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PLANTS-SANGUINARIA

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) PLANT: Sanguinaria canadensis, also called bloodroot, is a perennial, woodland plant known to contain several benzophenanthridine alkaloids and has the potential to cause poisoning in animals and man.
    B) EXTRACT: Sanguinaria extract is from Sanguinaria canadensis, and is primarily comprised of 6 benzophenanthridine alkaloids: sanguinarine (50%), chelerythrine (25%), sanguilutine (10%), chelilutine (7%), chelirubine (6%), and sanguirubine (2%). Commercial extracts may have lower percentage of these products.
    C) COMMERCIAL PRODUCTS: A toothpaste (Viadent(R)) containing bloodroot is no longer available worldwide. Although the reason is unclear, there have been some studies that reported an increased risk of leukoplakia with these products.

Specific Substances

    1) Bloodroot
    2) Puccoon Root
    3) Red Puccoon
    4) Red Root
    5) Sanguinaria
    6) Tetterwort
    7) BLOODROOT (PLANT)
    8) PLANTS - BLOODROOT
    9) SANGUINARIA (PLANT)

Available Forms Sources

    A) FORMS
    1) Sanguinaria extract is from Sanguinaria canadensis, and is primarily comprised of 6 benzophenanthridine alkaloids: sanguinarine (50%), chelerythrine (25%), sanguilutine (10%), chelilutine (7%), chelirubine (6%), and sanguirubine (2%). Commercial extracts may have lower percentage of these products. Commercial extracts may have lower percentages of these products (Harkrader et al, 1990).
    B) SOURCES
    1) In Europe, bloodroot may be used as a natural food flavoring; however, insufficient data exists to determine potential toxicity ((Anon, 2000)).
    2) Viadent (toothpaste and rinses) by Vipont Pharmaceuticals. The extract used by this company has about 75% alkaloids, about half of which is sanguinarine (Harkrader et al, 1990). As of 2001, bloodroot was removed from these products. More recently the product can no longer be found worldwide (Vlachojannis et al, 2012)
    C) USES
    1) HERBAL
    a) HERBAL USES: American Indians used bloodroot to treat rheumatism. Other uses have included treatment of breast tumors, skin cancers, warts, and nasal polyps, and as an expectorant, emetic, and dental analgesia (Morton, 1977; Duke, 1986).
    b) Traditionally it has been used in the treatment of bronchitis (sub-acute or chronic), asthma, croup, laryngitis, pharyngitis, deficient capillary circulation, nasal polyps (as a snuff) ((Anon, 2000)).
    2) COMMERCIAL PRODUCTS
    a) DENTAL PRODUCTS: Sanguinarine extracts have been found to be effective in retarding the development of gingivitis in some studies (Wennstrom & Lindhe, 1985) (Southguard et al, 1987) (Parsons et al, 1987). However, there have been more recent reports that these products may be linked to pre-neoplastic lesions (ie, leukoplakia) (Vlachojannis et al, 2012).
    1) They have been found to have little effect on plaque and gingivitis in others (Etemadzadeh & Ainamo, 1987; Mauriello & Bader, 1988).
    2) TOOTHPASTE: NO LONGER AVAILABLE: Viadent(R), a toothpaste that contained sanguinarine extract was suspected of producing leukoplakia and in 2001 bloodroot was removed from the product formula and more recently the product is no longer found in worldwide market (Vlachojannis et al, 2012).
    b) EXPECTORANT: Sanguinaria was formerly used as an expectorant, but was discontinued based on its potential toxicity (JEF Reynolds , 2000).

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: Sanguinaria canadensis, also known as bloodroot, is a perennial, woodland plant known to contain several benzophenanthridine alkaloids and found in the woodlands of the eastern half of North America.
    B) USES: A traditional herbal remedy; American Indians used bloodroot to treat rheumatism. In general, it has been used for its antiinflammatory and antimicrobial activities. Salve containing blood root has been used to treat skin lesions and nasal polyps. Sanguinarine has also been added to oral agents to treat plaque.
    C) TOXICOKINETICS: All parts of the sanguinaria canadensis plant contain alkaloids similar to ones found in the opium poppy with most of the alkaloids being concentrated in the root. Several isoquinoline alkaloids (ie, sanguinarine, chelerythrine, protopine, and homochelidonine) have been identified but the actual toxic component is unclear.
    D) EPIDEMIOLOGY: Exposures have occurred; severe toxicity has been reported following sporadic epidemic exposures to argemone mexicana (contains sanguinarine) found in contaminated cooking oil used in India.
    E) COMMERCIAL PRODUCTS: EXTRACT: Commercial sanguinaria extract is from Sanguinaria canadensis plant; it contains similar alkaloids as the plant but the exact concentration of the alkaloids is unknown. TOOTHPASTE: Bloodroot had been added to some brands of toothpaste and mouth rinses. SALVE: Topical black salve containing bloodroot is available via the internet to "self" treat various skin conditions (eg, moles, skin tags, skin cancer).
    F) WITH POISONING/EXPOSURE
    1) TOXICITY: Adverse events related to sanguinaria can vary depending on how it is formulated and used or exposure to the plant itself. Limited overdose data.
    2) ORAL EXPOSURE: As a dental product, the alkaloids may be mildly irritating. Leukoplakia has also been associated with these products. Large ingestions (eg, oral rinse) may cause nausea and vomiting, but other ingredients in these dental agents are likely to cause as much toxicity as sanguinaria itself.
    3) DERMAL EXPOSURE: Topical products containing bloodroot act as escharotic agents. Chronic topical applications of this salve has produced severe pain and severe tissue damage including deep tissue necrosis and eschar.
    4) PLANT ROOT: Ingestion of the plant root itself may cause nausea, vomiting, and diarrhea. Large amounts may produce CNS depression, ataxia, dyspnea and respiratory paralysis.
    5) EPIDEMICS: Epidemic dropsy is caused by chronic ingestion of argemone mexicana that contains the alkaloid sanguinarine, and is usually in the form of adulterated cooking oil. Manifestations include gastrointestinal symptoms, anasarca, pulmonary and cerebral edema, pleural and pericardial effusions.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Fever has been reported following exposure to argemone oil. Of note, sanguinarine and dihydrosanguinarine (alkaloids) are the toxic agents of argemone oil.
    0.2.4) HEENT
    A) Sanguinaria is mildly irritating to the eyes, but solutions should not cause severe or permanent damage.
    0.2.12) FLUID-ELECTROLYTE
    A) WITH POISONING/EXPOSURE
    1) Two children died from progressive generalized edema following more than 20 days exposure to mustard oil used for cooking that was contaminated with argemone mexicana.
    0.2.20) REPRODUCTIVE
    A) Chronic exposure to plant extract in rats and rabbits resulted in NO teratogenic or reproductive effects.
    B) Rats and rabbits developed increased mortality and clinical signs, as well as, body weight loss, when given 100 mg/kg/day of sanguinaria extract. Toxic signs were also present at 30 mg/kg/day.
    1) Reduced pup body weight occurred only at higher levels. No teratogenic or developmental signs were noted.
    C) Rabbits exhibited dose related maternal toxicity when given sanguinaria extract during pregnancy. Clinical effects (increased mortality, respiratory distress, and weight loss) occurred at doses greater than 15 mg/kg/day.
    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) Routine laboratory studies are not indicated, unless the patient develops significant symptoms.
    B) Monitor fluid status if patient develops significant vomiting or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Limited reports of human toxicity. Ingestion of bloodroot found in herbal products (ie, toothpaste) is unlikely to produce toxicity due to sanguinaria, and it appears that these products may no longer be widely available. Ingestion of large amounts of plant material, in particular the root (ie, contains the highest concentration of the alkaloid) may produce alterations in mental status and respiratory depression. Rehydrate if significant vomiting and diarrhea develop; IV fluids as necessary. Monitor CNS and respiratory function. DERMAL EXPOSURE: Chronic exposure to salves containing bloodroot may produce severe pain and moderate to severe tissue damage. Rinse exposed skin with soap and water. Give analgesics for pain. Further dermal treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. If significant amounts of the plant or of the alkaloids in the sanguinaria plant were to be ingested, patients should be monitored for CNS depression, dyspnea or respiratory insufficiency, and hypotension.
    C) DECONTAMINATION
    1) PREHOSPITAL: INGESTION: Activated charcoal may be indicated in patients that have ingested a significant amount of plant material (all parts of the plant contain alkaloids) who remain alert and able to maintain their airway. DERMAL EXPOSURE: Rinse exposed area with soap and water.
    2) HOSPITAL: INGESTION: Give activated charcoal if significants amounts of plant material have been ingested; secure airway as needed in patient's that develop CNS or respiratory insufficiency.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary following a minor exposure. Ingestion of large amounts of plant material may produce CNS or respiratory depression that may require airway support.
    E) ANTIDOTE
    1) No specific antidote is available.
    F) ENHANCED ELIMINATION
    1) The role of hemodialysis in the removal of sanguinaria alkaloids is unknown.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic child or a child with mild gastrointestinal symptoms following a minor exposure (eg, a taste ingestion) can be managed at home with adult supervision.
    2) OBSERVATION CRITERIA: Patients with persistent clinical effects (eg, drowsiness, CNS or respiratory depression) or more than mild toxicity should be referred to a healthcare facility.
    3) ADMISSION CRITERIA: Due to the minimal adverse effects reported with limited human exposures, it is unlikely that patients would require hospital admission following a sanguinaria exposure. Patients with evidence of significant neurologic toxicity (i.e., drowsiness, CNS depression) or respiratory depression should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Patients that develop severe tissue damage following chronic exposure to bloodroot salve, may need to be referred to a dermatologist or plastic surgeon.
    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) TOXICITY: A maximum tolerated dose has not been established.
    B) DERMAL EXPOSURE: Severe pain and permanent skin and structural injuries have been reported with ongoing use of topical products containing bloodroot (sanguinaria) extract.
    C) ANIMAL DATA: In animals, the acute toxic IV dose of sanguanarine chloride is 29 mg/kg. In rats and rabbits, chronic toxicity tests did not demonstrate significant toxicity.

Clinical Effects

Summary Of Exposure

    A) BACKGROUND: Sanguinaria canadensis, also known as bloodroot, is a perennial, woodland plant known to contain several benzophenanthridine alkaloids and found in the woodlands of the eastern half of North America.
    B) USES: A traditional herbal remedy; American Indians used bloodroot to treat rheumatism. In general, it has been used for its antiinflammatory and antimicrobial activities. Salve containing blood root has been used to treat skin lesions and nasal polyps. Sanguinarine has also been added to oral agents to treat plaque.
    C) TOXICOKINETICS: All parts of the sanguinaria canadensis plant contain alkaloids similar to ones found in the opium poppy with most of the alkaloids being concentrated in the root. Several isoquinoline alkaloids (ie, sanguinarine, chelerythrine, protopine, and homochelidonine) have been identified but the actual toxic component is unclear.
    D) EPIDEMIOLOGY: Exposures have occurred; severe toxicity has been reported following sporadic epidemic exposures to argemone mexicana (contains sanguinarine) found in contaminated cooking oil used in India.
    E) COMMERCIAL PRODUCTS: EXTRACT: Commercial sanguinaria extract is from Sanguinaria canadensis plant; it contains similar alkaloids as the plant but the exact concentration of the alkaloids is unknown. TOOTHPASTE: Bloodroot had been added to some brands of toothpaste and mouth rinses. SALVE: Topical black salve containing bloodroot is available via the internet to "self" treat various skin conditions (eg, moles, skin tags, skin cancer).
    F) WITH POISONING/EXPOSURE
    1) TOXICITY: Adverse events related to sanguinaria can vary depending on how it is formulated and used or exposure to the plant itself. Limited overdose data.
    2) ORAL EXPOSURE: As a dental product, the alkaloids may be mildly irritating. Leukoplakia has also been associated with these products. Large ingestions (eg, oral rinse) may cause nausea and vomiting, but other ingredients in these dental agents are likely to cause as much toxicity as sanguinaria itself.
    3) DERMAL EXPOSURE: Topical products containing bloodroot act as escharotic agents. Chronic topical applications of this salve has produced severe pain and severe tissue damage including deep tissue necrosis and eschar.
    4) PLANT ROOT: Ingestion of the plant root itself may cause nausea, vomiting, and diarrhea. Large amounts may produce CNS depression, ataxia, dyspnea and respiratory paralysis.
    5) EPIDEMICS: Epidemic dropsy is caused by chronic ingestion of argemone mexicana that contains the alkaloid sanguinarine, and is usually in the form of adulterated cooking oil. Manifestations include gastrointestinal symptoms, anasarca, pulmonary and cerebral edema, pleural and pericardial effusions.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Fever has been reported following exposure to argemone oil. Of note, sanguinarine and dihydrosanguinarine (alkaloids) are the toxic agents of argemone oil.
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) Fever has been reported following exposure to argemone oil (Lakshmi et al, 2014; Verma et al, 2001). Of note, sanguinarine and dihydrosanguinarine (alkaloids) are the toxic agents of argemone oil (Babu et al, 2007).

Heent

    3.4.1) SUMMARY
    A) Sanguinaria is mildly irritating to the eyes, but solutions should not cause severe or permanent damage.
    3.4.3) EYES
    A) GLAUCOMA: Extracts of this plant have been used to induce glaucoma experimentally in animals, but the propensity of these agents to induce this condition in humans has not been studied (Hakim et al, 1961) and may have been refuted (Dobbie & Langham, 1961).
    B) IRRITATION: Mild irritation of the eye has been noted with sanguinarine (Anon, 1992; Frankos et al, 1990). Sanguinarine is not generally considered an irritant in concentrations of 0.03 to 0.045% (Anon, 1992).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a single joint family of 10 individuals (ranging in age from 2 to 60 years), a single adult developed persistent tachycardia following argemone oil exposure due to consumption of contaminated mustard oil. This patient also developed signs and symptoms of cardiac involvement and died of cardiogenic shock (Lakshmi et al, 2014).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOTENSION
    a) Hypotension has been observed in animals given large doses (Anon, 1990).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) BACKGROUND: Sanguinarine and dihydrosanguinarine (alkaloids) are the toxic agents of argemone oil (Babu et al, 2007).
    b) Dyspnea was reported in a young child exposed to argemone oil containing 5% sanguinarine from adulterated mustard oil for more than 20 days. The child (age 10) and her younger sibling (age 5) both died within 11 days of hospital admission. The parents and youngest child (age 3) developed symptoms of toxicity, but completely recovered (Verma et al, 2001).
    c) Pedal edema, erythema, dyspnea, pain in lower limbs and diarrhea have been described in other outbreaks of argemone oil exposure due to consumption of contaminated mustard oil (Babu et al, 2007).
    d) CASE SERIES: In a single joint family of 10 individuals (ranging in age from 2 to 60 years), a child died of respiratory symptoms that were consistent with pneumonia (ie, fever, breathlessness) following argemone oil exposure due to consumption of contaminated mustard oil (Lakshmi et al, 2014).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DYSPNEA
    a) Respiratory distress was the primary symptom observed during animal studies with oral sanguinarine. Animals died from respiratory paralysis, similar to curare's action.
    b) In animals given oral sanguinarine, respiratory distress was the primary symptom observed (Frankos et al, 1990). Animals died from respiratory paralysis, similar to curare's action (Smith, 1876).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) Drowsiness and slight narcosis may occur from plant (alkaloid portion) ingestion.
    B) SYNCOPE
    1) WITH POISONING/EXPOSURE
    a) Syncope may occur following ingestion (Hardin & Arena, 1974).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) COMA
    a) Coma has developed in animals given large doses (Anon, 1990).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting may occur if significant amounts of the root extract is ingested (Anon, 1990).
    B) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea may occur (Hardin & Arena, 1974).
    b) Pedal edema, erythema, dyspnea, pain in lower limbs and diarrhea have been described in other outbreaks of argemone oil exposure due to consumption of contaminated mustard oil (Babu et al, 2007).
    c) CASE SERIES: In a single joint family of 10 individuals (ranging in age from 2 to 60 years), all cases initially developed diarrhea following argemone oil exposure due to consumption of contaminated mustard oil. Most patients presented with profuse diarrhea, fever and restlessness (Lakshmi et al, 2014).
    C) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) BACKGROUND: Sanguinarine and dihydrosanguinarine (alkaloids) are the toxic agents of argemone oil (Babu et al, 2007).
    b) Abdominal pain and swelling of the abdomen were reported in 2 children in a family that for at least 20 days used mustard oil for cooking that had been contaminated with argemone mexicana oil . Both children received conservative care and died within 11 days of hospital admission. The parents and youngest child (age 3) developed symptoms of toxicity, but completely recovered (Verma et al, 2001). This family was part of a cluster of at least 3000 cases (65 fatal) of epidemic dropsy that occurred in Delhi, India.
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) GASTROENTERITIS
    a) Monkeys given 0 to 60 mg/kg of sanguinarine chloride in subchronic studies showed dose-related gastrointestinal irritation toxicity (Frankos et al, 1990).
    2) DIARRHEA
    a) INCIDENCE: 40% of animals given 200 mg/kg of sanguinaria extract developed diarrhea (Becci et al, 1987).
    3) ANOREXIA
    a) INCIDENCE: 40% of the animals given 200 mg/kg of sanguinaria extract developed anorexia (Becci et al, 1987).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH POISONING/EXPOSURE
    a) ANIMAL DATA: Rats given a single intraperitoneal dose (10 mg/kg) of sanguinarine developed elevated liver enzymes; however, a direct correlation to macroscopic lesions observed in the liver could not be directly related to sanguinarine use ((Anon, 2000)).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOTOXICITY
    a) Elevated liver enzymes (SGPT and SGOT) have been reported in rats given single intraperitoneal doses (10 mg/kg) of sanguinarine ((Anon, 2000)).

Hematologic

    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEMORRHAGE
    a) In ANIMALS fatally poisoned with 20 to 40 mg/kg of sanguinarine chloride, blood and fluid were found in the lungs and thoracic cavity (Becci et al, 1987).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH POISONING/EXPOSURE
    a) In a primary skin irritation test, sanguinarine chloride was slightly irritating (Frankos et al, 1990).
    B) TISSUE NECROSIS
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Chronic dermal use of black salve containing bloodroot (sanguinaria) extract has produced severe pain along with skin ulceration, severe eschar and tissue necrosis and keloids. The salve is sold over the internet to treat moles and skin tags and as a purported treatment for various skin cancers (Ong et al, 2014; Ma et al, 2012; Wang & Warshaw, 2012; Cienki & Zaret, 2010; Saltzberg et al, 2009; Affleck & Varma, 2007). DermaTend(R) is a product commonly available via the internet that contains bloodroot extract (Wang & Warshaw, 2012).
    b) PATHOLOGY: Sanguinarine is thought to produce tissue necrosis by blocking the sodium potassium pump, inhibiting nuclear factor kB or impeding cell cycle progression (Ong et al, 2014).
    c) CASE REPORT: A 53-year-old healthy man developed a 5 mm papule on his chest that blackened over time and applied bloodroot salve to treat the area for 10 days. Six months later, the lesion grew in size and bloodroot was restarted even though it produced significant burning pain upon application. The lesion continued to grow and it had doubled in size within 6 weeks with ulceration and purulent discharge. The patient sought medical care, following a chest x-ray and a CT of the chest, a mass was noted on the chest wall; a biopsy revealed malignant melanoma (Saltzberg et al, 2009).
    d) CASE REPORT: A 42-year-old man with metastatic colon cancer had developed palpable subcutaneous nodules on his abdominal wall and began applying bloodroot salve to shrink these nodules. Approximately, 8 days after using the salve, fecal discharge was noted on the areas where the salve had been applied. A CT scan of the abdomen revealed 2 enterocutaneous fistulae. Treatment included IV antibiotics and bowel rest and by day 6 he was restarted on oral feedings. He developed no further complications (Cienki & Zaret, 2010)
    e) CASE REPORT: A 63-year-old man developed an undiagnosed neoplasm (suspected to be melanoma) of his left naris. He refused a biopsy and decided to self treat the lesion with a black salve containing 300 mg of bloodroot, galangal, red clover, and sheep sorrel. The salve was used for many months and resulted in extensive tissue damage leaving the patient with no left naris (Eastman et al, 2011).
    f) CASE REPORT: A 82-year-old man was admitted with a one year history of a fumigating tumor on his scalp. He had a previous history of excision of the site secondary to squamous cell carcinoma (SCC); however, the tumor recurred 2 months later and was treated at home with black salve containing bloodroot extract derived from the Sanguinaria canadensis plant. The lesion was treated for 9 months before seeking medical treatment due to severe pain. At presentation, the patient had a soft-ball size, exophtyic tumor that had foul smelling purulent drainage. A biopsy of the scalp confirmed SCC with perineural involvement. A CT scan of the region showed the presence of regional lymph node metastasis. The patient was lost to follow-up (Ma et al, 2012).
    C) LEUKOPLAKIA
    1) WITH THERAPEUTIC USE
    a) Oral leukoplakia, a premalignant condition, has been associated with Viadent(R) oral care agents (ie, toothpaste, mouth rinse) containing sanguinaria extract. (The author noted that Viadent products were no longer available in the US, however, other products containing bloodroot extract are available) (Allen et al, 2001).
    D) LACK OF EFFECT
    1) WITH POISONING/EXPOSURE
    a) Sensitization has not been reported in humans (Anon, 1992).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) IRRITATION
    a) There was no mucosal irritancy noted in a 28 day dog study, and a hamster cheek pouch test showed only slight irritancy (Frankos et al, 1990).

Reproductive

    3.20.1) SUMMARY
    A) Chronic exposure to plant extract in rats and rabbits resulted in NO teratogenic or reproductive effects.
    B) Rats and rabbits developed increased mortality and clinical signs, as well as, body weight loss, when given 100 mg/kg/day of sanguinaria extract. Toxic signs were also present at 30 mg/kg/day.
    1) Reduced pup body weight occurred only at higher levels. No teratogenic or developmental signs were noted.
    C) Rabbits exhibited dose related maternal toxicity when given sanguinaria extract during pregnancy. Clinical effects (increased mortality, respiratory distress, and weight loss) occurred at doses greater than 15 mg/kg/day.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Chronic exposure to plant extract in rats and rabbits resulted in NO teratogenic or reproductive effects (Keller & Meyer, 1989).
    2) Rats and rabbits developed increased mortality and clinical signs, as well as body weight loss when given 100 mg/kg/day of sanguinaria extract. Toxic signs were also present at 30 mg/kg/day.
    a) Reduced pup body weight occurred only at higher levels. No teratogenic or developmental signs were noted (Frankos et al, 1990).
    3.20.3) EFFECTS IN PREGNANCY
    A) GENERAL
    1) Based on its active constituents, sanguinaria is NOT recommended during pregnancy or lactation ((Anon, 2000)).
    B) ANIMAL STUDIES
    1) RABBITS exhibited dose related maternal toxicity when given sanguinaria extract during pregnancy. Clinical effects (increased mortality, respiratory distress, and weight loss) occurred at doses greater than 15 mg/kg/day (Frankos et al, 1990).

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 EFFECT
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Genotoxicity

    A) Mutagenicity was not noted in the Ames mutagen test.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Routine laboratory studies are not indicated, unless the patient develops significant symptoms.
    B) Monitor fluid status if patient develops significant vomiting or diarrhea.
    4.1.2) SERUM/BLOOD
    A) OTHER
    1) Routine laboratory studies are not indicated, unless the patient develops significant symptoms.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) These alkaloids may be isolated and quantified by proton nuclear magnetic resonance, ultraviolet and infrared spectroscopy, melting point, mass spectrometry, and high performance liquid chromatography (Krane et al, 1984; Thorne et al, 1986; Labriola et al, 1966; Slavik et al, 1968).

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) Due to the minimal adverse effects reported with limited human exposures, it is unlikely that patients would require hospital admission following a sanguinaria exposure. Patients with evidence of significant neurologic toxicity (i.e., drowsiness, CNS depression) or respiratory depression should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic child or a child with mild gastrointestinal symptoms following a minor exposure (eg, a taste ingestion) can be managed at home with adult supervision.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Patients that develop severe tissue damage following chronic exposure to bloodroot salve, may need to be referred to a dermatologist or plastic surgeon.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with persistent clinical effects (eg, drowsiness, CNS or respiratory depression) or more than mild toxicity should be referred to a healthcare facility.

Monitoring

    A) Routine laboratory studies are not indicated, unless the patient develops significant symptoms.
    B) Monitor fluid status if patient develops significant vomiting or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Gastric decontamination is not indicated specifically for the sanguinaria in dental products. It may be indicated for the dental product itself, but not for the bloodroot component.
    2) If significant amounts of the plant itself or the alkaloids are ingested, gastric decontamination is indicated barring the usual contraindications.
    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) 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) DENTAL PRODUCTS: If dental products containing sanguinaria are ingested, treatment should be as for the product without the sanguinaria. Some slight increase in nausea and diarrhea might be observed.
    2) PLANT MATERIAL: If significant amounts of the plant or of the alkaloids in this plant were to be ingested, no specific antidote is available. Patients should be monitored for CNS depression, dyspnea or respiratory insufficiency, or hypotension.
    B) MONITORING OF PATIENT
    1) Monitor fluid status if patient develops significant vomiting or diarrhea. Routine laboratory studies are not indicated, unless the patient develops significant symptoms.
    2) Patients should be monitored for CNS depression, dyspnea or respiratory insufficiency, or hypotension if significant amounts of the plant material have been ingested.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

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).

Enhanced Elimination

    A) SUMMARY
    1) The role of hemodialysis in the removal of sanguinaria alkaloids is unknown.

Range Of Toxicity

Summary

    A) TOXICITY: A maximum tolerated dose has not been established.
    B) DERMAL EXPOSURE: Severe pain and permanent skin and structural injuries have been reported with ongoing use of topical products containing bloodroot (sanguinaria) extract.
    C) ANIMAL DATA: In animals, the acute toxic IV dose of sanguanarine chloride is 29 mg/kg. In rats and rabbits, chronic toxicity tests did not demonstrate significant toxicity.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) Rhizome - 0.06 to 0.5 gram (1 to 2 grams for emetic dose) three times daily ((Anon, 2000)).
    2) Liquid Extract - 0.06 to 0.3 milliliters (1:1 in 60% alcohol) (1 to 2 milliliters for emetic dose) three times daily ((Anon, 2000)).
    3) Tincture - 0.3 to 2 milliliters (1:5 in 60% alcohol) (2 to 8 milliliters for emetic dose) three times daily ((Anon, 2000)).

Minimum Lethal Exposure

    A) ANIMAL DATA
    1) ANIMALS: The acute IV toxic dose of sanguanarine chloride was 29 mg/kg (Becci et al, 1987).

Maximum Tolerated Exposure

    A) ANIMAL DATA
    1) In experiments sponsored by a company using sanguinaria extract in dental products, a panel of scientist found the no adverse effects limit in animals to be 25 mg/kg/day in normal animals and 15 mg/kg/day in maternal animals (Frankos et al, 1990). Since this study, dental products containing sanguinaria extract may not be widely available due to reports of leukoplakia with ongoing use (Vlachojannis et al, 2012).
    B) DERMAL EXPOSURE
    1) Chronic dermal use of black salve containing bloodroot (sanguinaria) extract has produced severe pain along with skin ulceration, deep tissue necrosis and eschar. The salve is sold over the internet to "self" treat moles and skin tags and as a purported treatment for skin cancer (Ma et al, 2012; Cienki & Zaret, 2010; Saltzberg et al, 2009; Affleck & Varma, 2007).
    C) ORAL EXPOSURE
    1) The estimated safe concentration of oral rinses containing sanguinaria extracts is 0.03% to 0.075% as determined by the US FDA. However, there is inadequate evidence to suggest its overall safety or efficacy (Wang & Warshaw, 2012).
    a) LEUKOPLAKIA
    1) Oral leukoplakia, a premalignant condition, has been associated with Viadent(R) oral care agents (ie, toothpaste, mouth rinse) containing sanguinaria extract (Allen et al, 2001).
    D) OUTBREAK OF ARGEMONE MEXICANA EXPOSURE
    1) CASE SERIES: In a single joint family of 10 individuals (ranging in age from 2 to 60 years), all cases initially developed diarrhea following argemone oil (contains sanguinarine) exposure due to consumption of contaminated mustard oil that was grown on their land. Most patients presented with profuse diarrhea, fever and restlessness. Pedal edema also developed in all patients and 4 patients had a recurrence of bilateral pitting edema. Severe events occurred in 2 patients. A young adult developed persistent tachycardia and went on to develop signs and symptoms of cardiac involvement and died of cardiogenic shock. In the second case, a child died of respiratory symptoms that were consistent with pneumonia (ie, fever, breathlessness). Of note, nearby neighbors did not become ill and it was suspected that this outbreak was due to contamination of mustard seeds with argemone seeds that were grown on the families land and contamination was limited to the individual household (Lakshmi et al, 2014).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) 1440 mg/kg (sanguinaria extract)
    2) 1700 mg/kg (sanguinarine)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) SUMMARY - Sanguinaria, an isoquinoline alkaloid (benzophenanthridine-type), has the following pharmacological activities: anti-microbial, anti-inflammatory, antihistaminic, cardiotonic, and anti-plaque ((Anon, 2000)).
    1) Sanguinaria canadensis L., (alkaloid extract) contains 33% sanguinarine chloride and 68% total benzophenanthrine alkaloid (RTECS , 2000).
    B) The alkaloids found in this plant have shown the following activities:
    1) Mild CNS depression (Anon, 1991)
    2) In vitro antibacterial activity at concentrations of 1 to 16 micrograms per milliliter (Dzink & Socransky, 1985; Eisenberg, 1985; Vichkanova et al, 1969; Stickl, 1928) Johnson et al, 1952; (Nandi et al, 1983).
    3) In vitro antifungal activity (Vichkanova & Adgina, 1971)
    4) A papavarine-like action on smooth muscle (Becci et al, 1987)
    5) A papavarine-like action on cardiac muscle (Becci et al, 1987)
    6) In vitro antiprotozoan activity (Bodalski et al, 1958)
    7) In vitro inhibition of sodium/potassium ATPase activity in guinea pig brain (Straub & Carver, 1975)
    8) An antineoplastic effect on:
    a) Ehrlich carcinomas and some sarcomas in mice (sanquinarine and chelerythrine) (Stickl, 1929; Hartwell, 1960)
    b) Cancers of the ear and nose in humans (Phelan & Juardo, 1963)
    9) Dental plaque reduction (Southard et al, 1984; Bonesvoll & Gjermo, 1978; Godowski, 1989)
    10) Reduction of glycolysis rates in saliva (Boulware, 1984)
    11) In humans, sanguinarine reacts with various nucleophiles (Vichkanova & Tolkachev, 1978). This includes sulfhydryl enzymes, thus producing an inhibition of the oxidative decarboxylation of pyruvate (Sarkar, 1948).
    12) Inhibition of sodium/potassium ATPase, and D-glucose transport in a dose dependent manner in rat intestine (Tandon et al, 1993).

Toxicologic Mechanism

    A) This plant contains primarily benzophenanthridine alkaloids, primarily in the rhizome (Harkrader et al, 1990; Tin-Wa et al, 1970).

References

General Bibliography

    1) Affleck AG & Varma S: A case of do-it-yourself Mohs' surgery using bloodroot obtained from the internet. Br J Dermatol 2007; 157(5):1078-1079.
    2) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    3) Allen CL, Loudon J, & Mascarenhas AK: Sanguinaria-related leukoplakia: epidemiologic and clinicopathologic features of a recently described entity. Gen Dent 2001; 49(6):608-614.
    4) Ames BN, McCann J, & Yamasaki I: Methods for detecting carcinogens and mutagens with the Salmonella mammalian microsome mutagenicity test. Mutat Res 1975; 31:347.
    5) Anon: Bloodroot monograph. Lawrence Rev Nat Prod, 1990.
    6) Anon: Bloodroot. Lawrence Rev Nat Prod 1992; 1-2.
    7) Anon: Royal Pharmaceutical Society's Herbal Medicines: Bloodroot monograph.. The Pharmaceutical Press. London, UK (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    8) Babu CK, Khanna SK, & Das M: Adulteration of mustard cooking oil with argemone oil: do Indian food regulatory policies and antioxidant therapy both need revisitation?. Antioxid Redox Signal 2007; 9(4):515-525.
    9) Bailey LH & Bailey EZ: Hortus Third, MacMillan Publishing Co, Inc, New York, NY, 1976.
    10) Becci PJ, Schartz H, & Barnes HH: Short-term toxicity studies of sanguinarine and of two alkaloid extracts of Sanguinaria canadensis (L). J Toxicol Environ Health 1987; 20:199.
    11) Bodalski T, Pelczarska H, & Vjec M: Action of some alkaloids of C. majus on Trichomonas vaginalis in vitro. Arch Immunol Tet Dosw 1958; 6:705.
    12) Bonesvoll P & Gjermo A: A comparison between chlorhexidine and some quaternary ammonium compounds with regard to retention, salivary concentration and plaque-inhibiting effect in the human mouth after mouth rinses. Arch Oral Biol 1978; 23:289.
    13) Burgess JL, Kirk M, Borron SW, et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 1999; 34(2):205-212.
    14) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    15) Cienki JJ & Zaret L: An Internet misadventure: bloodroot salve toxicity. J Altern Complement Med 2010; 16(10):1125-1127.
    16) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    17) Dobbie GC & Langham ME: Reactions of animal eyes to sanguinarine and argemone oil. Br J Ophthalmol 1961; 45:81.
    18) Duke JA: Handbook of Medicinal Herbs, CRC Press, Boca Raton, FL, 1986.
    19) Dzink J & Socransky SS: Comparative in vitro activity of sanguinarine against oral microbial isolates. Antimicrob Agents Chemother 1985; 27:663-665.
    20) Eastman KL, McFarland LV, & Raugi GJ: Buyer beware: a black salve caution. J Am Acad Dermatol 2011; 65(5):e154-e155.
    21) Eisenberg AD: J Dental Res 1985; 64:341.
    22) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    23) Etemadzadeh H & Ainamo J: Lacking anti-plaque efficacy of 2 sanguinarine mouth rinses. J Clin Periodontol 1987; 14:176-180.
    24) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    25) Frankos VH, Brusick DJ, & Johnson EM: Safety of sanguinaria extract as used in commercial toothpaste and oral rinse products. J Can Dent Assoc 1990; 56(Suppl):41-47.
    26) Godowski KC: J Clin Dentistry 1989; 1:96.
    27) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    28) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    29) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    30) Hakim SAE, Mijovic V, & Walker J: Distribution of certain poppy-fumaria alkaloids and a possible link with the incidence of glaucoma. Nature 1961; 189:198.
    31) Hardin JW & Arena JM: Human Poisonings from Native and Cultivated Plants, 2nd ed, Duke University Press, Durham, NC, 1974.
    32) Harkrader RJ, Reinhart PC, & Rogers JA: The history, chemistry and pharmacokinetics of sanguinaria extract. J Can Dental Assoc 1990; 56(Suppl):7-12.
    33) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    34) Hartwell JL: Plant Remedies for cancer. Cancer Chemother Rep 1960; 7:19-24.
    35) JEF Reynolds : Martindale: The Extra Pharmacopoeia. The Pharmaceutical Press. London, England (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    36) Keller KA & Meyer DL: J Clin Dentistry 1989; 1:59.
    37) Kingsbury JM: Poisonous Plants of the United States and Canada, Prentice-Hall Inc, Englewood Cliffs, NJ, 1964.
    38) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    39) Krane BD, Fagbule MO, & Shamma M: The benzophenanthridine alkaloids. J Nat Prod 1984; 47:1-43.
    40) Labriola RA, Kuck AM, & Comin A: Ann Assoc Quim Arg 1966; 54:29.
    41) Lakshmi PV, Sharma A, Bhatia D, et al: Dropsy outbreak in a single family in Punjab, India. Am J Trop Med Hyg 2014; 91(4):786-789.
    42) Ma L, Dharamsi JW, & Vandergriff T: Black salve as self-treatment for cutaneous squamous cell carcinoma. Dermatitis 2012; 23(5):239-240.
    43) Mauriello SM & Bader JD: Six-month effects of a sanguinarine dentifrice on plaque and gingivitis. J Periodontol 1988; 59:238-243.
    44) Morton JF: Major Medicinal Plants, Charles C. Thomas, Springfield, IL, 1977.
    45) Nandi R, Maiti M, & Chaudhuri K: Sensitivity of vibrios to sanquinarine. Experientia 1983; 39:524.
    46) Naradzay J & Barish RA: Approach to ophthalmologic emergencies. Med Clin North Am 2006; 90(2):305-328.
    47) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    48) Ong NC, Sham E, & Adams BM: Use of unlicensed black salve for cutaneous malignancy. Med J Aust 2014; 200(6):314.
    49) Parsons LG, Thomas LG, & Southard GL: Effect of sanguinaria extract on established plaque and gingivitis when supragingivally delivered as a manual rinse or under pressure in an oral irrigator. J Clin Periodontol 1987; 14:381-385.
    50) Peate WF: Work-related eye injuries and illnesses. Am Fam Physician 2007; 75(7):1017-1022.
    51) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    52) Phelan JT & Juardo J: Chemosurgical management of carcinoma of the nose. Surgery 1963; 53:310.
    53) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    54) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    55) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    56) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    57) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    58) Saltzberg F, Barron G, & Fenske N: Deforming self-treatment with herbal "black salve". Dermatol Surg 2009; 35(7):1152-1154.
    59) Sarkar SN: Isolation from argemone oil of dihydrosanguinarine and sanguinarine: Toxicity of sanguinarine. Nature (London) 1948; 162:265.
    60) Slavik J, Dolejs L, & Hanus V: Chelirubine, chelilutine, sanguirubine and sanguilutine mass and nuclear magnetic resonance spectra of benzophenanthridine alkaloids. Collect Czech Chem Commun 1968; 33:1619-1623.
    61) Smith RM: The physiological action of sanguinaria, the alkaloid of Sanguinaria canadensis. Am J Med Sci 1876; 72:346.
    62) Southard GL, Boulware RT, & Walborn DR: Sanguinarine, a new antiplaque agent: Retention and plaque specificity. J Am Dent Assoc 1984; 108:338-341.
    63) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    64) Stickl O: Chemotherapeutische Versuche gegen das ubertragbare Mausecarcinom. Virchow's Arch Pathol Anat 1929; 270:801-867.
    65) Stickl O: Die bactericide wirkung der extrakte und alkaloide des scholkrautes auf grampositive pathogene mikroorganisme. Z Hyg Infektionskr 1928; 108:567.
    66) Straub KD & Carver P: Sanguinarine, inhibitor of Na-K dependent ATPase. Biochem Biosphys Res Commum 1975; 62:913.
    67) Tandon S, Das M, & Khanna SK: Effect of sanguinarine on the transport of essential nutrients in an everted gut sac model: role of Na+, K+, -ATPase. Nat Toxins 1993; 1:235-240.
    68) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    69) Thorne EM, Boulware RT, & Harkrader RJ: HPLC analysis of sanguinarine in oral health care products. J Soc Cosmet Chem 1986; 37:279-286.
    70) Tin-Wa M, Farnsworth NR, & Fong HHS: Biological and phytochemical evaluation of plants VIII. Isolation of an alkaloid from Sanguinaria canadensis. J Nat Prod 1970; 63:1476.
    71) Verma SK, Dev G, Tyagi AK, et al: Argemone mexicana poisoning: autopsy findings of two cases. Forensic Sci Int 2001; 115(1-2):135-141.
    72) Vichkanova SA & Adgina VV: The antifungal properties of sanguinarine. Antibiotiki (Mosc) 1971; 16:609.
    73) Vichkanova SA & Tolkachev ON: Dependence of antimicrobial activity on the structure and reactivity of natural quanternary heteroaromatic compounds and their analogues. Farmatsiva (Mosc) 1978; 27:38.
    74) Vichkanova SA, Rubinchik MA, & Adgina VV: A study of the chemotherapeutic action of sanguinarine. Farmakol Toxsikol (Mosc) 1969; 32:325.
    75) Vlachojannis C, Magora F, & Chrubasik S: Rise and fall of oral health products with Canadian bloodroot extract. Phytother Res 2012; 26(10):1423-1426.
    76) Wang MZ & Warshaw EM: Bloodroot. Dermatitis 2012; 23(6):281-283.