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PLANTS-SESQUITERPENE LACTONES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Many species contain sesquiterpene lactones which are generally concentrated in glands on the leaves, the roots, root bark, and flowers of certain species.

Specific Substances

    A) SESQUITERPENE LACTONES
    1) Ambrosanolides
    2) Bakkenolides
    3) Cadinanolides
    4) Chrymoranolides
    5) Elemanolides
    6) Eremophilanolides
    7) Eudesmanolides
    8) Germacranolides
    9) Guaianolides
    10) Helenanolides
    11) Seco-ambrosanolides
    12) Seco eudesmanolides
    13) Seco-germacranolides
    14) Seco-helenamolides
    15) Xanthanolides
    RELATED COMPOUNDS
    1) Alantolactone
    2) Amaralin
    3) Arbusculin B
    4) Aromaticin
    5) Arteglasin A
    6) Carpesiolin
    7) Chromolaenide
    8) Conchosin A
    9) Costunolide
    10) Damsinic acid
    11) Encelin
    12) Eupachlorin acetate
    13) Eupaserrin
    14) Farinosin
    15) Frullanolide
    16) Frutescin
    17) Helenalin
    18) Hymenovin
    19) Hymenoxynin
    20) Mexicanin E
    21) Milkanolide
    22) Neopulchellidine
    23) Parthenin
    24) Parthenolide
    25) Peroxyferolide
    26) Phantomolin
    27) Plenolin
    28) Psilostachyin B
    29) Pyrethrosin
    30) Sulferalin
    31) Tenulin
    32) Vernolepin
    33) Zaluzanin C

Available Forms Sources

    A) USES
    1) Artemisinin derivatives have been used in the treatment of complicated and uncomplicated malaria (Arnold, 1994; Davidson, 1994; JEF Reynolds , 2000).
    2) ANTIMICROBIAL EFFECT - Several sesquiterpene alkaloids have been shown to have antibacterial or antiprotozoan effects. These include: carpesiolin, chromolaenide, farinosin, helenalin, hymenovin, mexicanine, milkanolide, parthenin, phenolin and tenulin.
    a) Artemisinin is a sesquiterpene lactone with antimalarial activity. The endoperoxide linkage is the clinically active antimalarial constituent. Artemisinin (known in China as Qinghaosu) has been used in Chinese folk medicine to treat malarial diseases for centuries (Lee & Hufford, 1990).
    b) ANTHELMINTIC PROPERTIES - Several of the sesquiterpene lactones have anthelmintic properties, including costunolide, alphacyclocos tunolide, eremanthine, goyazen solide, and alpha santonin (Lee et al, 1971).
    3) INSECTICIDAL - Eight sesquiterpene lactones have shown mild activity as insecticide or insect antifeedants. Their primary activities, rather than being a contact insecticide, has been to inhibit larval insect growth and oviposition (Ivie & Witzel, 1983).
    4) PLANT GROWTH REGULATORS - At least 18 sesquiterpene lactones have been identified as plant growth regulators. This property has not been associated with a toxicologic effect (Ivie & Witzel, 1983).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Many plants contain sesquiterpene lactones. These plants are primarily livestock poisons. Sesquiterpene alkaloids are extremely bitter and are irritating to all mucous membranes.
    B) Humans are generally not poisoned orally, but may develop various allergic dermatoses. Toxic ingestions in humans are exceedingly rare. Other possibilities include ingestion of contaminated milk or meat, but this route of human poisoning is extremely unlikely.
    0.2.4) HEENT
    A) Plants containing these substances may cause irritation of nose, mouth, throat, and eyes.
    0.2.6) RESPIRATORY
    A) Acute congestion, edema, dyspnea, and pulmonary hemorrhages have been seen in poisoned animals.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) ANIMAL STUDIES - Muscle tremors and seizures have been seen in fatally poisoned animals; CNS depression has also been noted.
    0.2.8) GASTROINTESTINAL
    A) Loss of appetite, abdominal pain, vomiting, and bloating have all been symptoms seen in animals.
    0.2.9) HEPATIC
    A) Fatally poisoned animals have had edematous liver with vacuolar degeneration of hepatocytes.
    0.2.10) GENITOURINARY
    A) Glomerulonephrosis has been reported in animals.
    0.2.14) DERMATOLOGIC
    A) Sesquiterpene lactones are important causes of allergic contact dermatitis in humans. There are more than 50 species which are known to cause allergic contact dermatitis.
    0.2.17) METABOLISM
    A) Hypolipidemia and hypoglycemia have been reported in poisoned animals.
    0.2.20) REPRODUCTIVE
    A) Human and animal teratogenic potential is still unknown.

Laboratory Monitoring

    A) Thin layer chromatography has been used to identify sesquiterpene lactones. Sheep treated with hymenovin showed increases of BUN, creatinine, inorganic phosphorus, alkaline phosphatase, SGPT, SGOT, LDH, and CPK.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) SUMMARY
    1) Human poisonings are extremely rare. In cases of large ingestions or chronic administration of an herbal remedy containing these plants occur, patients should be observed for gastrointestinal, liver, and cardiac damage. Ingestion of a single flower or plant part is unlikely to cause human toxic effects.
    B) PREVENTION OF ABSORPTION
    1) Gastric decontamination is seldom necessary unless large amounts have been ingested. Ingestion of a single plant part is unlikely to produce human poisoning. Consider decontamination after large ingestions.
    C) DERMATITIS: Should be treated symptomatically. Consult a dermatologist concerning the necessity of antihistamines or steroids.
    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).
    D) 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.
    E) CNS DEPRESSION
    1) Respiratory and CNS support may be necessary in severely poisoned animals. These symptoms have not been seen in humans.
    F) HEPATITIS
    1) Liver enzymes should be evaluated to determine if hepatic damage has occurred. There is not a specific antidote; treatment is symptomatic.

Range Of Toxicity

    A) Sesquiterpene lactones appear to be much more toxic parenterally than orally. As much as 5 percent of the dry weight of some species may contain these compounds. The LD50's in animals orally, range from 50 to 1,000 mg/kg.

Clinical Effects

Summary Of Exposure

    A) Many plants contain sesquiterpene lactones. These plants are primarily livestock poisons. Sesquiterpene alkaloids are extremely bitter and are irritating to all mucous membranes.
    B) Humans are generally not poisoned orally, but may develop various allergic dermatoses. Toxic ingestions in humans are exceedingly rare. Other possibilities include ingestion of contaminated milk or meat, but this route of human poisoning is extremely unlikely.

Heent

    3.4.1) SUMMARY
    A) Plants containing these substances may cause irritation of nose, mouth, throat, and eyes.
    3.4.2) HEAD
    A) Sesquiterpene alkaloids are extremely bitter and are irritating to all mucous membranes. This may result in irritation of nose, mouth, throat, and eyes (Lamson, 1913).
    3.4.3) EYES
    A) IRRITATION may occur (Lamson, 1913).
    3.4.5) NOSE
    A) NASAL IRRITATION may be seen (Lamson, 1913).
    3.4.6) THROAT
    A) IRRITATION of the mucous membranes of the throat may be seen (Lamson, 1913).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) Bradycardia was reported in 10 of 34 patients who received artemether orally for 4 days for the treatment of malaria (JEF Reynolds , 2000).
    B) LACK OF EFFECT
    1) In single and multiple dose studies of parenteral arteether (artemisinin derivative) administration for malaria, no change in patients' ECGs were observed (Kager et al, 1994).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEMORRHAGE
    a) Epicardial hemorrhages have been seen on necropsy examination (Ivie & Witzel, 1983).

Respiratory

    3.6.1) SUMMARY
    A) Acute congestion, edema, dyspnea, and pulmonary hemorrhages have been seen in poisoned animals.
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PULMONARY EDEMA
    a) Acute congestion, edema and hemorrhages of the lungs have been seen on necropsy (Ivie & Witzel, 1983).
    2) DYSPNEA
    a) Dyspnea is often seen with terminally poisoned animals (Aanea, 1961).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) ANIMAL STUDIES - Muscle tremors and seizures have been seen in fatally poisoned animals; CNS depression has also been noted.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) LACK OF EFFECT
    a) In single and multiple dose studies of parenteral arteether (artemisinin derivative) administration, no neurological changes were reported (Kager et al, 1994).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CNS DEPRESSION
    a) CNS depression has been noted as an early clinical sign in poisoned animals. The depression becomes more severe as the poisoning progresses (Rowe et al, 1976).
    2) SEIZURES
    a) Muscle tremors and seizures may be seen in fatally poisoned animals (Ivie & Witzel, 1983; Cooper & Johnson, 1984).

Gastrointestinal

    3.8.1) SUMMARY
    A) Loss of appetite, abdominal pain, vomiting, and bloating have all been symptoms seen in animals.
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANOREXIA
    a) Loss of appetite and cessation of rumination may be seen early in animal intoxications (Rowe et al, 1976).
    2) ABDOMINAL PAIN
    a) Back arching and other behavior suggestive of abdominal pain are seen in animals poisoned by these substances (Ivie & Witzel, 1983).
    3) FLATULENCE
    a) Bloating is a common early symptom in animals (Ivie & Witzel, 1983).
    4) EDEMA
    a) Edema as well as hemorrhage and intestinal fluid retention have been noted (Ivie & Witzel, 1983).
    5) MELENA
    a) Blood stained feces has been seen in poisoned cattle (Cooper & Johnson, 1984).
    6) SALIVA INCREASED
    a) Salivation has been seen in fatally poisoned cattle (Cooper & Johnson, 1984).
    7) VOMITING
    a) Vomiting is another symptom which is often seen more commonly with Dugaldia and Geigeria species than with Helenium odorata (Ivie & Witzel, 1983).

Hepatic

    3.9.1) SUMMARY
    A) Fatally poisoned animals have had edematous liver with vacuolar degeneration of hepatocytes.
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATITIS
    a) The liver may be edematous and characterized by vacuolar degeneration of hepatocytes (Witzel et al, 1977).
    2) ENZYME ABNORMALITY
    a) A single (IP) dose of 25 mg helenalin/kg, in mice, resulted in an increased serum alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and sorbitol dehydrogenase within 6 hours of the dose (Chapman et al, 1988).
    b) Serum cholesterol and ALT levels were increased, in mice, following multiple (IP) injections of 25 mg helenalin/kg/day for 3 days (Chapman et al, 1988).
    c) Mice exposed to multiple (IP) injections of 25 mg helenalin/kg/day resulted in a profound inhibition of hepatic microsomal enzyme activities and hepatic microsomal cytochrome P-450 content (Chapman et al, 1988).
    d) Administration of helenalin (25 mg/kg) or hymenoxon (30 mg/kg) to mice resulted in a decrease in hepatic glutathione levels within 1 hour post-treatment. This decrease in glutathione proved to be lethal to more than 60% of the animals within 6 days (Merrill et al, 1988).

Genitourinary

    3.10.1) SUMMARY
    A) Glomerulonephrosis has been reported in animals.
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) GLOMERULONEPHRITIS
    a) Glomerulonephrosis characterized by proteinaceous casts, swollen and degenerated glomerular tufts, and degeneration and necrosis in the inner renal cortex and outer medulla (Ivie & Witzel, 1983).
    2) BUN INCREASED
    a) A single (IP) dose of 25 mg helenalin/kg, in mice, resulted in an increased BUN within 6 hours of the dose (Chapman et al, 1988).

Acid-Base

    3.11.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ACIDOSIS
    a) Metabolic acidosis with lactacidemia and pyruvemia has been seen in poisoned sheep (Witzel et al, 1974).

Dermatologic

    3.14.1) SUMMARY
    A) Sesquiterpene lactones are important causes of allergic contact dermatitis in humans. There are more than 50 species which are known to cause allergic contact dermatitis.
    3.14.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) Sesquiterpene lactones are important causes of allergic contact dermatitis in humans (Ross et al, 1993; Paulsen et al, 1993; Goncalo & Goncalo, 1991; Pinedo et al, 1987). Dermatitis in the Compositae family is due primarily to sesquiterpene lactones (Paulsen, 1992).
    2) An alpha-methylene group exocyclic to the gamma-lactone appears to be responsible for the allergic contact dermatitis associated with sesquiterpene lactones (Mitchell & Dupuis, 1971).
    B) HYPERSENSITIVITY REACTION
    1) CROSS-REACTIVITY - There is considerable cross-sensitivity to the sesquiterpene lactones (Ivie & Witzel, 1983).
    2) There are more than 50 plant species which contain sesquiterpene lactones and have been reported to cause allergic contact dermatitis.
    3) Some of the sesquiterpene lactones implicated in causing contact dermatitis are alanolactone, arbusculin B, arteglasin A, costunolide, 2-deacetoxyxanthinin, frullanolide, isoalantolactone, inusviscolide, parphenin and pyrethrosin (Mitchell & Rook, 1979; Bohlmann et al, 1977; Pinedo et al, 1987).

Immunologic

    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) WBC ABNORMAL
    a) Multiple (IP) injections of 25 mg helenalin/kg/day for 3 days, in mice, increased differential polymorphonuclear leukocyte counts and decreased lymphocyte counts and thymic cortical lymphocytes (Chapman et al, 1988).
    b) Chapman et al (1988) report pathological changes in the immune system of mice treated with helenalin and suggests that thymus-dependent lymphocytes may be a major target organ of helenalin toxicity.

Reproductive

    3.20.1) SUMMARY
    A) Human and animal teratogenic potential is still unknown.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) Human and animal teratogenic potential is still unknown (Ivie & Witzel, 1983).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Tenulin is excreted into bovine milk in amounts of 0.1% of the amount ingested. It is extremely bitter and detectable in concentrations as low as 1 part per million (Ivie et al, 1975).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) CYTOTOXICITY AND ANTITUMOR ACTIVITY - Several sesquiterpene lactones are known to be both cytotoxic and antitumor agents (Kupchan et al, 1971). At least part of their activity is due to enzyme inhibition (Hall et al, 1977). The effect of these agents are generally cytotoxic rather than specifically antitumor (Burnett et al, 1978).
    2) Some specific sesquiterpene lactones which have cytotoxic and antitumor activity include: aromaticin, encelin, eupahyssopin, eupaserrin, forinosin, helenalin, parthenolide, phantomolin, phenolin, tenulin, vernolepin, and zaluzanin C (Ivie & Witzel, 1983).

Genotoxicity

    A) Mutagenicity has been noted in bacterial test models with hymenovin and its derivatives (Ivie & Witzel, 1983).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Thin layer chromatography has been used to identify sesquiterpene lactones. Sheep treated with hymenovin showed increases of BUN, creatinine, inorganic phosphorus, alkaline phosphatase, SGPT, SGOT, LDH, and CPK.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Sheep treated with hymenovin showed increases of BUN, creatinine, inorganic phosphorus, alkaline phosphatase, SGPT, SGOT, LDH, and CPK (Terry et al, 1981).
    4.1.4) OTHER
    A) OTHER
    1) DERMAL
    a) PATCH TESTING has been done to identify those who are sensitized (Ducombs et al, 1990).

Methods

    A) CHROMATOGRAPHY
    1) Thin layer chromatography has been used to identify sesquiterpene lactones (Kelsey et al, 1973).
    2) Kager et al (1994) described a reversed-phase high performance liquid chromatography method using reductive electrochemical detection with a sensitivity of approximately 10 nanograms/milliliter to measure arteether in human plasma.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Thin layer chromatography has been used to identify sesquiterpene lactones. Sheep treated with hymenovin showed increases of BUN, creatinine, inorganic phosphorus, alkaline phosphatase, SGPT, SGOT, LDH, and CPK.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Ingestions of a single plant part are unlikely to produce human poisonings, and in animals, poisonings are generally of a chronic nature. Gastric decontamination is seldom necessary unless large amounts have been ingested. Consider decontamination after large ingestions.
    B) 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) SUMMARY
    1) Gastric decontamination is seldom necessary unless large amounts have been ingested. Ingestions of a single plant part are unlikely to produce human poisonings. Consider decontamination after large ingestions.
    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) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    B) DERMATITIS
    1) Should be treated symptomatically. There is considerable cross-sensitivity between plants containing sesquiterpene lactones and individuals need to be aware of this cross-sensitivity. Consult a dermatologist concerning the necessity of antihistamines or steroids for treating these reactions.
    C) SUPPORT
    1) Respiratory and CNS support may be necessary in severely poisoned animals. These symptoms have NOT been seen in humans.
    D) 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).
    E) MONITORING OF PATIENT
    1) Liver enzymes should be evaluated to determine if hepatic damage has occurred. There is not a specific antidote for humans. Treatment is symptomatic. Monitor if renal damage has occurred. Dehydration and metabolic acidosis may need correction.
    F) EXPERIMENTAL THERAPY
    1) Sulfhydryl Groups: Some sesquiterpene lactones react with sulfhydryl groups; it would appear that administration of sulfhydryl groups would have an antagonistic effect.
    a) In some experiments where the sulfhydryl groups were given shortly after the ingestion of the sesquiterpene lactones, a beneficial effect was seen (Rowe et al, 1980).
    b) The usefulness of this treatment in animals, where ingestions may not be recognized for some time after actual consumption of the plant is questionable. This has not yet been tried in humans, who seldom ingest these plants (Rowe et al, 1980).
    2) N-ACETYLCYSTEINE - Rat hepatocyte cultures treated with helenalin or hymenoxon (4 to 16 micromoles) and cotreated with N-acetylcysteine at concentrations as high as 4 millimolar were afforded profound protection from lethal hepatocyte injury by both toxins (Merrill et al, 1988).

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).
    6.9.2) TREATMENT
    A) EXPERIMENTAL THERAPY
    1) Guinea pigs sensitized to the allergic reactions induced by helenin were treated with an aqueous L-cysteine solution (13 or 1.3 percent) which reduced the recovery time in these animals by 50 percent (Picman & Picman, 1990).
    2) Picman & Picman (1990) found that washing the helenin off the exposed skin with ethanol followed by multiple applications of the cysteine solution further reduced the recovery time in guinea pigs.
    3) Prevention: Guinea pigs treated with the cysteine solution prior to helenin exposure required less time for recovery, suggesting that the cysteine application prevented the full scale development of an allergic reaction (Picman & Picman, 1990).
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) Sesquiterpene lactones appear to be much more toxic parenterally than orally. As much as 5 percent of the dry weight of some species may contain these compounds. The LD50's in animals orally, range from 50 to 1,000 mg/kg.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) ARTEMISININ DERIVATIVES
    a) ORAL
    1) MALARIA - The following doses are recommended by the World Health Organization:
    a) UNCOMPLICATED MALARIA -
    1) ARTEMISININ - 25 milligrams/kilogram on day 1 and 12.5 milligrams/kilogram on days 2 and 3 (JEF Reynolds , 2000).
    2) ARTESUNATE - Initial dose is 5 milligrams/kilogram on day 1, with 2.5 milligrams/ kilogram on days 2 and 3 (JEF Reynolds , 2000). A single dose of mefloquine 15 milligrams/kilogram is also given on the second day.
    b) PARENTERAL
    1) ARTEMETHER - 3.2 milligrams/kilogram IM, followed by 1.6 milligrams/kilogram daily for a maximum of 7 days (JEF Reynolds , 2000).
    2) ARTESUNATE - Initial - 2 milligrams/kilogram IM or IV followed by a daily dose of 1 milligram/kilogram for a maximum of 7 days (JEF Reynolds , 2000).
    c) RECTAL
    1) In Asian countries, suppositories are also available in 400 and 600 milligram strengths for adults, and in severe cases 600 to 1200 milligrams may be given (Hien, 1994).
    2) Dosing for children is 15 milligrams/kilogram (Hien, 1994).
    d) NOTE - A single dose of mefloquine (15 milligrams/kilogram) is also given on the second day for any of the above prescribed treatments (JEF Reynolds , 2000).

Minimum Lethal Exposure

    A) ROUTE OF EXPOSURE
    1) The sesquiterpene lactones appear to be much more toxic parenterally (by an order of magnitude or more) than orally (Ivie & Witzel, 1983).
    2) Acute toxicity is associated with two reactive groups located in helenalin, mexicanin E, and hymenovin.
    B) ANIMAL DATA
    1) In mice exposed to 100 milligrams helenalin/kilogram, death occurred within 24 hours of exposure, but was delayed up to 8 days at lower lethal doses (Chapman et al, 1988).
    2) Mice given 3 daily doses of 25 mg helenalin/kilogram/day resulted in a 30 percent mortality rate (Chapman et al, 1988).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) As much as 5% of the dry weight of some species may be sesquiterpene lactones (Rodriguez et al, 1976), but the amount varies depending upon species, season, growth stage, climate, altitude, and stressors. Bohlmann et al (1977) reported less than 0.1% in their examination of Inula viscosa.
    B) ANIMAL DATA
    1) In animal studies of artemisinin and arteether, the target organs for toxicity have been the liver, kidney, bone marrow, heart (prolonged QT and PQ intervals), and brain (Davidson, 1994; White, 1994). Neurotoxicity has been reported in rats and dogs with evidence of neuronal degeneration.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ARTEMISININ RTECS, 2000
    1) LD50- (INTRAMUSCULAR)MOUSE:
    a) 263 mg/kg
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 390 mg/kg
    B) DIHYDROGRIESENIN
    C) GEIGERIN
    D) HELENALIN
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 10 mg/kg
    b) Male, 43 mg/kg -- BDF1-MOUSE (Chapman et al, 1988)
    2) LD50- (ORAL)MOUSE:
    a) 150 mg/kg
    E) HYENOLANE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) >200 mg/kg
    F) HYMENOVIN
    1) LD50- (ORAL)MOUSE:
    a) 150 mg/kg
    G) HYMENOVIN DIMETHYL ETHER
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 3 mg/kg
    H) MEXICANIN - E
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 3 mg/kg
    I) PSILOTROPIN
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 112 mg/kg
    J) TENULIN
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 185 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) ALLERGENICITY - The alpha methylene gamma-lactone moiety on these compounds are the primary allergens. If the alpha methylene group is reduced, the compounds are no longer active allergens (Mitchell, 1975).
    B) CYTOTOXICITY - These compounds interfere with several enzymes necessary for vital metabolic functions within the cell. Alkylation of sulfhydryl groups through a Michael-type reaction most likely is the primary inhibitor mechanism (Ivie & Witzel, 1983).
    C) ANALGESIA -
    1) Several of the agents have shown analgesic and anti-inflammatory action, without activity against seizures, hyperpyrexia or allergy. The order of potency in one study was (most to least) amaralin, helenalin, tenulin, isotenulin, dihydroamaralin, helenalin oxide, isotenulin oxide, dihydroisotenulin, aromaticin oxide (Lucas et al, 1964).
    2) Other sesquiterpene lactones noted as having analgesic and/or anti-inflammatory properties include aromaticin, deoxyelephantopin, eupaformasanin, eupahyssopin, eupatolide, molephantin, molephantinin, and phantomolin (Ivie & Witzel, 1983).
    D) ANTIHYPERLIPIDEMIA - The sesquiterpene lactones are inhibitors of several key enzymes necessary as regulators of fatty acid and cholesterol synthesis (Hall et al, 1980).

Toxicologic Mechanism

    A) The toxic manifestations are generally thought to be due to reactive functional groups that can form covalent bonds with critical biological nucleophiles (Ivie & Witzel, 1983).
    B) Animal studies indicate that the toxicity of hymenoxon and helenalin is dependent on hepatic glutathione levels which are depleted by these sesquiterpene lactones at very low concentrations (Merrill et al, 1988).
    C) An alpha-methylene group exocyclic to the gamma-lactone appears to be responsible for the allergic contact dermatitis associated with sesquiterpene lactones (Mitchell & Dupuis, 1971).

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