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PLANTS-PROTOANEMONIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Protoanemonin is the lactone of gamma-hydroxyvinylacrylic acid and is formed from glycoside precursors, most likely ranunculosides or ranoculins. It is further converted to anemonin (Frohne & Pfander, 1983).
    B) It is found in species of the Anemone, Caltha, Ceratocephalus, Clematis, Helleborus, Myosurus, and Ranunculus genera (Cooper & Johnson, 1984; Ruijgrok, 1966). Protoanemonin has also been studied for its antibiotic and antileukemic activity (Bonora et al, 1985).

Specific Substances

    1) 4-hydroxy-2,4-pentadienoic acid gamma-lactone
    2) 5-methylene-2(5H)-furanone
    3) 5-methylene-2-oxodihydrofuran
    4) Anemone camphor
    5) Pulsatilla N.F.

Available Forms Sources

    A) SOURCES
    1) Protoanemonin is formed enzymatically from ranunculin found in various plant genera including Anemone, Caltha, Clematis, Ceratocephalus, Helleborus, Myosurus, Ranunculus, and possibly Actaea (Didry et al, 1993).
    2) The concentration of protoanemonin found is extremely variable, even within a genus (Didry et al, 1993). Protoanemonin is unstable and is converted to the inactive dimer anemonin upon drying or heating (Shearer, 1938). Protoanemonin can be obtained by steam distillation, alkaline hydrolysis, or by crushing the plant tissues containing the oil (Didry et al, 1993). The highest concentrations are found during the flowering period (Cooper & Johnson, 1984).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Plants containing protoanemonin have an acrid taste and cause a burning sensation in the mouth and throat. Protoanemonin must be formed enzymatically from ranunculin, so the immediacy of a burning sensation will vary depending upon the amount of protoanemonin present.
    B) Human ingestions producing systemic symptoms are rare, possibly due to the bad taste and oral pain. If ingested, abdominal pain, diarrhea, oral pain and ulceration, hematemesis, and severe gastroenteritis may occur.
    0.2.4) HEENT
    A) Visual impairment and loss has been seen in animals. Lacrimation and conjunctivitis has also been seen.
    B) Both the nose and the throat may be irritated. Prolonged sneezing is possible.
    0.2.7) NEUROLOGIC
    A) Paralysis and seizures have been seen in animals, and dizziness in both animals and humans.
    0.2.8) GASTROINTESTINAL
    A) Ulceration of the mouth and throat may occur. Other symptoms include vomiting, abdominal pain, diarrhea, and salivation.
    0.2.10) GENITOURINARY
    A) Renal damage has been seen in animals who have ingested large quantities of plants containing protoanemonin.
    0.2.12) FLUID-ELECTROLYTE
    A) Patient should be monitored for electrolyte abnormalities.
    0.2.14) DERMATOLOGIC
    A) Blisters and hyperpigmentation have been reported after exposure.

Laboratory Monitoring

    A) Routine laboratory analysis will not detect protoanemonin. Monitor patients with vomiting and/or diarrhea for adequate fluid intake and electrolytes.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Serious exposures involving humans are rare. Treatment is directed at maintaining adequate fluid and electrolyte concentrations. There is no specific antidote.
    B) Decontamination is often accomplished by the plant itself since vomiting and diarrhea are primary symptoms. Serious intoxications with systemic absorption should be observed and treated symptomatically for the occurrence of seizures or renal damage.
    C) Lavage may be considered in cases where large amounts have been ingested.
    D) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    E) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    F) Demulcents are generally recommended by texts, but there have been no studies to indicate their usefulness.
    G) Adequate hydration and urine flow should be maintained to reduce concentration of protoanemonin in the urine.
    H) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 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) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 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).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    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 place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) A toxic serum level or amount of ingestion has not been established.
    B) Small amounts may cause local irritation.

Clinical Effects

Summary Of Exposure

    A) Plants containing protoanemonin have an acrid taste and cause a burning sensation in the mouth and throat. Protoanemonin must be formed enzymatically from ranunculin, so the immediacy of a burning sensation will vary depending upon the amount of protoanemonin present.
    B) Human ingestions producing systemic symptoms are rare, possibly due to the bad taste and oral pain. If ingested, abdominal pain, diarrhea, oral pain and ulceration, hematemesis, and severe gastroenteritis may occur.

Heent

    3.4.1) SUMMARY
    A) Visual impairment and loss has been seen in animals. Lacrimation and conjunctivitis has also been seen.
    B) Both the nose and the throat may be irritated. Prolonged sneezing is possible.
    3.4.3) EYES
    A) Visual impairment or loss has been reported with ANIMALS grazing on protoanemonin containing plants. exposure. This has yet to be reported in humans (Cooper & Johnson, 1984).
    B) LACRIMATION due to irritation may be seen after ocular contact (Lampe & Fagerstrom, 1968).
    C) CONJUNCTIVITIS may be seen after ocular contact (Lampe & Fagerstrom, 1968).
    3.4.5) NOSE
    A) SNEEZING and nasal congestion may be seen if there has been contact with nasal membranes (Lampe & Fagerstrom, 1968).
    3.4.6) THROAT
    A) Chewing may result in acute burning of the throat and possible ulceration (Lampe & McCann, 1985).

Cardiovascular

    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEART DISORDER
    a) Although cardiotoxicity has been suggested in animal studies, it has not been a common finding in human poisonings (Osol & Farrar, 1955).

Neurologic

    3.7.1) SUMMARY
    A) Paralysis and seizures have been seen in animals, and dizziness in both animals and humans.
    3.7.2) CLINICAL EFFECTS
    A) SYNCOPE
    1) Syncope and dizziness may occur after absorption (Lampe & Fagerstrom, 1968).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PARALYSIS
    a) Animals have experienced hindleg paralysis after ingestion (Cooper & Johnson, 1984).
    2) SEIZURES
    a) Animals have experienced seizures after ingestions and it has been suggested as a potential symptom after severe human exposure (Cooper & Johnson, 1984; Lampe & Fagerstrom, 1968).

Gastrointestinal

    3.8.1) SUMMARY
    A) Ulceration of the mouth and throat may occur. Other symptoms include vomiting, abdominal pain, diarrhea, and salivation.
    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL IRRITATION
    1) Mild to strong irritation of the mouth and gastrointestinal tract may occur (Kelch et al, 1992). Ulceration or vesication of the mouth and throat may occur with chewing ((Russell, 1997); Didry et al, 1993; Lampe & McCann, 1985).
    B) VOMITING
    1) Vomiting is a common symptom and may become bloody (Lampe & McCann, 1985).
    C) ABDOMINAL PAIN
    1) Abdominal pain is a frequent symptom following ingestion by both humans and animals (Cooper & Johnson, 1984).
    D) DIARRHEA
    1) Diarrhea, sometimes bloody, may be seen after ingestion (Cooper & Johnson, 1984; Lampe & McCann, 1985).
    E) EXCESSIVE SALIVATION
    1) Salivation may be profuse after ingestion by either humans or animals (Lampe & McCann, 1985; Cooper & Johnson, 1984).

Genitourinary

    3.10.1) SUMMARY
    A) Renal damage has been seen in animals who have ingested large quantities of plants containing protoanemonin.
    3.10.2) CLINICAL EFFECTS
    A) POLYURIA
    1) Polyuria and painful urination may be seen if the toxin is absorbed by humans (Klaassen et al, 1986).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEPHROPATHY TOXIC
    a) Renal damage has been seen with ANIMALS who have ingested plants containing protoanemonin. Urine may be bloody (Cooper & Johnson, 1984).

Dermatologic

    3.14.1) SUMMARY
    A) Blisters and hyperpigmentation have been reported after exposure.
    3.14.2) CLINICAL EFFECTS
    A) BULLOUS ERUPTION
    1) This compound has direct vesicant action and may cause blisters of the skin and mucous membranes (Lampe & McCann, 1985; Aaron & Muttitt, 1964; Duke, 1985). The foliage of Anemone patens has caused itching, burning, erythema, edema and bullae formation (Vance, 1982).
    B) DISCOLORATION OF SKIN
    1) Hyperpigmentation was seen after dermal exposure to the leaves and stems of protoanemonin containing Anemone species (Vance, 1982; Aaron & Muttitt, 1964) Mitchell & Rook, 1972).
    C) CONTACT DERMATITIS
    1) Contact dermatitis has been reported with buttercup (Ranunculus) exposure (Rudzki & Dajek, 1975).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) URTICARIA
    a) DOG - Urticaria in a dog was seen, possibly an allergic reaction (Winters, 1976).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Routine laboratory analysis will not detect protoanemonin. Monitor patients with vomiting and/or diarrhea for adequate fluid intake and electrolytes.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor the patient for adequate fluid and electrolyte concentrations if significant vomiting and diarrhea has occurred.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Routine laboratory analysis will not detect protoanemonin. Several methods exist to quantitate this compound, including paper and thin layer chromatography, colorimetry and spectrophotometry.
    2) The most sensitive methods are by normal and reverse phase HPLC (Bonora et al, 1985; Bruni et al, 1986).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Routine laboratory analysis will not detect protoanemonin. Monitor patients with vomiting and/or diarrhea for adequate fluid intake and electrolytes.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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).
    6.5.2) PREVENTION OF ABSORPTION
    A) GASTRIC LAVAGE
    1) The strong irritant action of the plants usually causes vomiting. Lavage might be considered in cases were large amounts have been ingested (Lampe & McCann, 1985).
    2) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    3) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    4) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    5) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    6) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    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) Serious exposures involving humans are rare. Treatment is directed at maintaining adequate fluid and electrolyte concentrations. There is no specific antidote.
    B) DEMULCENT
    1) Are generally recommended by texts, but there have been no studies to indicate their usefulness (Lampe & McCann, 1985; Cooper & Johnson, 1984; Klaassen et al, 1986).
    C) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Adequate hydration and urine flow should be maintained to reduce the concentration of protoanemonin in the urine and; therefore, its irritant action (Klaassen et al, 1986).
    D) SEIZURE
    1) Seizures have not been a common effect in either human or animal poisonings.
    2) 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).
    3) 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 .
    4) 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).
    5) 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).
    6) 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).
    7) 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).
    E) SUPPORT
    1) Supportive care should be administered for those cases experiencing renal damage, polyurea, or hematuria.

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) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

Summary

    A) A toxic serum level or amount of ingestion has not been established.
    B) Small amounts may cause local irritation.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) PULSATILLA - Is the powdered plant containing protoanemonin. The dose used by eclectics as a strong local irritant was 120 to 600 milligrams (Osol & Farrar, 1955).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) A toxic level has not been established. Although lethal outcomes have been seen in animals, human fatalities have not been reported.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Osol & Farrar (1955) state that 20 milligrams/kilogram is a powerful depressant to the CNS and heart. This figure could not be substantiated in other literature.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) Have not yet been established.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 190 mg/kg (Martin et al, 1990)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Protoanemonin inhibits mitosis in plant cells (Erickson, 1948). It is also known to be an antifungal and antibacterial (aerobes and anaerobes). Minimal inhibitory concentrations ranged from 8 mcg/mL to 62.5 mcg/mL during in-vitro testing. It has also been shown to have synergistic effects with several antibiotics (Didry et al, 1993).

Toxicologic Mechanism

    A) Protoanemonin reacts readily with SH groups. Its toxic action as a sub-epidermal vesicant may depend on its proposed ability to inactivate enzymes containing SH groups, especially those used in glycolysis (Frohne & Pfander, 1983). Protoanemonin may block SH groups in bacterial enzymes and is known to penetrate bacterial cells (Didry et al, 1993).
    B) It is capable of inhibiting the acantholytic effect of cantharidin (Mitchell & Rook, 1979).
    C) Protoanemonin is detoxified by a dienelactone hydrolase produced by various species of Pseudomonas. This enzyme degrades protoanemonin to cis-acetylacrylate (Bruckman et al, 1998). This enzyme is not available clinically, and has not been tested.

Physicochemical

Physical Characteristics

    A) Protoanemonin has a pale yellow color and a burning, acrid taste.

Molecular Weight

    A) PROTOANEMONIN: 96.08

Animal Toxicology

Clinical Effects

    11.1.2) BOVINE/CATTLE
    A) Ingestion of Ranunculus bulbosus by an 18-month-old heifer resulted in urticaria, bilateral ocular discharge, diarrhea, dehydration, blistering, scabbing, and cracking.
    1) CBC found leukocytosis and neutrophilia with a left shift. Liver enzymes were elevated.
    2) The heifer was diagnosed as having photosensitization and subsequent hepatotoxicity from ingestion of the above plant (Kelch et al, 1992).
    11.1.3) CANINE/DOG
    A) URTICARIA was seen in a dog, possibly an allergic reaction (Winters, 1976).

References

General Bibliography

    1) AB Russell : Poisonous Plants of North Carolina. North Carolina State University. Raleigh, NC. 1997. Available from URL: http://www.ces.ncsu.edu/depts/hort/consumer/poison/Anemosp.htm. As accessed Accessed on 7/11/01.
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