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Oleandrin
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Oleandrin
Names
IUPAC name
16β-(Acetyloxy)-3β-(2,6-dideoxy-3-O-methyl-α-L-arabino-hexopyranosyloxy)-14-hydroxy-5β-card-20(22)-enolide
Systematic IUPAC name
(1R,2S,3aS,3bR,5aR,7S,9aS,9bS,11aR)-3a-Hydroxy-7-{[(2R,4S,5S,6S)-5-hydroxy-4-methoxy-6-methyloxan-2-yl]oxy}-9a,11a-dimethyl-1-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-2-yl acetate
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.006.693 Edit this at Wikidata
UNII
  • InChI=1S/C32H48O9/c1-17-29(35)24(37-5)14-27(39-17)41-21-8-10-30(3)20(13-21)6-7-23-22(30)9-11-31(4)28(19-12-26(34)38-16-19)25(40-18(2)33)15-32(23,31)36/h12,17,20-25,27-29,35-36H,6-11,13-16H2,1-5H3/t17-,20+,21-,22-,23+,24-,25-,27-,28-,29-,30-,31+,32-/m0/s1 checkY
    Key: JLPDBLFIVFSOCC-XYXFTTADSA-N checkY
  • InChI=1/C32H48O9/c1-17-29(35)24(37-5)14-27(39-17)41-21-8-10-30(3)20(13-21)6-7-23-22(30)9-11-31(4)28(19-12-26(34)38-16-19)25(40-18(2)33)15-32(23,31)36/h12,17,20-25,27-29,35-36H,6-11,13-16H2,1-5H3/t17-,20+,21-,22-,23+,24-,25-,27-,28-,29-,30-,31+,32-/m0/s1
    Key: JLPDBLFIVFSOCC-XYXFTTADBR
  • O=C\1OC/C(=C/1)[C@H]2[C@@H](OC(=O)C)C[C@@]6(O)[C@]2(C)CC[C@H]4[C@H]6CC[C@@H]5C[C@@H](O[C@@H]3O[C@H]([C@H](O)[C@@H](OC)C3)C)CC[C@]45C
Properties
C32H48O9
Molar mass 576.72 g/mol
Appearance Oleandrin forms colourless, odourless, acicular crystals that are very bitter
Density 1.261 g/ml
Melting point 250.0 °C (482.0 °F; 523.1 K)
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Acute Toxicity (Oral, inhalation)
GHS labelling:
GHS06: ToxicGHS08: Health hazard
Danger
H300, H330, H373
P260, P264, P270, P271, P284, P301+P310, P304+P340, P310, P320, P330, P403+P233, P405, P501
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 4: Very short exposure could cause death or major residual injury. E.g. VX gasFlammability 0: Will not burn. E.g. waterInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
4
0
0
Lethal dose or concentration (LD, LC):
0.248 mg/kg (Cat, Intravenous)
Safety data sheet (SDS) Safety Data Sheet
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Oleandrin is a cardiac glycoside found in the poisonous plant oleander (Nerium oleander L.).[1] As a main phytochemical of oleander, oleandrin is associated with the toxicity of oleander sap, and has similar properties to digoxin.[1] Oleandrin and other oleander chemicals are potentially toxic to the heart, liver, and kidneys.[1]

Although oleander has been used in traditional medicine and as a dietary supplement, there is no clinical evidence that oleander and its constituents, including oleandrin, are safe or effective for any therapeutic purpose. Oleandrin is not approved by regulatory agencies as a prescription drug.[1]

Structure and reactivity

[edit]

The structure of oleandrin contains a central steroid nucleus with an unsaturated lactone ring structure on C17 and a dideoxy arabinose group on C3. In addition, the steroid ring has a substitute of an acetyloxy group on C16.[2] The sugar forming the glycoside is L-oleandrose.

Oleandrin resembles very much other glycosides like ouabain and digoxin but has less effect than digoxin. It is however, just like its derivate oleandrigenin, a more potent glycoside than ouabain.[2]

Synthesis

[edit]

Oleandrin and its derivate oleandrigenin are formed in the N. oleander plant. The oleandrin itself can be won out of the leaves and other parts of the plant but can also be produced in the lab by using cell cultures. Here, the oleandrin synthesis (along with other metabolites) can be stimulated in untransformed plant cell cultures with supplementation of phytohormone. However, this is not enough to produce large quantities because of early cell death. Transgenic cultures of Agrobacteria are able to synthesize great quantities of oleandrin and other metabolites of the oleander plants, fit for pharmaceutical purposes.[3]

[edit]

Oleandrin is, apart from its pure form, also closely related to structural similar glycosides and alkaloids, which all have more or less the same characteristics as oleandrin:[1]

  • Oleandrigenin is a deglycosylated metabolite of oleandrin. It has however a more mild effect.[2]
  • Conessine
  • Neritaloside
  • Odorside

Metabolism

[edit]

Although oleandrigenin is not formed in human plasma, it was found in the volunteers injected with oleandrin, suggesting that it is formed in other human tissues.[4] Because of its lipophilic properties, oleandrin can be easily absorbed in the gastrointestinal tract after oral dosing.[1] The clearance is slow. The plasma concentration obtains its maximum at twenty minutes after oral intake (half-life of about 2 hours, but half-life after IV administration is half an hour).[5]

It is excreted mostly in feces, but also in urine.[5] Because the main route of excretion is through biliary excretion into the feces, it is mainly the liver that is exposed to oleandrin.[5] As excretion in urine is only a smaller route, the kidneys are less exposed. There is also accumulation in the heart, which explains its potential for cardiac toxicity.[5]

Mechanism of action

[edit]

Because of its properties as a cardiac glycoside, oleandrin interferes in some essential processes within the cell, the most important of these being the inhibition of the Na-K ATPase.[1] This protein enables the cell to exchange the cations Na+ and K+ between the intercellular and extracellular spaces by which, for instance, electric signaling is made possible in nerve cells. Oleandrin binds to specific amino acids in the protein, causing it to lose its function.[6][7]

Apart from being a potent toxic compound, there are no results on oleandrin from human clinical research that support its use as a treatment for cancer or any disease.[1]

Toxicity

[edit]

Due to its considerable toxicity, use of oleander or its constituents, such as oleandrin, is regarded as unsafe and potentially lethal.[1] Use of oleander may cause contact dermatitis, headache, nausea, lethargy, and high blood levels of potassium, with symptoms appearing within a few hours of ingestion.[1] In one fatality, the blood concentration of oleandrin and a related cardiac glycoside from the oleander plant was estimated at 20 ng/ml.[8] In practice, there have been adult cases wherein 14–20 oleander leaves (of unknown oleandrin concentration) proved not to be fatal, but also a lethal case of a child that consumed only one leaf.[9]

Symptoms

[edit]

Symptoms of oleandrin poisoning can cause both gastrointestinal and cardiac effects.[1] The gastrointestinal effects can consist of nausea, abdominal pain, and vomiting, as well as higher salivation and diarrhea (which may contain blood).[1] After these first symptoms, the heart may be affected by tachyarrhythmia, bradyarrhythmia, premature ventricular contractions, or atrioventricular blockage. Also, xanthopsia (yellow vision), a burning sensation of the mucous membranes of the eyes, and gastrointestinal tract and respiratory paralysis can occur.[1][2] Reactions to poisonings from this plant can also affect the central nervous system. These symptoms can include drowsiness, tremors, or shaking of the muscles, seizures, collapse, and even coma that can lead to death.[1] Oleander sap can cause skin irritations, severe eye inflammation and irritation, and allergy reactions characterized by dermatitis when administered topically.[1][10]

Diagnosis

[edit]

Diagnosis of oleandrin poisoning is mainly based on description of the plant, how much of it was ingested, time since ingestion, and symptoms.[1]

Three methods are used for detecting oleandrin in the blood. Fluorescence polarization immunoassay is widely used. This test is slower and has a lower sensitivity than digoxin immunoassay (Digoxin III).[11] A direct analytic technique like liquid chromatography-electrospray tandem mass spectrometry is used when there are medical or legal issues.[12]

Treatment

[edit]

Oleander toxicity should be treated aggressively, including as needed gastric lavage or induced emesis.[1] Onset of symptoms may vary with the way of intake. Teas made of leaves or root of N. oleander give rise to a more acute onset, while eating raw leaves causes a slower onset of symptoms.[13] Management of oleandrin poisoning is done in the following steps:[14]

There is a lack of evidence that weighs efficacy versus harm.[15] Activated charcoal is still used, since it binds toxins in the gastrointestinal tract to reduce absorption. It is uncertain whether repeated administration of activated charcoal is effective, in theory interrupting enterohepatic cycling. This treatment is used for digoxin poisoning, another cardiac glycoside.[16] Supportive care like monitoring vitals and electrolyte and fluid balance is important. Patients may present hypovolemic due to vomiting and diarrhea, but severely elevated potassium can also occur.[17] Electrolyte balance is vital, since patients with low cardiac glycoside levels can still die after adequate digoxin Fab antibody treatment if they have disturbed electrolyte levels.[18]

Treatment of slow heart rate and heart rhythm irregularities may require intravenous isoprenaline or atropine.[19] In moderate cases, prolonging of the PR interval and progression to AV dissociation, cardiac pacing is used.[20]

The effectiveness of all these interventions is unknown and are associated with side-effects. Therefore, consultation with a cardiologist is recommended when managing significant N. Oleander induced arrhythmias.[17] The use of anti-digoxin Fab IV has proven successful in cases of oleandrin poisoning[21]

A dose of 400 mg is used in digoxin poisoning, but a dose of 800 mg is recommended for oleandrin poisoning due to the lower binding affinity of the antibody to oleandrin.[22][23] Patients receiving an adequate dose of anti-digoxin Fab show a good response, resolving serious arrhythmias in two hours in fifty percent of the cases. Treated patients showed a rapid increase in heart rate and a significant decline in serum potassium levels.[23] The reason anti-digoxin Fab is sparingly used in developing countries is its high cost, even though it is such an effective treatment.[24]

Traditional medicine

[edit]

Although oleander has been used in traditional medicine for treating various disorders, there is no evidence that it is safe or effective for any medicinal purpose.[1]

Political controversy

[edit]

During the COVID-19 pandemic, Donald Trump's Secretary of Housing and Urban Development Ben Carson, and MyPillow CEO Mike Lindell, a major Trump booster and an investor in a company that develops oleandrin, promoted oleandrin as a potential treatment of the disease in a July 2020 Oval Office meeting with Trump, who expressed enthusiasm for the substance.[25][26][27][28] These claims were widely regarded by scientists as dubious, misleading, and alarming, as well as having no clinical proof of safety or effectiveness.[25][28][29]

The unproven claims of benefit further caused concern among scientists that the Trump administration might force unwarranted FDA approval of oleandrin as a safe and effective treatment for COVID-19 infection.[26][28][29] However, on 14 August 2020, the FDA rejected the application for marketing an oleandrin dietary supplement by Phoenix Biotechnology, Inc. – the manufacturer of the product – due to concerns that oleandrin would not be safe to consume.[30]

Effects on animals

[edit]

Oleandrin poisoning by eating oleander leaves can be lethal at low dosages.[31] Cases of sheep lethality have been reported to only one leaf of oleander.[9] Symptoms present in poisoned animals include bloody diarrhea and colic, the latter especially in horses. Because the leaf itself is quite bitter, only starving animals will be likely to eat the plant. The lethal dosage for animals is estimated to be about 0.5 mg/kg.[9]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Oleandrin

View on Grokipedia
from Grokipedia

Oleandrin is a highly lipid-soluble cardiac glycoside toxin derived from the leaves and other parts of the oleander plant (Nerium oleander), consisting of the aglycone oleandrigenin linked to a 2,6-dideoxy-3-O-methyl-α-L-arabino-hexopyranosyl sugar moiety. Like other cardiac glycosides, oleandrin exerts its primary pharmacological effect by inhibiting the Na⁺/K⁺-ATPase pump in cell membranes, which disrupts ion gradients and leads to increased intracellular calcium, enhanced cardiac contractility at low doses, but severe cardiotoxicity—including arrhythmias, hyperkalemia, and potentially fatal ventricular fibrillation—at higher exposures due to its narrow therapeutic index. While historically employed in traditional herbal medicine for purported diuretic and emetic properties, oleandrin's extreme toxicity has resulted in numerous documented human poisonings and deaths from accidental or intentional ingestion, with no approved therapeutic uses in modern pharmacopeia owing to safer alternatives like digoxin. Recent preclinical research has explored its cytotoxicity against cancer cells via mechanisms such as apoptosis induction, cell cycle arrest, and immunogenic cell death, though clinical translation remains limited by dose-dependent toxicities. In vitro studies have also indicated antiviral effects against certain enveloped viruses, including bovine pathogens, at subtoxic concentrations, highlighting potential but unproven mechanistic insights into membrane disruption.

Chemical Properties

Molecular Structure and Reactivity


Oleandrin possesses the molecular formula C32H48O9 and a molar mass of 576.72 g/mol. It is classified as a cardenolide glycoside, comprising the aglycone oleandrigenin—a bufadienolide-like steroid with a tetracyclic core, a β-oriented hydroxyl at C14, an α-acetoxy at C16, and a five-membered α,β-unsaturated γ-lactone ring fused at C17—and linked via a β-glycosidic bond at C3 to oleandrose, a 2,6-dideoxy-3-O-methyl-α-L-arabino-hexopyranose sugar unit. The full IUPAC name is (3β,5β,16β)-16-(acetyloxy)-3-{[(2,6-dideoxy-3-O-methyl-α-L-arabino-hexopyranosyl)oxy]}-14-hydroxycard-20(22)-enolide, highlighting the specific stereochemistry and functional groups essential to its chemical identity. The structural features confer , enabling in and organic solvents such as DMSO (≥19 mg/mL). Key reactive sites include the glycosidic linkage, which undergoes acid-catalyzed to release oleandrigenin and oleandrose, a process that enhances absorption in biological systems. Under basic conditions, the C16 is susceptible to elimination reactions, potentially altering the aglycone's conformation. The α,β-unsaturated ring exhibits electrophilic character, prone to , though this reactivity is more pronounced in enzymatic or biological contexts than in standard chemical assays. These properties underscore oleandrin's instability in aqueous acidic or basic environments, necessitating careful handling in extraction and .

Synthesis and Biosynthesis

Oleandrin is biosynthesized in oleander through enzymatic transformations that assemble the cardenolide aglycone oleandrigenin and attach the L-oleandrose moiety at the 3β-position. Studies using cell suspension cultures of N. oleander demonstrate the plant's capacity to glycosylate exogenous cardenolide aglycones, such as digitoxigenin and gitoxigenin, into their 3-O-β-D-glucosides and further diglycosides, highlighting the role of UDP-glycosyltransferases in the final steps of formation. Similar biotransformations occur with precursors like 5βH-pregnan-3β-ol-20-one, which are hydroxylated and glycosylated to yield compounds akin to oleandrin intermediates, confirming active enzymatic machinery for cardenolide maturation . The upstream biosynthesis parallels general cardenolide pathways in , initiating from derived via the , followed by P450-mediated hydroxylations at C-5β, C-14β, C-16β (with subsequent ), and side-chain modification to the 17β-(20S)-butenolide ring. L-oleandrose is likely synthesized from GDP-D-mannose via epimerization and 2,6-dideoxygenation, though specific genes and enzymes in N. oleander remain incompletely characterized. Production can be enhanced in untransformed plant cell cultures by supplementing phytohormones, increasing oleandrin yields alongside other metabolites. Chemical total synthesis of oleandrin addresses the challenges of its sterically hindered ring D and deoxy sugar. The aglycone oleandrigenin has been synthesized in 12 steps from a bicyclic enone intermediate, delivering a 3.9% overall yield through stereoselective aldol additions and oxidative modifications to install the 16β-acetoxy and butenolide functionalities. Glycosylation is achieved via α-selective coupling of L-oleandrose donors, such as activated L-oleandral derivatives, to oleandrigenin under conditions promoting axial stereochemistry at the anomeric center, completing the natural product in high efficiency. These routes enable analog preparation for structure-activity studies, though scalability remains limited by the complexity of the polycyclic core. Oleandrin is a cardenolide, a subclass of cardiac glycosides featuring a steroidal aglycone with a five-membered α,β-unsaturated ring attached at the C-17 position and typically a sugar moiety at C-3. Cardenolides differ from bufadienolides, the other major subclass, which possess a six-membered ring; oleandrin's cardenolide structure confers high lipid solubility and potent Na+/K+-ATPase inhibition similar to other members of this group. Structurally, oleandrin's aglycone, oleandrigenin, shares the core nucleus with hydroxyl groups at C-3, C-5, C-11, C-14, and an at C-10, but variations in sugar chains (e.g., oleandrose in oleandrin) and substituents distinguish it from congeners. Prominent related cardenolides include and , derived from species such as foxglove ( and Digitalis lanata), which feature digitoxose sugars and a hydroxyl or hydrogen at C-12, respectively, enabling therapeutic use in via positive inotropic effects despite overlapping profiles with oleandrin. , sourced from and Acokanthera plants, exhibits a similar steroid backbone with a sugar and hydroxyls at C-1, C-5, C-11, and C-19, resulting in rapid absorption and strong cardioactive potency comparable to oleandrin's. Convallatoxin from lily-of-the-valley (Convallaria majalis) shares the cardenolide but includes a rhamnose-strophanthobiose , contributing to its historical use in cardiac tonics with akin to oleandrin ingestion cases. Within Nerium oleander, oleandrin co-occurs with structurally analogous cardenolides like odoroside A (differing by a glucose instead of oleandrose sugar, yielding reduced endothelial cytotoxicity but retained anticancer activity) and adynerin, which features modifications in the aglycone leading to varying Na+/K+-ATPase binding affinities. These relatives underscore the chemotaxonomic diversity of cardenolides, where subtle structural differences modulate pharmacokinetics, such as oleandrin's higher lipophilicity versus digoxin's polarity, influencing bioavailability and therapeutic windows. Cross-reactivity in digoxin immunoassays with oleandrin and similar cardenolides complicates clinical diagnosis of poisoning.

Natural Sources and Pharmacokinetics

Occurrence in Plants

Oleandrin, a lipid-soluble , occurs primarily in Nerium oleander L. (family ), an evergreen shrub native to the Mediterranean Basin and widely cultivated in temperate and subtropical regions for ornamental purposes. The compound is distributed throughout the plant, including stems, leaves, flowers, buds, nectar, and sap, with all parts exhibiting toxicity due to its presence. Concentrations of oleandrin vary by part and , with the highest levels typically found in leaves, rendering them the most hazardous. Red-flowered varieties generally contain elevated content, including oleandrin, relative to white-flowered forms. Reported oleandrin levels in N. oleander tissues approximate 0.08% by weight, though values range from 0.18 to 0.31 mg/g dry weight across roots, leaves, stems, and flowers, with roots showing maximal accumulation followed by leaves. , such as in cooked or burned material, does not degrade oleandrin. Oleandrin is not documented in other plant species at biologically significant levels; related cardiac glycosides like thevetin A occur in Thevetia peruviana (yellow oleander), but this species lacks oleandrin. N. oleander's production of oleandrin serves as a mechanism, contributing to its against herbivores.

Extraction and Isolation Methods

Oleandrin, a lipophilic cardiac glycoside, is primarily extracted from the leaves of Nerium oleander, where concentrations are highest among plant parts, using organic solvents such as methanol, ethanol, or chloroform due to its poor water solubility. Early isolation efforts date to 1861, when it was first obtained from oleander, though specific procedural details from that era remain undocumented in modern literature. A documented method for extraction from flowers involves initial defatting of powdered material with hexane-diethyl ether-acetic acid (50:50:1 v/v), followed by extraction of glycosides including oleandrin using chloroform-methanol (1:1.7 v/v). The resulting fractions are separated via thick-layer on 2 mm plates or on 250 µm Kieselgel F254 plates, employing multiple solvent systems such as chloroform-methanol-water mixtures; oleandrin is identified in specific fractions (e.g., F3) by visualization with or reagents, matching retention and color reactions to standards. For leaf material, solvent extraction with or via maceration or Soxhlet apparatus is common, followed by concentration and purification through preparative layer on , where oleandrin elutes in defined solvent fronts and is quantified spectrophotometrically post-isolation. (HPTLC) has been applied for both isolation from plant extracts and forensic purification from sticky latex juice, using plates developed in ethyl acetate-methanol-water (100:13.5:10 v/v) and detection at 254 nm or via derivatization. Patented processes for obtaining oleandrin-enriched extracts include heating 100 g powdered dried leaves and stems with 900 g leaf juice (pH 3.7-4.1) at 80-85°C for 5 hours without agitation, followed by cooling, decanting, straining, and through 0.5-1 µm screens to yield a fraction substantially free of debris. Advanced isolation from crude extracts often employs liquid chromatography-mass spectrometry (LC-MS/MS) or (HPLC) for final purification and verification, with oleandrin confirmed by retention times (e.g., 1.2 min in optimized systems) and mass spectra matching standards like m/z 518 for [M+Na]+. These chromatographic techniques ensure separation from co-occurring glycosides such as odoroside and neritaloside, though yields vary with plant part, season, and environmental factors.

Absorption, Metabolism, and Excretion

Oleandrin, a lipophilic , is rapidly absorbed from the following , with peak plasma concentrations (Cmax) achieved within 10–20 minutes in murine models. Oral varies across studies, estimated at approximately 30% in pure form and up to 61.6% when administered as part of a Nerium oleander extract, reflecting potential enhancements in absorption due to co-occurring plant matrix components. This rapid uptake is attributed to its high solubility, facilitating passive diffusion across intestinal membranes, though saturation of absorption sites may occur at higher doses. Metabolism of oleandrin primarily occurs in the liver and intestines via Phase I enzymatic processes, including to its aglycone form, oleandrigenin, and potentially or demethylation mediated by enzymes. The conversion to oleandrigenin reduces the sugar moiety, yielding a with retained but altered biological activity, as observed in both and studies. Limited data indicate minimal involvement of specific CYP isoforms, with speculation on enzymatic deglycosylation rather than extensive oxidative , contributing to its relatively slow clearance compared to other cardiac glycosides like . Excretion of oleandrin and its metabolites occurs predominantly via the fecal route through biliary , accounting for approximately 66% of elimination, with renal clearance contributing about 8% via . The elimination following oral dosing is around 2.3 hours in mice, shorter after intravenous administration (0.4 hours), while human estimates range from 2.3 hours to 5–22 hours depending on individual factors such as hepatic function. This hepatobiliary dominance underscores the liver's central role in , with incomplete urinary excretion potentially prolonging systemic exposure and risk in overdose scenarios.

Mechanism of Action

, a , primarily acts by binding to and inhibiting the Na⁺/K⁺-ATPase enzyme on cell membranes, disrupting the of sodium and potassium ions essential for maintaining cellular electrochemical gradients. This inhibition elevates intracellular sodium concentrations, which in turn impairs the sodium-calcium exchanger (NCX), reducing calcium extrusion and causing a net increase in cytosolic calcium levels. In cardiac myocytes, the resulting calcium overload enhances calcium release during , thereby increasing at therapeutic-like doses, akin to other cardiac glycosides such as . However, excessive inhibition leads to delayed afterdepolarizations and triggered arrhythmias due to prolonged duration and oscillatory calcium transients. Oleandrin shows preferential affinity for the α3 subunit isoform of Na⁺/K⁺-ATPase, which is abundant in neuronal and cardiac tissues, contributing to its potent cardiotoxic profile. Beyond cardiac effects, Na⁺/K⁺-ATPase inhibition in non-cardiac cells, including tumor cells, triggers downstream signaling cascades such as elevated production, stress, and activation of apoptotic pathways via caspase-independent mechanisms like PERK/eIF2α//CHOP. This culminates in immunogenic and antiproliferative effects observed , though these are extensions of the primary pump inhibition rather than independent actions. Secondary interactions, such as suppression, have been reported but appear contingent on disruption.

Toxicity Profile

Acute and Chronic Toxicity in Humans

Oleandrin, a found in oleander, exhibits high in humans primarily through of contaminated plant material, leading to rapid onset of gastrointestinal and cardiovascular disturbances. Common initial symptoms include severe , , , and , often progressing within hours to cardiac manifestations such as , atrioventricular blocks, ventricular dysrhythmias, and due to inhibition of the Na⁺/K⁺-ATPase pump. Blood oleandrin concentrations of 1–2 ng/mL are typically associated with toxic effects, while levels of 9.8–10 ng/mL or higher have been linked to fatal outcomes in documented cases. Numerous case reports detail acute poisonings, often from attempts involving oleander leaves, blooms, or extracts like boiled infusions, with fatalities resulting from acute circulatory failure or arrhythmias despite medical intervention. Non-fatal cases have shown recovery with supportive care, including antiarrhythmic therapy and digoxin-specific antibodies, though with oleandrin is variable. In one series, imbalances and electrocardiographic changes, such as prolonged QT intervals and ST depressions, were prevalent in acute exposures to oleander containing oleandrin. Chronic toxicity from oleandrin in s is poorly documented and rare, as exposures are typically acute rather than sustained low-level. However, repeated or prolonged low-dose ingestion may lead to cumulative effects, manifesting as depression, anorexia, and visual disturbances like halos around lights, akin to chronic digitalis toxicity. Oleandrin's narrow exacerbates risks in any chronic scenario, potentially causing insidious , though no large-scale studies confirm specific thresholds or long-term sequelae beyond acute case extrapolations. Veterinary and anecdotal data suggest possible hepatic and renal involvement in subacute exposures, but evidence remains limited to indirect associations in endemic regions with habitual contact.

Clinical Symptoms and Diagnosis

Ingestion of oleandrin, the principal cardiotoxic glycoside in Nerium oleander, typically produces gastrointestinal symptoms within 30 minutes to 2 hours, including nausea, profuse vomiting, abdominal pain, and diarrhea, which may contain blood. These are followed by cardiovascular manifestations resembling digitalis toxicity, such as bradycardia, atrioventricular (AV) block, ventricular dysrhythmias, hypotension, and bidirectional ventricular tachycardia. Hyperkalemia is a common electrolyte abnormality, often correlating with severity and poor prognosis if untreated. Neurological effects like dizziness, lethargy, confusion, seizures, or coma may occur in severe cases, particularly with yellow oleander (Thevetia peruviana), though less emphasized in Nerium poisoning. Diagnosis begins with clinical suspicion in patients presenting with a history of oleander exposure—common in suicidal ingestions or accidental plant contact—and compatible symptoms of combined gastrointestinal distress and cardiac dysrhythmias. (ECG) reveals characteristic changes, including , PR prolongation, AV dissociation, or ventricular ectopy, aiding differentiation from other causes. Laboratory findings support this, with elevated serum (>5.0 mEq/L) and nonspecific elevations in or CK-MB indicating myocardial involvement. Confirmatory involves detection of oleandrin or related glycosides in blood, , or gastric contents via liquid chromatography-mass spectrometry (LC-MS), though this is not routinely available; alternatively, immunoassays show cross-reactivity (up to 80-100% for oleandrin), providing a rapid screening proxy with levels often exceeding 2 ng/mL in symptomatic cases. Identification of plant fragments in emesis or confirms exposure but requires botanical expertise. In non-endemic regions, awareness of oleander's ornamental prevalence is crucial to avoid misdiagnosis as primary cardiac or infectious etiologies.

Treatment of Oleandrin Poisoning

Treatment of oleandrin poisoning primarily involves supportive care, as no specific antidote exists for oleandrin itself, though digoxin-specific Fab antibody fragments (such as DigiFab) are administered empirically due to structural and functional similarities between oleandrin and digoxin, both inhibiting the Na+/K+-ATPase pump. In cases of severe toxicity, such as life-threatening arrhythmias or hyperkalemia, a typical dose of 5-10 vials (200-400 mg) of Fab fragments has been used successfully, titrated based on clinical response rather than serum levels, as oleandrin assays are not routinely available. Gastrointestinal is recommended if occurred within 1-2 hours, using single- or multiple-dose activated charcoal (1 g/kg initially, followed by 0.5 g/kg every 4-6 hours for up to 72 hours) to interrupt enterohepatic recirculation and reduce absorption, though evidence for multiple doses is stronger in related poisonings like yellow oleander. may be considered in early presentations with protected airway, but emesis induction is contraindicated due to risk of aspiration from oleander's irritant effects. is not typically indicated unless large amounts of plant material are involved. Patients require continuous cardiac monitoring with serial ECGs to detect arrhythmias, including , , or ventricular ectopy, which occur in up to 20-30% of symptomatic cases. and conduction delays are managed with atropine (0.5-1 mg IV, repeatable), while ventricular arrhythmias respond to lidocaine (1-1.5 mg/kg IV bolus followed by infusion) or ; avoid class Ia/III antiarrhythmics or beta-blockers, as they may exacerbate toxicity. , a hallmark of severe from Na+/K+-ATPase inhibition, is treated with insulin-dextrose infusion (10 units insulin with 50 mL 50% dextrose), if acidotic, and avoidance of calcium salts, which can potentiate cardiac effects; temporary cardiac pacing is reserved for refractory or high-degree blocks with heart rates below 40 bpm. Supportive measures include intravenous fluid resuscitation for from and , antiemetics for gastrointestinal symptoms, and supplemental oxygen or if respiratory compromise develops. imbalances beyond , such as hypomagnesemia, should be corrected, and is ineffective for oleandrin removal due to high protein binding and but may aid refractory . Prognosis improves with early intervention, with mortality under 5% in managed cases at tertiary centers, though delayed presentation increases risks of fatal arrhythmias.

Effects on Animals and Veterinary Cases

Oleandrin exerts potent cardiotoxic effects in multiple animal species, primarily through inhibition of Na+/K+-ATPase, leading to hyperkalemia, arrhythmias, and gastrointestinal distress following ingestion of Nerium oleander plant material. Affected species include dogs, cats, horses, cattle, sheep, goats, and others, with all plant parts containing the toxin at concentrations sufficient to cause poisoning even in small quantities. Clinical manifestations typically onset within 30 minutes to several hours, encompassing hypersalivation, vomiting, diarrhea, colic, tachycardia, irregular heartbeats, tremors, seizures, and sudden death. In livestock, toxicity thresholds are low; for cattle, the oral LD50 of oleander leaves is approximately 50 mg/kg body weight, resulting in acute signs like ruminal atony, serous nasal discharge, , and cardiac failure. Experimental administration of 50 mg/kg oleander leaves to calves induced fatal outcomes with pathological evidence of myocardial and congestion. Horses are particularly susceptible, with as little as 30-50 g (about 1 ) of green leaves proving lethal, causing , arrhythmias, and death within 8-10 hours due to oleandrin-induced . In sheep, a single oral dose of 110 mg/kg dried leaves led to depression, arrhythmias, and histopathological changes including epicardial hemorrhages. Veterinary cases underscore the risks in grazing or accidental exposure scenarios. An outbreak in dairy cattle exposed to contaminated feed on July 24, 2020, presented with severe depression, anorexia, diarrhea, and irregular heartbeats, confirming oleandrin transfer into milk and highlighting zoonotic contamination potential. In a September 2025 incident, inhalation of oleandrin-laden smoke from burning oleander trimmings killed 76 of 205 beef cattle within 30 hours, with necropsy revealing pulmonary edema and cardiac glycoside-positive tissues despite no ingestion. Companion animals face similar perils; dogs ingesting oleander exhibit vomiting, irregular heartbeats, and neurological signs like tremors, while cats show comparable GI and cardiac responses. Treatment focuses on and supportive care, as no specific exists. Activated charcoal (2-5 g/kg orally) binds residual in ruminants and monogastrics, while intravenous fluids address and imbalances; antiarrhythmics such as lidocaine or manage refractory . Prognosis varies with dose and intervention speed, with survival reported in cases like a hospitalized for six days in February 2023 after oleander ingestion, recovering via fluid therapy and monitoring despite initial arrhythmias and renal compromise. Early digoxin-specific Fab fragments have shown promise in experimental settings but lack routine veterinary approval.

Historical and Traditional Uses

Ancient and Ethnomedicinal Applications

Oleander (Nerium oleander), the primary natural source of oleandrin, has been documented in ancient Greco-Roman texts primarily for its potent toxicity rather than widespread therapeutic applications, though limited remedial uses were noted. Pedanius Dioscorides, in his 1st-century AD pharmacopeia De Materia Medica, described oleander leaves and flowers, when consumed with wine, as a potential remedy against snakebites, reflecting an early recognition of its pharmacological effects despite inherent dangers. Similarly, classical authors including Dioscorides and Pliny the Elder acknowledged its use as an antidote for venomous bites when combined with rue (Ruta graveolens), attributing this to its cardiac glycoside content, which could induce emesis or counteract toxins, though such applications carried high risks of fatal overdose. These references underscore oleander's dual perception in antiquity as both a hazard and a crude counterpoison, with no evidence of systematic empirical validation. In ethnomedicinal practices, particularly in regions where N. oleander grows natively such as the Mediterranean, , , and , various plant parts—including leaves, roots, flowers, and extracts rich in oleandrin—have been employed for diverse ailments, often leveraging its cardiotonic properties from cardiac glycosides. Traditional Indian folk medicine utilized root decoctions for treating , ulcers, skin conditions, and , while leaf preparations addressed cardiac illnesses, , epilepsy, , corns, , and wounds. In Turkish folklore, oleander served to alleviate , severe pains, swellings, and common colds, with roots applied topically for dermal issues. Other documented uses include effects, management of , , ringworm, , and venereal diseases, as well as applications for cancer and congestive in broader traditional systems. These ethnomedicinal applications persisted despite awareness of oleander's lethality, often involving diluted preparations to mitigate risks from oleandrin and related glycosides, which inhibit Na+/K+-ATPase and can cause arrhythmias or gastrointestinal distress. Historical accounts emphasize empirical trial-and-error over controlled dosing, with variability in preparation methods contributing to inconsistent outcomes and occasional poisonings, highlighting the causal link between its bioactive compounds and both intended effects and toxicity. No ancient or traditional sources provide quantitative data on efficacy, and modern reviews attribute reported benefits to unverified pharmacological actions rather than rigorous evidence.

Documented Historical Cases

Reports from the CE, attributed to Libantius, describe a case of from meat roasted on oleander skewers, resulting in symptoms such as agitation, , syncope, and death among affected individuals. During the , multiple incidents of oleander were documented among French troops in . In 1809 near , 12 soldiers experienced toxicity after cooking meat on oleander branches used as skewers, leading to 5 deaths and subsequent bans on the practice. A similar event in 1857 in affected over 300 soldiers amid food scarcity, causing widespread illness and fatalities from the same inadvertent exposure. In 1841 in Northern , 5 soldiers became ill after stirring barley with an oleander stick but recovered within 8 days following treatment. These military cases underscore accidental via oleander in resource-limited settings, though retrospective analyses suggest some accounts may stem from unverified reports or urban legend-like transmissions rather than primary eyewitness documentation. Historically, intentional oleander ingestions for or have been rare compared to accidental exposures, with most verified fatalities involving small quantities sufficient to cause toxicity from oleandrin and related compounds.

Potential Therapeutic Applications

Cardiovascular Effects

Oleandrin exerts its primary cardiovascular effects through inhibition of the Na⁺/K⁺-ATPase pump in cardiac myocytes, leading to an accumulation of intracellular sodium. This sodium buildup indirectly inhibits the Na⁺/Ca²⁺ exchanger, resulting in elevated cytosolic calcium concentrations that enhance calcium release from the during . The increased calcium availability strengthens myocardial contractions, producing a positive inotropic effect that can improve in failing hearts. This mechanism mirrors that of established cardiac glycosides like , which are employed clinically to manage congestive by augmenting contractility and reducing symptoms of low output. Preclinical studies have demonstrated oleandrin's distribution to cardiac tissues and its capacity to induce stronger contractions in isolated cardiomyocytes, suggesting analogous therapeutic utility for or arrhythmias where enhanced inotropy is desired. However, oleandrin's solubility facilitates rapid tissue penetration, including to the heart, but also contributes to a narrow , with effective doses approaching toxic levels that provoke delayed afterdepolarizations and ventricular arrhythmias. Despite historical traditional applications and the shared pharmacological profile with approved glycosides, oleandrin lacks clinical endorsement for cardiovascular due to its pronounced profile, including dose-dependent bradyarrhythmias, , and potential for fatal from pump inhibition. Animal models, such as canine hemodynamic assessments, have shown transient reductions in at sublethal doses, underscoring the challenges in achieving sustained benefits without adverse electrophysiological disruptions. Ongoing prioritizes its anticancer properties over cardiovascular indications, with no large-scale human trials validating safe inotropic use.

Anticancer Research

Oleandrin, a derived from oleander, has demonstrated preclinical anticancer activity primarily through inhibition of the Na+/K+-ATPase pump, leading to elevated intracellular calcium levels, stress, and subsequent in cancer cells. studies across multiple cancer types, including , , , colon, pancreatic, and cells, show oleandrin reduces , induces arrest at G2/M phase, and triggers DNA damage responses such as phosphorylation of H2AX and activation of /ATR kinases. For instance, in human cell lines, oleandrin activates caspase-dependent via mitochondrial pathways and enhances sensitivity to TRAIL-induced death by upregulating death receptors DR4 and DR5 at both mRNA and protein levels. Systematic reviews of and data indicate oleandrin's antitumor effects extend to 19 cancer types, with mechanisms including immunogenic that promotes antitumor immunity through exposure and ATP release. In murine models of mammary and , oleandrin administered intraperitoneally at doses of 0.1–0.56 mg/kg reduced tumor volume by up to 80% and inhibited , though efficacy varied by cancer type and was often accompanied by at higher doses. Derivatives like odoroside A exhibit similar potency, suggesting structural modifications could mitigate while preserving anticancer effects. Clinical evidence remains limited, with no dedicated trials for purified oleandrin due to its narrow and inherent toxicity. Extracts enriched in oleandrin, such as PBI-05204 (containing 10–20% oleandrin), have undergone phase I and II testing; a 2020 phase II trial in advanced pancreatic ductal reported stable in some patients at doses of 0.14–0.33 mg/kg orally, attributing activity to oleandrin's cytotoxic component, though overall response rates were modest and cardiac monitoring was required. Earlier phase I studies of Anvirzel (another oleandrin-containing extract) in advanced cancer patients documented tolerability up to 0.6 mg/ IV but highlighted risks of arrhythmias, underscoring the need for cardioprotective strategies. Despite promising preclinical with chemotherapeutics like , human translation is hindered by oleandrin's profile, which mirrors digoxin's risks, and lack of randomized controlled trials confirming efficacy beyond extracts.

Antiviral and Other Antimicrobial Properties

Oleandrin has demonstrated antiviral activity primarily against enveloped viruses. Studies indicate that nanogram concentrations of oleandrin, when administered prophylactically or therapeutically, inhibit replication in cell cultures by up to 3,000-fold, reducing infectious virus production through mechanisms that disrupt protein incorporation into virions. This effect extends to other enveloped viruses, including HIV-1, where oleandrin acts as a inhibitor of replication, potentially by interfering with viral assembly. Additional research shows broad-spectrum inhibition against viruses such as virus (BVDV), bovine (BRSV), and bovine (BCV), with dose-dependent reductions in viral titers when oleandrin or oleander extracts containing it are applied prior to infection. The antiviral mechanism of oleandrin is linked to its ability to alter host cell membrane dynamics and inhibit viral egress, rather than direct virucidal action, as evidenced by reduced incorporation of envelope glycoproteins into progeny virions across multiple enveloped models. assays with defined oleander extracts enriched in oleandrin (e.g., PBI-05204) confirm significant suppression of infectivity, with values in the low nanomolar range, though these findings are limited to cell-based systems and have not been replicated for most viruses. Regarding other antimicrobial properties, evidence for oleandrin's direct antibacterial or antifungal effects is sparse and primarily inferred from Nerium oleander extracts containing it, rather than isolated compound studies. Crude oleander flower extracts exhibit moderate antibacterial activity against Gram-positive bacteria such as Staphylococcus aureus and Bacillus subtilis, with minimum inhibitory concentrations (MICs) around 0.5–2 mg/mL, but show limited efficacy against Gram-negative strains like Escherichia coli. Antifungal activity has been reported in extracts against pathogens like Fusarium oxysporum and wood-decay fungi, attributed partly to cardiac glycosides including oleandrin disrupting fungal membrane integrity. However, purified oleandrin lacks robust standalone data for non-viral antimicrobials, with most claims relying on plant matrix synergies rather than isolated effects. No clinical evidence supports oleandrin's use as an antibacterial or antifungal agent, and its narrow therapeutic index limits exploration.

Modern Research and Clinical Evidence

Preclinical Studies

Preclinical investigations of oleandrin, a derived from oleander, have primarily utilized cell culture models and limited animal studies to evaluate its therapeutic potential against cancer, viral infections, and cardiovascular conditions, often revealing mechanisms tied to Na⁺/K⁺-ATPase inhibition but constrained by dose-dependent . In , oleandrin demonstrates across multiple cell lines by inducing stress and immunogenic (ICD). For instance, in human cells ( at 15 nM, MDA-MB-231 at 25 nM, T47D at 12.5 nM), it activates the PERK/eIF2α/ATF4/CHOP pathway, leading to (CRT) exposure on the cell surface within 10 hours, ATP secretion peaking at 12 hours, and release at 24-48 hours, independent of activity. These damage-associated molecular patterns (DAMPs) promote dendritic cell maturation (upregulating and ) and enhance T-cell-mediated in co-culture assays. , at 0.6 mg/kg in tumor-bearing mice reduced tumor weight by 2.66-fold compared to controls, correlating with increased immune infiltration. Similar apoptotic effects via have been observed in gastric cancer xenografts, though broader efficacy remains inconsistent due to cardiac thresholds. Antiviral preclinical data emphasize oleandrin's activity against enveloped in vitro, with mechanisms potentially involving interference with viral entry or replication. Against in Vero E6 cells, prophylactic treatment at 0.05 µg/mL yielded an 800-fold reduction in viral production, escalating to over 3,000-fold at 0.1 µg/mL, with EC₅₀ values of 11.98 ng/mL (24 hours) and 7.07 ng/mL (48 hours); therapeutic post-infection dosing at 0.05-0.1 µg/mL achieved 78- to over 100-fold reductions without up to 130 µg/mL for related extracts. Complementary studies confirm inhibition of infectivity and HTLV-1 virological synapse formation, while extracts containing oleandrin blocked porcine like porcine reproductive and respiratory virus. In vivo, a defined N. oleander extract (PBI-06150, oleandrin-enriched) reduced nasal turbinate titers in hamsters, supporting translation potential despite absent direct oleandrin animal antiviral data. Cardiovascular preclinical models underscore oleandrin's positive inotropic effects akin to other cardiac glycosides, achieved via Na⁺/K⁺-ATPase blockade and elevated intracellular calcium, but with species-specific risks. In anesthetized dogs with intact circulation, oleandrin enhanced cardiac contractility without initial arrhythmias at low doses, mirroring digoxin-like actions. However, escalating doses beyond 6.9 μg/kg induced electrocardiographic abnormalities, including ventricular ectopy, in dogs monitored via , establishing a narrow margin where therapeutic benefits invert to . Neuroprotective extensions in rat models via extract formulations (PBI-05204) suggest oleandrin-mediated benefits at subtoxic levels, though pure compound cardiovascular data prioritize profiling over . Overall, these studies affirm oleandrin's multimodal bioactivity but necessitate refined dosing to mitigate cardiac hazards observed across models.

Human Trials and Observational Data

A phase I clinical trial of Anvirzel, a patented aqueous extract of Nerium oleander leaves containing oleandrin as a primary cardiac glycoside, evaluated its safety and maximum tolerated dose in 15 patients with advanced refractory solid tumors. The trial, conducted between 2004 and 2005, administered intravenous doses escalating from 0.1 to 3.125 mg/m² daily for 21 days per cycle, identifying 0.775 mg/m² as the maximum tolerated dose with primarily mild gastrointestinal adverse events and no dose-limiting cardiotoxicity observed. Disease stabilization occurred in some patients, but no objective tumor responses were reported, limiting conclusions on efficacy. Another phase I trial explored sublingual Anvirzel in patients with advanced , aiming to determine the highest tolerable dose when combined with standard . Initiated in 2012 and completed by 2015, this study enrolled participants but reported no published efficacy outcomes, focusing instead on and in a small cohort. Similarly, preclinical extensions to human lines suggested potential antiproliferative effects, but higher-phase trials confirming therapeutic benefits in humans remain absent. No randomized controlled trials or phase III studies of oleandrin-containing extracts have demonstrated clinical for anticancer, antiviral, or other therapeutic applications in s. For , while data indicated inhibition, no trials have been conducted, and regulatory bodies have explicitly warned against its use due to insufficient and risks. Observational data on oleandrin exposure in humans derive predominantly from incidents, highlighting its narrow therapeutic window and cardiotoxic potential. A of acute oleander cases reported electrocardiographic abnormalities in up to 15% of patients, including , atrioventricular blocks, and ventricular arrhythmias, with mortality rates ranging from 3-10% depending on dose and intervention timeliness. Toxicological analyses in fatal cases confirmed elevated oleandrin levels in blood and tissues, correlating with digoxin-like and , underscoring the compound's lethality even in non-therapeutic contexts. These reports, spanning global case series from regions with oleander prevalence, provide no evidence of incidental therapeutic benefits but consistently affirm dose-dependent cardiac risks.

Limitations and Ongoing Developments

Despite promising preclinical data, oleandrin's clinical translation is severely limited by its narrow therapeutic window, where efficacious doses closely approximate toxic thresholds, primarily due to potent inhibition of the Na⁺/K⁺-ATPase pump leading to , gastrointestinal distress, and potentially fatal arrhythmias. Ingestion of as little as 4 grams of oleander leaf, containing oleandrin, has proven lethal in humans, underscoring the compound's high potency and risk of accidental or intentional . This toxicity profile, compounded by complex including variable and rapid onset of adverse effects, restricts safe dosing and necessitates rigorous monitoring, akin to other cardiac glycosides like . Human clinical evidence remains inadequate, with most research confined to and animal models showing inconsistent efficacy across indications such as cancer and viral infections; phase I/II trials have been small, non-randomized, and often industry-sponsored, limiting generalizability and raising concerns over bias in outcome reporting. No large-scale, placebo-controlled randomized trials have established long-term safety or superiority over standard therapies, partly due to ethical challenges in testing a known . Ongoing developments focus on mitigating through purified extracts like Anvirzel™ (containing oleandrin as the active component) for anticancer applications, with preclinical studies exploring synergies with to enhance selectivity. Pharmacokinetic trials, such as NCT04674709 evaluating oleandrin in healthy volunteers, continue to inform dosing strategies, though and completion remain pending as of 2023 data. Recent reviews emphasize the need for advanced delivery systems, such as nanoparticles, to widen the , but regulatory hurdles and toxicity precedents slow progression to phase III trials. Antiviral research persists , yet human validation lags, prioritizing mechanistic studies over immediate clinical deployment.

Controversies and Regulatory Status

Promotion as COVID-19 Treatment

In August 2020, oleandrin, a extracted from the toxic oleander plant, was promoted as a potential treatment for primarily by , CEO of MyPillow and a financial supporter of then-President Donald Trump. Lindell, who had donated over $100,000 to Trump's campaign, claimed during media appearances that oleandrin represented a "miracle cure" capable of addressing the pandemic, citing preliminary studies suggesting antiviral activity against SARS-CoV-2. The promotion intensified after a July 2020 meeting attended by Trump, Lindell, Phoenix Biotechnology executive Dr. Robert Newman, and FDA officials, where an oleandrin extract (PBI-05204) was pitched for . Trump reportedly described the compound as "very interesting" and expressed interest in fast-tracking its approval, though no such authorization followed due to insufficient clinical . Phoenix Biotechnology, the developer, referenced lab data from Newman showing oleandrin's inhibition of in cell cultures, but emphasized these findings were not from human trials. Lindell and proponents argued oleandrin's mechanism—disrupting viral envelopes—could offer broad-spectrum antiviral effects, drawing parallels to its historical use in , but without randomized controlled trials for . Efforts to market it as a were rejected by the FDA on September 4, 2020, citing lack of safety data for that use, followed by a December 2020 warning letter to Phoenix Biotechnology for unsubstantiated health claims. Despite the hype, no regulatory body approved oleandrin for treatment, and poison control centers issued alerts against self-administration due to its documented toxicity.

Scientific and Medical Criticisms

functions as a that potently inhibits the Na+/K+-ATPase pump, elevating intracellular calcium levels and precipitating , ventricular arrhythmias, and potentially fatal , even at sub-milligram doses in humans. Documented cases confirm lethality from ingestion of oleander plant parts containing oleandrin, with postmortem analyses revealing elevated oleandrin concentrations correlating to acute cardiac toxicity as the . A of incidents reports high morbidity, including , , and gastrointestinal distress, underscoring oleandrin's role in substantial global healthcare burdens from accidental or intentional exposures. The compound's narrow poses a primary barrier to clinical viability, as doses required for purported anticancer or antiviral effects approximate those inducing , rendering safe dosing regimens elusive in practice. Preclinical veterinary studies indicate cardiac abnormalities emerge at oleandrin doses exceeding 6.9 μg/kg, with gastrointestinal manifesting as dose-dependent and prolonged recovery times. Pharmacokinetic limitations, including low aqueous solubility, poor polarity, and erratic due to rapid tissue distribution, exacerbate risks of unpredictable profiles. Professional toxicology bodies, such as the American College of Medical Toxicology, American Academy of Clinical Toxicology, and American Association of Poison Control Centers, have jointly cautioned that oleandrin constitutes a cardiac poison capable of inducing bradycardia, irregular rhythms, and death, advising against its extraresearch application absent rigorous evidence of benefit. Reported adverse reactions from therapeutic extracts encompass nausea, vomiting, diarrhea, fatigue, injection-site pain, and neurological effects like tremors or coma, often mirroring raw plant poisoning symptoms. Despite demonstrations of against cancer cells or virions, translational critiques emphasize the paucity of phase III human trials establishing superior to , with preclinical promise failing to materialize into approved indications due to overriding safety concerns. Additive risks with concurrent cardiac glycosides like further contraindicate use in vulnerable populations. or extract forms have similarly yielded acute toxicities, as evidenced by mass fatalities from airborne oleandrin exposure.

Regulatory Approvals and Restrictions

Oleandrin has not received approval from the for any therapeutic indication in humans, despite investigational use in clinical trials. Extracts containing oleandrin, such as PBI-05204 from Phoenix Biotechnology, received designation in 2008 for treating malignant pleural and have progressed to Phase I and II trials for anticancer applications, but these do not constitute marketing authorization. The has emphasized that oleandrin remains unapproved for and efficacy in treating any disease, including , due to insufficient evidence from controlled human studies and known risks of cardiac toxicity. In response to a June 2, 2020, New Dietary Ingredient (NDI) notification by Phoenix Biotechnology seeking to market oleandrin as a supplement ingredient, the FDA rejected the submission on August 14, 2020. The agency ruled that oleandrin was ineligible under the Dietary Supplement Health and Education Act of 1994, as it had been subject to substantial clinical investigations as a new drug prior to the notification, disqualifying it from supplement status. On December 15, 2020, the FDA issued a warning letter to Phoenix Biotechnology for unlawfully promoting oleander extracts containing oleandrin to treat or prevent and other conditions without an approved , citing violations of the Federal Food, Drug, and Cosmetic Act for unproven claims and lack of substantial evidence. Internationally, oleandrin lacks marketing approval from regulatory authorities such as the (EMA), with no records of authorization for human therapeutic use in major jurisdictions. organizations, including the American College of Medical , American Academy of Clinical , and American Association of Poison Control Centers, issued a joint statement in August 2020 strongly advising against oleandrin use outside FDA-supervised , highlighting its potent toxicity profile akin to other cardiac glycosides, which can cause severe arrhythmias and gastrointestinal distress at low doses. Regulatory restrictions stem primarily from these safety concerns, with oleander-derived products generally prohibited from over-the-counter sale or self-administration due to documented poisoning risks.

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