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PLANTS-DAPHNE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Daphne mezereum is a common hedge and shrub in the United States and Europe. The bark contains daphnetoxin and the fruits about 0.04% mezerein .
    B) These toxins are related to the phorbol esters seen in members of the Euphorbiaceae family.
    C) Daphne species considered to be dangerous include: D. mezereum, D. laureola, D. cneorum, D. gnidium, and D. genkwa .

Specific Substances

    A) Daphne caucasica
    1) Caucasian daphne
    Daphne cneorum
    1) Garland Daphne
    2) Garland Flower
    3) Rose daphne
    Daphne feddei
    1) Daphine feddei
    2) Ding Ruei Xan (Chinese)
    Daphne genkwa
    1) Yuan Hua (Chinese)
    2) Lilac daphne
    Daphne giraldii
    1) Giraldi daphne
    Daphne koreane
    1) Chang Bai Ruei Xiang (Chinese)
    Daphne laureola
    1) Spurge laurel
    Daphne mezereum
    1) Bark (Cortex Mezerei)
    2) Dwarf Bay
    3) Ecorce de mexereon (French)
    4) February Daphne (alternative scientific name)
    5) Flax olive
    6) Fruit (Fructus Coccognidii)
    7) Kellerhalsrinde (German)
    8) Lady Laural
    9) Magell
    10) Mezereon
    11) Mysterious Plant
    12) Olive spurge
    13) Paradise Plant
    14) Seidelbastrinde (German)
    15) Spurge Flax
    16) Wild Pepper
    Daphne odora
    1) Winter Daphne

Available Forms Sources

    A) FORMS
    1) Mezereum is the dried bark (and unofficially the seed) from the aerial parts of Daphne mezereum, D. gnidium, and D. laureola. It was formerly used in medicine as a vesicant and epispastic (Budavari, 1989).
    a) The bark is known to contain mezerein, daphnin, umbelliferone, acrid resin, and a fixed oil (Budavari, 1989).
    b) The seeds contain acrid resin and a fixed oil (Budavari, 1989).
    2) The coumarins (daphnin, daphnetin, daphnetin 8-glucoside, daphnoretin, and esculin) have been isolated from the Daphne species (Ulubelen et al, 1986).
    3) The flavinoids (apigenin 7-glucoside, luteolin 7-glucoside, luteolin 4'- glucoside, isovitexin, vicenin 2, and quercetin 3-glucoside) have been isolated from Daphne gnidioides (Ulubelen et al, 1986).
    4) Daphnane is a diterpene ester isolated from Daphne feddei (Dagang, 1991).
    5) Extracts from Daphne giraldii (Nitsche)(DGN) is a commercial product available in the Peoples Republic of China.
    B) USES
    1) At one time this plant was used as a counterirritant for gout, arthritis, and other illnesses (Frohne & Pfander, 1984). The sap was applied to the skin of those who wished to beg to create wounds for sympathy.
    2) Mezerein from Daphne mezereum has demonstrated anti-tumor activity, possible secondary to activation of the cytotoxic activity of lymphocytes. It was investigated as a therapeutic agent, but was deemed too toxic for therapeutic use (Ulubelen et al, 1986; Barton et al, 1989). Mezerein is also potent anti-inflammatory agent.
    3) Odorocin from Daphne odora is used as a nematocide (Ulubelen et al, 1986; Keeler & Tu, 1983).
    4) The roots of Daphne genkwa has been used as an abortifacient (Ulubelen et al, 1986).
    5) Yuanhuafin from Daphne genkwa has been used as an abortifacient (Ulubelen et al, 1986).
    6) Daphnetin isolated from the dried root and stem of Daphne koreane (Nakei) is used in Chinese folk medicine to improve blood circulation. It has been shown to be effective in the treatment of angina pectoris and arthritis (Huang, 1993).
    7) Subcutaneous administration of extracts from Daphne giraldii (Nitsche)(DGN), a commercial product available in the Peoples Republic of China, in a rat model of chronic Pseudomonas aeruginosa lung infection produced increased clearance of bacteria from the lung and altered inflammatory process in the lung. Antimicrobial activity was not demonstrated (Song et al, 1996).
    8) The powdered bark of Daphne gnidium has been used as an abortifacient in the Mediterranean (Lewis & Elfin-Lewis, 1977).
    9) These toxins are related to the phorbol esters seen in members of the Euphorbiaceae family (Frohne & Pfander, 1984).
    10) Daphne species considered to be dangerous include: D. mezereum, D. laureola, D. cneorum, D. gnidium, and D. genkwa (Evans, 1986; Tampion, 1977).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) BACKGROUND: A deciduous rounded shrub that grows 4 to 5 feet in height. It is a cultivated ornamental found throughout the United States, Canada, the mountains of Europe, and in Siberia. Daphne mezereum is a common hedge and shrub in the United States and Europe. The bark contains daphnetoxin and the fruits about 0.04% mezerein. Of the numerous daphne species, the following species are considered more toxic: D. mezereum, D. laureola, D. cneorum, D. gnidium, and D. genkwa.
    B) TOXICOKINETICS: All parts of the plant are considered to be toxic including the flower. The toxins identified: daphnin, the glucoside of daphnetin (a hydroxycoumarin), and mezerein (a vesicant).
    C) EPIDEMIOLOGY: These plants have a long history of toxicity, however, there are few cases reported in the literature and only one recent case D. caucasica exposure that resulted in no toxicity.
    D) WITH POISONING/EXPOSURE
    1) SUMMARY: Limited experience. Toxicity appears to vary depending on the particular species. Adverse events associated with these species are based on historical reports of toxicity in a limited number of cases. Ingestion of the fruits, flowers, bark, or roots may cause burning or ulceration of the throat, mouth, and stomach, nausea, vomiting, bloody diarrhea, weakness, dehydration, electrolyte imbalance, coma and death. The acute clinical picture has been described as being similar to that of appendicitis. Toxicity is reportedly still present even after the plant is dried.
    2) DERMAL: Contact with the sap can cause skin irritation which may progress from mild erythema to edema and blister formation. Juice from the berries or bark may be absorbed through broken skin in sufficient amounts to produce systemic symptoms.
    3) INGESTION: MILD TO MODERATE TOXICITY: Nausea, vomiting, and oral irritation can develop, along with irritation, blistering and swelling of the lips and throat. Abdominal pain and persistent, watery, or bloody diarrhea may also occur. Persistent symptoms may lead to fluid loss and electrolyte imbalance. Kidney damage leading to hematuria and albuminuria may occur. Drowsiness, headache, and delirium can develop. CASE REPORT: A 4-year-old boy ingested 3 leaves of D. caucasica and was monitored for several hours and developed no symptoms. SEVERE TOXICITY: Muscle twitching may be seen in severe cases. In serious cases, stupor, delirium, disorientation, weakness, seizures, and coma may occur.
    4) OCULAR: Edema of the eyelids, lips and nostrils have been reported. It is anticipated to be an eye irritant.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

    A) Monitor for electrolyte imbalance in those patients with significant fluid loss due to vomiting and diarrhea.
    B) Monitor for albuminuria and hematuria.
    C) No specific, commonly used laboratory test is available to measure Daphne toxins either qualitatively or quantitatively.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Limited experience. Treatment is symptomatic and supportive. Dilution with milk or water may clear the material from the mouth and provide some demulcent action. Examine patients for evidence of oropharyngeal injury and possible blistering of the mouth and throat (D. mezereum is a vesicant) following ingestion. Pain relief may be accomplished by ice or analgesics, if necessary. Correct fluid and electrolyte abnormalities in patients that develop significant vomiting and/or diarrhea.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Limited experience. Treatment is symptomatic and supportive. Monitor vital signs and neurologic function. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) DECONTAMINATION
    1) PREHOSPITAL: Gastrointestinal decontamination may not be necessary, since some daphne species may cause spontaneous vomiting following ingestion. If the patient is not vomiting, dilution with milk or water may clear the material from the mouth and provide some demulcent action.
    2) HOSPITAL: Consider activated charcoal following a recent, significant ingestion, if the patient is not vomiting and the airway can be protected. Some daphne species can cause spontaneous vomiting.
    D) AIRWAY MANAGEMENT
    1) Airway support is unlikely to be necessary following a taste or mild exposure. Ensure adequate ventilation in patients that develop significant CNS symptoms, seizure activity or as indicated.
    E) ANTIDOTE
    1) There is no specific antidote.
    F) ENHANCED ELIMINATION
    1) No studies are available that describe the use of extracorporeal elimination techniques following ingestion of daphne species.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: An adult or child with a minor "taste" ingestion, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with an intentional ingestion, an asymptomatic child with an unknown (amount or type of) ingestion and those children who are symptomatic, may require monitoring for several hours to assess for oropharyngeal pain and/or blistering, gastrointestinal symptoms or electrolyte and fluid imbalance. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, electrolyte abnormalities and seizure activity.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) TOXICOKINETICS
    1) DAPHNE MEZEREUM SPECIES: All parts of the plant are considered to be toxic including the flower, but the fruits and seeds have been associated most frequently with toxicity. The toxins identified: daphnin, the glucoside of daphnetin (a hydroxycoumarin), and mezerein (a vesicant). Ingesting the fruit or chewing on the bark may cause oropharyngeal pain, vesication and dysphagia, which could be followed by gastrointestinal symptoms.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and irrigate exposed areas with copious amounts of water. A physician may need to examine the area if irritation or pain persists.

Range Of Toxicity

    A) TOXICITY: The exact toxic dose is unknown. The following are based on limited data from historical reports of toxicity in a small number of cases. It is commonly believed that one to a few of the drupes (berries) may be fatal in a child and 12 berries may be fatal in an adult. The mortality rate with ingestion has been as high as 30%. As few as one berry or leaf may cause symptoms. LACK OF EFFECT: PEDIATRIC: A 4-year-old boy ingested 3 leaves of D. caucasica and developed no symptoms.

Clinical Effects

Summary Of Exposure

    A) BACKGROUND: A deciduous rounded shrub that grows 4 to 5 feet in height. It is a cultivated ornamental found throughout the United States, Canada, the mountains of Europe, and in Siberia. Daphne mezereum is a common hedge and shrub in the United States and Europe. The bark contains daphnetoxin and the fruits about 0.04% mezerein. Of the numerous daphne species, the following species are considered more toxic: D. mezereum, D. laureola, D. cneorum, D. gnidium, and D. genkwa.
    B) TOXICOKINETICS: All parts of the plant are considered to be toxic including the flower. The toxins identified: daphnin, the glucoside of daphnetin (a hydroxycoumarin), and mezerein (a vesicant).
    C) EPIDEMIOLOGY: These plants have a long history of toxicity, however, there are few cases reported in the literature and only one recent case D. caucasica exposure that resulted in no toxicity.
    D) WITH POISONING/EXPOSURE
    1) SUMMARY: Limited experience. Toxicity appears to vary depending on the particular species. Adverse events associated with these species are based on historical reports of toxicity in a limited number of cases. Ingestion of the fruits, flowers, bark, or roots may cause burning or ulceration of the throat, mouth, and stomach, nausea, vomiting, bloody diarrhea, weakness, dehydration, electrolyte imbalance, coma and death. The acute clinical picture has been described as being similar to that of appendicitis. Toxicity is reportedly still present even after the plant is dried.
    2) DERMAL: Contact with the sap can cause skin irritation which may progress from mild erythema to edema and blister formation. Juice from the berries or bark may be absorbed through broken skin in sufficient amounts to produce systemic symptoms.
    3) INGESTION: MILD TO MODERATE TOXICITY: Nausea, vomiting, and oral irritation can develop, along with irritation, blistering and swelling of the lips and throat. Abdominal pain and persistent, watery, or bloody diarrhea may also occur. Persistent symptoms may lead to fluid loss and electrolyte imbalance. Kidney damage leading to hematuria and albuminuria may occur. Drowsiness, headache, and delirium can develop. CASE REPORT: A 4-year-old boy ingested 3 leaves of D. caucasica and was monitored for several hours and developed no symptoms. SEVERE TOXICITY: Muscle twitching may be seen in severe cases. In serious cases, stupor, delirium, disorientation, weakness, seizures, and coma may occur.
    4) OCULAR: Edema of the eyelids, lips and nostrils have been reported. It is anticipated to be an eye irritant.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) FEVER has been reported after ingestion or dermal absorption (Lampe & Fagerstrom, 1968).

Heent

    3.4.2) HEAD
    A) EDEMA of the lips, tongue, eyelids, nostrils, and pharynx may occur (Lampe & Fagerstrom, 1968; Turner & Szczawinski, 1991).
    3.4.3) EYES
    A) Eye irritation is possible.
    B) EYELID SWELLING and swelling of the nostrils occurred after chewing of the bark and fruit (Turner & Szczawinski, 1991).
    3.4.6) THROAT
    A) Ingestion is likely to cause irritation of the throat (Lampe & Fagerstrom, 1968; Turner & Szczawinski, 1991).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH POISONING/EXPOSURE
    a) Drowsiness which may lead to coma has occurred after ingestion (Westbrooks & Preacher, 1986).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures, along with signs of meningitis, may occur, but are uncommon (Noller, 1955).
    C) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headache may occur after either ingestion or dermal exposure (Lampe & Fagerstrom, 1968).
    D) DELIRIUM
    1) WITH POISONING/EXPOSURE
    a) Delirium and disorientation, alternating with periods of complete consciousness, may develop after ingestion (Noller, 1955).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL IRRITATION
    1) WITH POISONING/EXPOSURE
    a) A burning sensation of the mouth and corrosive lesions of the oral membranes can occur because the plant is intensely acrid (Kingsbury, 1964; Turner & Szczawinski, 1991). The toxin mezerein can act as a vesicant; chewing on the bark or ingesting the fruit can produce oropharyngeal pain, vesication and dysphagia (Nelson et al, 2007).
    B) VOMITING
    1) WITH THERAPEUTIC USE
    a) Vomiting occurs frequently (Frohne & Pfander, 1984; Kingsbury, 1964), but may resolve over 24 hours without treatment (Lamminpaa & Kinos, 1996).
    b) D. MEZEREUM: Ingesting the fruit or chewing on the bark may cause oropharyngeal pain, vesication and dysphagia, which could be followed by gastrointestinal symptoms (ie, vomiting, abdominal cramping, diarrhea) dehydration and electrolyte imbalance (Nelson et al, 2007).
    C) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) Abdominal pain is common (Lampe & Fagerstrom, 1968). The acute clinical picture may be similar to that of appendicitis (Noller, 1955).
    D) PHARYNGITIS
    1) WITH POISONING/EXPOSURE
    a) Edema of the lips, tongue, and pharynx may be seen (Lampe & Fagerstrom, 1968).
    E) EXCESSIVE SALIVATION
    1) WITH POISONING/EXPOSURE
    a) Salivation, dysphagia, and hoarseness may occur (Fuller & McClintock, 1986; Lampe & Fagerstrom, 1968).
    F) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Watery, bloody diarrhea may be persistent (Hardin & Arena, 1974).
    b) Bloody diarrhea and internal bleeding have been reported secondary to dihydroxycoumarin ingestion (Hardin & Arena, 1974).
    c) D. MEZEREUM: Ingesting the fruit or chewing on the bark may cause oropharyngeal pain, vesication and dysphagia, which could be followed by gastrointestinal symptoms (ie, vomiting, abdominal cramping, diarrhea) dehydration and electrolyte imbalance (Nelson et al, 2007).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) BLOOD IN URINE
    1) WITH POISONING/EXPOSURE
    a) Hematuria, albuminuria, and strangury have developed with daphne ingestion (Lampe & Fagerstrom, 1968).
    b) Hematuria, that persisted for 2 weeks, developed in a child after presumed ingestion of Daphne mezereum. The symptom resolved without treatment (Lamminpaa & Kinos, 1996).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) BULLOUS ERUPTION
    1) WITH POISONING/EXPOSURE
    a) Blistering and erythematous swelling may occur after contact with the sap (Evans & Schmidt, 1980).
    b) Seed fragments placed on human skin produced local erythema within 4 to 6 hours. Over the next 10 hours, the area swelled and pustules and blisters formed. The effects slowly disappeared over the next 48 hours (Frohne & Pfander, 1984). The fruit pulp does not contain the skin-irritant substances.

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) SPASMODIC MOVEMENT
    1) WITH POISONING/EXPOSURE
    a) Muscle twitching and general motor unrest may be observed after ingestion (Noller, 1955; Lampe & Fagerstrom, 1968).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    3.21.4) ANIMAL STUDIES
    A) NEOPLASM
    1) Mezerein, a phorbol ester, demonstrates moderate to considerable tumor- promoting activity when applied to mouse skin. Daphnane is also a tumor promoter (Keeler & Tu, 1991).
    2) Diterpene esters extracted from soil surrounding plants of the Thymelaeaceae family can induce mild Epstein-Barr virus activity. The authors speculate a possible interaction between the diterpene esters and Epstein-Barr virus disease such as nasopharyngeal carcinoma. This has not been scientifically investigated (Ito et al, 1983).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor for electrolyte imbalance in those patients with significant fluid loss due to vomiting and diarrhea.
    B) Monitor for albuminuria and hematuria.
    C) No specific, commonly used laboratory test is available to measure Daphne toxins either qualitatively or quantitatively.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor for electrolyte imbalance in those patients with significant fluid loss due to vomiting and diarrhea.
    2) Monitor renal function tests in patients with significant exposure for possible nephrotoxicity.
    3) No specific, commonly used laboratory test is available for monitoring levels of Daphne toxins either qualitatively or quantitatively.
    4.1.3) URINE
    A) URINALYSIS
    1) Monitor urinalysis for patients with significant exposure for possible nephrotoxicity.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, electrolyte abnormalities and seizure activity.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An adult or child with a minor "taste" ingestion, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with an intentional ingestion, an asymptomatic child with an unknown (amount or type of) ingestion and those children who are symptomatic, may require monitoring for several hours to assess for oropharyngeal pain and/or blistering, gastrointestinal symptoms or electrolyte and fluid imbalance. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor for electrolyte imbalance in those patients with significant fluid loss due to vomiting and diarrhea.
    B) Monitor for albuminuria and hematuria.
    C) No specific, commonly used laboratory test is available to measure Daphne toxins either qualitatively or quantitatively.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Gastrointestinal decontamination may not be necessary, since some daphne species may cause spontaneous vomiting following ingestion. If the patient is not vomiting, dilution with milk or water may clear the material from the mouth and provide some demulcent action.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Daphne will likely cause vomiting.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Limited experience. Treatment is symptomatic and supportive. Dilution with milk or water may clear the material from the mouth and provide some demulcent action. Examine patients for evidence of oropharyngeal injury and possible blistering of the mouth and throat (D. mezereum is a vesicant) following ingestion. Pain relief may be accomplished by ice or analgesics, if necessary. Correct fluid and electrolyte abnormalities in patients that develop significant vomiting and/or diarrhea.
    b) Even after care for the immediate effects, symptoms may persist for several days (Lampe & Fagerstrom, 1968).
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Limited experience. Treatment is symptomatic and supportive. Monitor vital signs and neurologic function. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    B) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) Remove contaminated clothing and jewelry and irrigate exposed areas with copious amounts of water. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) LACK OF INFORMATION
    1) No studies are available that describe the use of extracorporeal elimination techniques following ingestion of daphne species.

Range Of Toxicity

Summary

    A) TOXICITY: The exact toxic dose is unknown. The following are based on limited data from historical reports of toxicity in a small number of cases. It is commonly believed that one to a few of the drupes (berries) may be fatal in a child and 12 berries may be fatal in an adult. The mortality rate with ingestion has been as high as 30%. As few as one berry or leaf may cause symptoms. LACK OF EFFECT: PEDIATRIC: A 4-year-old boy ingested 3 leaves of D. caucasica and developed no symptoms.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) DAPHNE KOREANE - For improvement of blood circulation, the dried root and stem is administered intramuscularly in a dose of 3 grams (Huang, 1993).
    2) DAPHNE GIRALDII - For use as an analgesic, anti-inflammatory agent and an anti-bacterial agent, 250 milligrams is diluted with glucose and administered as an intravenous infusion (Huang, 1993).

Minimum Lethal Exposure

    A) SUMMARY
    1) The exact amount is unknown. It is commonly believed that one to a few of the drupes (berries) may be fatal in a child (Howard et al, 1974), and 12 may be fatal in an adult (Hardin & Arena, 1974; Lampe & Fagerstrom, 1968).
    2) The mortality rate with ingestion has been as high as 30% (Lampe & Fagerstrom, 1968).

Maximum Tolerated Exposure

    A) SUMMARY
    1) A maximum tolerated exposure has not been established. As few as one berry or leaf may cause symptoms (Lampe & Fagerstrom, 1968).
    2) DAPHNE MEZEREUM SPECIES: All parts of the plant are considered to be toxic including the flower, but the fruits and seeds have been associated most frequently with toxicity. The toxins identified: daphnin, the glucoside of daphnetin (a hydroxycoumarin), and mezerein (a vesicant). Ingesting the fruit or chewing on the bark may cause oropharyngeal pain, vesication and dysphagia, which could be followed by gastrointestinal symptoms (Nelson et al, 2007).
    B) CASE REPORTS
    1) D. LAUREOLA: A young child ate a few fruits of Daphne laureola, developed typical symptoms, and recovered without treatment (Turner & Szczawinski, 1991).
    2) D. CAUCASICA: A 4-year-old boy ingested 3 leaves of D. caucasica and developed no symptoms. He was monitored at home and treated with dilution and over the next 4 hours he remained asymptomatic and was able to tolerate a normal diet (Spiller & Willias, 2008).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) Daphne genkwa
    1) LD50- (INTRAPERITONEAL)RAT:
    a) 9.25 g/kg (dried flower and bark)
    B) Daphnetoxin
    1) LD50- (ORAL)MOUSE:
    a) 275 mcg/kg -- estimate (Frohne & Pfander, 1984)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Mezerein (mezerenic acid anhydride), found in Daphne mezereum, has been shown to possess antileukemic activity (Lampe & Fagerstrom, 1968; Ulubelen et al, 1986; Kupchan & Baxter, 1975). It is a vesicant. The antitumor activity appears to be connected to the ester found at position 12 of mezerein's structure (Nyborg & La Cour, 1975).
    B) Daphnin, a glucoside, has as its aglycone 7,8-dihydroxycoumarin, and is similar to the glycoside aesculin (Lampe & Fagerstrom, 1968).
    C) Luteolin, luteolin 7-methylether and tiliroside have been isolated from Daphne genkwa SEIB, and demonstrate biological activity (Nikaido et al, 1987).

Toxicologic Mechanism

    A) Mezerein and daphnetoxins are irritant diesters similar to the phorbol esters found in the Euphorbiacieae. They are among the most irritating substances known (Evans, 1986).
    B) DAPHNE MEZEREUM SPECIES: All parts of the plant are considered to be toxic including the flower, but the fruits and seeds have been associated most frequently with toxicity. The toxins identified: daphnin, the glucoside of daphnetin (a hydroxycoumarin), and mezerein (a vesicant). Ingesting the fruit or chewing on the bark may cause oropharyngeal pain, vesication and dysphagia, which could be followed by gastrointestinal symptoms (Nelson et al, 2007).

Animal Toxicology

Clinical Effects

    11.1.10) PORCINE/SWINE
    A) Lesions of inflammation and white patches that looked burned were seen in the gastrointestinal tract of pigs poisoned by Daphne. Vomiting was seen (Kingsbury, 1964).

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) DOG
    1) Twelve grams of powdered bark has been reported lethal to dogs used in experiments (Kingsbury, 1964).
    B) HORSE
    1) As little as 30 grams of bark may be fatal in a horse (Liebenow & Liebenow, 1981; Stout et al, 1970).
    C) SWINE
    1) As few as three berries may be fatal in pigs (Liebenow & Liebenow, 1981; Stout et al, 1970).

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