly, P-gp and breast cancer resistance protein were detected in PMBECs of both female and male origin and P-gp function was similar in the two sexes. Our present study shows that PMBECs do not differ substantially between sexes. However, as this is the first study of its kind, it warrants further investigations into sex differences in PMBECs and whether these fully translates to the in vivo BBB.

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