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TRIPTERYGIUM

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Crude preparations of Tripterygium, a plant that grows in southern China and Taiwan, have been used as a medicinal herb for many years in Chinese medicine. Most of the herbal medicine is made from extracts of Tripterygium wilfordii Hook, triterpene and diterpene compounds have been isolated from the roots and are suspected to be the active constituents. The leaves, stock, flowers, and skin of the roots are poisonous when ingested.

Specific Substances

    1) Early rice flower
    2) Huang-t'eng ken
    3) Lei Gong Teng
    4) Lei-kung t'eng
    5) Mang Cao
    6) Seven-step vine
    7) Thunder God Vine
    8) Tripterygium hypoglaucum
    9) Tripterygium hypoglaucum (Levl) Hutch
    10) Tripterygium wilfordii
    11) Tripterygium wilfordii Hook
    12) Tripterygium wilfordii Hook f
    13) Tsao-ho-hua
    14) TwHf
    15) Yellow vine root

Available Forms Sources

    A) FORMS
    1) Aqueous, alcoholic, and methanol-chloroform extracts of the plant root have been prepared for medicinal use and have been used for 2000 years (Chou et al, 1995; Lipsky & Tao, 1997). Tablets have been formulated from the methanol-chloroform extract of the plant root, containing 33 mcg of the extract for experimental use in animals (Asano et al, 1998). A methanol-chloroform extract, T2, is commercially availabe in China for the treatment of autoimmune and inflammatory diseases (Pyatt et al, 2000).
    2) A diterpenoid triepoxide purified from Tripterygium wilfordii hook f, triptolide, is an active extract used in Chinese medicine for more than 2000 years. Triptolide is responsible for the immunosuppressive and anti-inflammatory effects of the herbal (Chen, 2001).
    B) SOURCES
    1) The medicinal herb is extracted from the roots of the plants Tripterygium wilfordii (most commonly) or Tripterygium hypoglaucum (RTECS , 2001; Lipsky & Tao, 1997).
    C) USES
    1) Common oral uses for this medicinal plant extract include: immune-related diseases, especially rheumatoid arthritis and systemic lupus erythematosus, psoriasis, chronic nephritis, tuberculosis and pulmonary diseases, male contraception, anti-inflammatory, anti-viral, anti-tumor, menorrhagia, and multiple sclerosis (Chen, 2001; Pyatt et al, 2000; Takei et al, 1997; Chou et al, 1995). Topical preparations have been used for treatment of arthritis and inflammatory tissue swelling (Chou et al, 1995).
    2) An extract of Tripterygium wilfordii was used to treat severe lupus nephritis with severe proteinuria. The authors reported a successful remission of the patient's disease state. The authors attribute the success of this patient to the herbal which may have potentiated the effects of prednisone, which she took concurrently (Kao et al, 1993).
    3) Tripterygium has been used as an insecticide (Chou et al, 1995).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) More common adverse effects of Tripterygium include gastrointestinal effects, amenorrhea, mucous membrane erosions, rash, and leukopenia. Most effects are due to chronic use.
    B) A fatality due to Tripterygium wilfordii has been reported, with death due to refractory shock with renal failure, profuse vomiting and diarrhea, metabolic acidosis, hypocalcemia, and leukopenia.
    C) Tripterygium can cause fetal anomalies and death when taken by mothers during pregnancy.
    0.2.3) VITAL SIGNS
    A) Decreased blood pressure and increased pulse rate may occur following excessive doses.
    0.2.4) HEENT
    A) Mucous membrane erosions have been reported.
    0.2.5) CARDIOVASCULAR
    A) Excessive doses may result in hypotension with potential shock.
    B) Toxic doses have been reported to cause sinus tachycardias and widened QRS complexes.
    0.2.7) NEUROLOGIC
    A) Fatigue and dizziness have been reported following use of this herbal drug.
    0.2.8) GASTROINTESTINAL
    A) Gastrointestinal disorders, including nausea, vomiting, diarrhea, and anorexia have been reported.
    0.2.10) GENITOURINARY
    A) A case of renal failure has been reported following a single potentially toxic dose of Tripterygium.
    0.2.11) ACID-BASE
    A) Metabolic acidosis has been reported following ingestions.
    0.2.12) FLUID-ELECTROLYTE
    A) Hypovolemia, with electrolyte disturbances, may occur following severe vomiting and diarrhea.
    B) Severe hypocalcemia has been reported.
    0.2.13) HEMATOLOGIC
    A) Leukopenia and thrombocytopenia have been reported following consumption of Tripterygium, and may occur within days of treatment. Aplastic anemia has been reported following use of the extract.
    0.2.14) DERMATOLOGIC
    A) Rashes may occur following consumption of Tripterygium.
    0.2.20) REPRODUCTIVE
    A) Occipital meningoencephalocele in an infant has been associated with taking Tripterygium wilfordii during the first 8 weeks of pregnancy.
    B) A high incidence of anomalies have been reported in mouse embryos during organogenesis where the embryos were give Tripterygium doses.

Laboratory Monitoring

    A) Tripterygium serum levels are not clinically useful or readily available.
    B) Monitor vital signs and ECG in all symptomatic patients.
    C) Fluid status, electrolytes including calcium and renal function should be monitored in patients with excessive vomiting and/or diarrhea.
    D) CBC should be obtained in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Treatment is SYMPTOMATIC and SUPPORTIVE.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) Fluid and electrolyte replacement therapy may be necessary following vomiting and diarrhea.
    D) Severe acidosis (pH less than 7.1) should be managed with IV sodium bicarbonate as needed. Monitor blood gases to guide bicarbonate dosing.
    E) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.

Range Of Toxicity

    A) Human toxicity reports are limited. Dosage is variable due to the nature of the plant, with extracts derived from the root. Other parts of the plant are highly toxic, and if ingested may cause more toxic effects. It is reported that the margin of safety of this herbal is narrow.
    B) A home-made extract from the plant roots was reported to cause death as a result of hypovolemic shock.

Clinical Effects

Summary Of Exposure

    A) More common adverse effects of Tripterygium include gastrointestinal effects, amenorrhea, mucous membrane erosions, rash, and leukopenia. Most effects are due to chronic use.
    B) A fatality due to Tripterygium wilfordii has been reported, with death due to refractory shock with renal failure, profuse vomiting and diarrhea, metabolic acidosis, hypocalcemia, and leukopenia.
    C) Tripterygium can cause fetal anomalies and death when taken by mothers during pregnancy.

Vital Signs

    3.3.1) SUMMARY
    A) Decreased blood pressure and increased pulse rate may occur following excessive doses.
    3.3.4) BLOOD PRESSURE
    A) Profound hypotension and shock have been reported within 3 days of a single ingestion (Chou et al, 1995).
    3.3.5) PULSE
    A) Increased pulse rate may occur following ingestions (Chou et al, 1995).

Heent

    3.4.1) SUMMARY
    A) Mucous membrane erosions have been reported.
    3.4.6) THROAT
    A) Dry mouth and throat, esophageal burning, and mucous membrane erosions have been reported (Chen, 2001; Lipsky & Tao, 1997). Oral ulcers have occurred weeks or months after treatment (Chen, 2001).

Cardiovascular

    3.5.1) SUMMARY
    A) Excessive doses may result in hypotension with potential shock.
    B) Toxic doses have been reported to cause sinus tachycardias and widened QRS complexes.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) Chou et al (1995) reported hypotension progressing to hypovolemic and cardiogenic shock, refractory to fluid replacement and vasopressor agents following a toxic dose of Tripterygium wilfordii. This 36-year-old male was admitted to the hospital 3 days after consuming a potentially large dose, with blood pressure of 74/44 mmHg.
    a) The hypotension progressed to refractory shock with metabolic acidosis and severe hypocalcemia prior to his death 15 hours after hospital admission. Evidence indicated possible cardiac damage that may have contributed to the refractory shock. Hypovolemic shock was secondary to severe intestinal tract disturbances.
    B) ELECTROCARDIOGRAM ABNORMAL
    1) Sinus tachycardia, widened QRS complexes with ST elevation, and low voltage was seen on ECG in a patient 3 days following a potentially large Tripterygium wilfordii dose. A previous ECG taken several years earlier revealed incomplete right bundle branch block. Severe hypokinesia of the heart was revealed on echocardiography. Chest x-ray showed normal heart size and no pulmonary congestion. Recurrent ventricular tachydysrhythmias developed, which did not respond to cardiac massage and cardioversion (Chou et al, 1995).
    2) The triptolide isolate of Tripterygium wilfordii has been reported to induce serious toxicities, including ECG changes indicative of myocardial damage (Lipsky & Tao, 1997).

Neurologic

    3.7.1) SUMMARY
    A) Fatigue and dizziness have been reported following use of this herbal drug.
    3.7.2) CLINICAL EFFECTS
    A) FATIGUE
    1) Fatigue was reported in 8 (n=537) patients and dizziness was reported in 11 (n=537) patients using methanol-chloroform extracts of Tripterygium wilfordii (Lipsky & Tao, 1997).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CNS EFFECTS
    a) Animal studies indicate that toxic doses may result in central nervous system damage, including necrosis of midbrain, medulla, and cerebellum (Takei et al, 1997).

Gastrointestinal

    3.8.1) SUMMARY
    A) Gastrointestinal disorders, including nausea, vomiting, diarrhea, and anorexia have been reported.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) Dose-related effects include gastric upset, mucous membrane erosions, loss of appetite, nausea and vomiting, diarrhea, and occasionally constipation (Chen, 2001; Lipsky & Tao, 1997; Chou et al, 1995). Gastric ulceration has been reported (Takei et al, 1997). Within days of starting an extract of Tripterygium (20 mg 3 times daily), gastric adverse effects of anorexia, vomiting, diarrhea, and esophageal burning were reported in several patients (Lipsky & Tao, 1997).
    2) Chou et al (1995) reported profuse vomiting and watery diarrhea for 3 days following a dose of Tripterygium wilfordii in a 36-year-old male. Estimated fluid loss was reported to be 4000 to 5000 mL. Severe hypotension progressed to refractory hypovolemic and cardiogenic shock and death within 4 days of the ingestion.

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) Mild elevation of hepatic enzymes (SGOT 346 IU/L) was reported following a potentially toxic dose (Chou et al, 1995). Increases in SGPT have reported as a toxic effect of triptolide, an isolate of Tripterygium (Lipsky & Tao, 1997).

Genitourinary

    3.10.1) SUMMARY
    A) A case of renal failure has been reported following a single potentially toxic dose of Tripterygium.
    3.10.2) CLINICAL EFFECTS
    A) ANURIA
    1) Azotemia (BUN 32 mg/dL and creatinine 2.7 mg/dL) was reported in a 36-year-old male following a single dose of Tripterygium wilfordii. Anuria progressing to renal failure developed. The patient died within 4 days from refractory hypovolemic shock and possible cardiac damage. The renal toxicity may have been secondary to prolonged shock (Chou et al, 1995).
    2) Urinary abnormalities have been reported as toxic effects of the triptolide isolate of Tripterygium (Lipsky & Tao, 1997).
    B) DISORDER OF MENSTRUATION
    1) Menstrual disorders, including amenorrhea and irregular or delayed menstrual periods, have been reported following therapeutic dosages (Lipsky & Tao, 1997). Amenorrhea has been reported following chronic therapy with Tripterygium extracts (Chen, 2001). Long-term high-dose administration of various extracts may induce damage to the reproductive organs.
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) TESTIS DISORDER
    a) MICE - Acute toxicity studies in mice revealed atrophy of the testes in addition to a decrease in the number and degeneration of spermatocytes (Lipsky & Tao, 1997). Changes in the testes were dose dependent.
    b) Reversible infertility in male animals is a demonstrated effect of extracts of Tripterygium (Chang et al, 1997).

Acid-Base

    3.11.1) SUMMARY
    A) Metabolic acidosis has been reported following ingestions.
    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) Severe metabolic acidosis (arterial pH 7.232, PO2 72.7 mmHg, PCO2 24.6 mmHg, bicarbonate 10.0 mmol/L) with hypocalcemia (total calcium 1.12 mmol/L) has been reported following a potentially toxic dose. The patient died due to refractory shock (Chou et al, 1995).

Hematologic

    3.13.1) SUMMARY
    A) Leukopenia and thrombocytopenia have been reported following consumption of Tripterygium, and may occur within days of treatment. Aplastic anemia has been reported following use of the extract.
    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) A usual adverse effect of this herbal drug is suppression of lymphocyte proliferation, with leukopenia and aplastic anemia resulting within days after treatment (Chen, 2001; Pyatt et al, 2000; Chou et al, 1995). Leukopenia was reported in 34 (n=537) patients in one study (Lipsky & Tao, 1997). Chou et al (1995) reported severe granulocytopenia (WBC 1000/mcL, with 4% bands, 18% segmented cells, and 71% lymphocytes) in a 36-year-old male following a single dose of Tripterygium. Aplastic anemia may occur with chronic use.
    a) Bone marrow suppression has been shown to be a dose-limiting consequence of Tripterygium administration (Pyatt et al, 2000). Most often, the hematologic effects are transient, and recovery is generally complete following discontinuation of the herbal.
    2) Following inadvertent dosing of 3 times the study dose, or 60 mg 3 times daily for 2 weeks, a patient developed bone marrow depression after 2 weeks (Lipsky & Tao, 1997). After discontinuing the medication, the blood parameters returned to normal.
    B) THROMBOCYTOPENIC DISORDER
    1) Thrombocytopenia may occur following higher doses. Onset may occur within days of treatment (Chen, 2001). Lipsky & Tao (1997) reported 3 (n=537) patients with thrombocytopenia in a clinical study. Chou et al (1995) reported a male adult with thrombocytopenia (118,000/mcL) and hemoconcentration (hemoglobin 20.5 g/dL) following a single dose of Tripterygium. This same patient was suspected to have disseminated intravascular coagulation (DIC) since his prothrombin time and activated partial thromboplastin time were also prolonged.
    a) Most often, the hematologic effects are transient, and recovery is generally complete following discontinuation of the herbal (Pyatt et al, 2000).

Dermatologic

    3.14.1) SUMMARY
    A) Rashes may occur following consumption of Tripterygium.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) Rashes were reported in 29 patients, herpetic rashes in 11 patients, and skin ulceration in 2 patients following doses of a methanol-chloroform extract of Tripterygium in a clinical study of 537 patients (Lipsky & Tao, 1997). In another study of an ethanol-ethyl acetate extract of Tripterygium used in rheumatoid arthritis, rash was reported in 15 (43%) of patients (Lipsky & Tao, 1997).
    B) DISCOLORATION OF SKIN
    1) Skin pigmentation has been reported to occur within weeks or months after treatment with Tripterygium extracts (Chen, 2001).

Immunologic

    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LYMPHOCYTES ATYPICAL
    a) MICE - Acute toxicity studies in mice determined the major target organ of toxicity was the lymphatic system. Decreased numbers of follicles and lymphocytes in lymph nodes, spleen, and intestines were noted (Lipsky & Tao, 1997). Changes in the lymphatic system were dose-dependent.

Reproductive

    3.20.1) SUMMARY
    A) Occipital meningoencephalocele in an infant has been associated with taking Tripterygium wilfordii during the first 8 weeks of pregnancy.
    B) A high incidence of anomalies have been reported in mouse embryos during organogenesis where the embryos were give Tripterygium doses.
    3.20.2) TERATOGENICITY
    A) EMBRYOTOXICITY
    1) Occipital meningoencephalocele was associated with taking Tripterygium wilfordii during the first 8 weeks of pregnancy. The mother took the herbal medication for rheumatoid arthritis. The infant was delivered at 38 weeks of gestation. A huge cystic mass protruding from the occiput was observed. A diagnosis of occipital meningoencephalocele and cerebellar agenesis was made and was attributed to Tripterygium use during the first trimester of pregnancy (Takei et al, 1997).
    3.20.3) EFFECTS IN PREGNANCY
    A) ANIMAL STUDIES
    1) Chan & Ng (1995) reported a high incidence of anomalies in mouse embryos during organogenesis, including branchial cleft anomalies, open cranial neural tube, microcephaly, abnormal optic and otic vesicles, absence of forelimb buds and others during in-vitro studies where mouse embryos were given Tripterygium doses of 50 and 100 mcg/mL.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation.

Genotoxicity

    A) Triptolide, an oxygenated diterpene isolate from Tripterygium wilfordii was shown not to be mutagenic toward Salmonella typhimurium strain TM677 (Shamon et al, 1997).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Tripterygium serum levels are not clinically useful or readily available.
    B) Monitor vital signs and ECG in all symptomatic patients.
    C) Fluid status, electrolytes including calcium and renal function should be monitored in patients with excessive vomiting and/or diarrhea.
    D) CBC should be obtained in symptomatic patients.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) Serum Tripterygium levels are not clinically useful and are not readily available.
    B) BLOOD/SERUM CHEMISTRY
    1) Monitor renal and hepatic function tests in patients with significant exposure.
    2) Monitor fluid status and serum electrolytes including calcium in patients with substantial fluid losses from vomiting and/or diarrhea.
    C) HEMATOLOGIC
    1) Following significant exposure, monitor CBC. Granulocytopenia and thrombocytopenia have been reported following excessive doses.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor ECG in all symptomatic exposures.

Methods

    A) CHROMATOGRAPHY
    1) High performance liquid phase chromatography (HPLC) has been used to identify Tripterygium wilfordii in an herbal fluid (Chou et al, 1995).

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) As there is very limited clinical experience with Tripterygium poisoning in humans, all patients with significant exposure or symptoms should be admitted to the hospital and carefully observed until all symptomatology has resolved.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Observe all patients following significant exposures as outpatients for 24 hours, and admit to hospital if severe diarrhea or vomiting occur or if vital signs decline.

Monitoring

    A) Tripterygium serum levels are not clinically useful or readily available.
    B) Monitor vital signs and ECG in all symptomatic patients.
    C) Fluid status, electrolytes including calcium and renal function should be monitored in patients with excessive vomiting and/or diarrhea.
    D) CBC should be obtained in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor CBC for hematologic disturbances, such as leukopenia and thrombocytopenia, and treat symptomatically. Monitor vital signs for possible decreased blood pressure and increased pulse rate.
    2) Cardiac disturbances may occur following large doses of Tripterygium, therefore ECG should be monitored in symptomatic patients.
    B) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Fluid and electrolytes should be monitored in all symptomatic patients. Administer fluids to overcome dehydration and shock. Replace electrolytes as necessary.
    C) ACIDOSIS
    1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.
    2) Repeat doses of no more than one-half the original amount may be given no more often than every 10 minutes if required.
    D) 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).
    4) Depressed cardiac contractility may contribute to hypotension. Central venous or pulmonary capillary wedge pressure monitoring may be useful to guide fluid and vasopressor therapy.
    E) VENTRICULAR ARRHYTHMIA
    1) VENTRICULAR DYSRHYTHMIAS SUMMARY
    a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    2) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    4) PROCAINAMIDE
    a) PROCAINAMIDE/INDICATIONS
    1) An alternative drug in the treatment of PVCs or recurrent ventricular tachycardia when lidocaine is contraindicated or not effective. It should be avoided when the ingestion involves agents with quinidine-like effects (e.g. tricyclic antidepressants, phenothiazines, chloroquine, antidysrhythmics) and when the ECG reveals QRS widening or QT prolongation suspected to be secondary to overdose(Neumar et al, 2010; Vanden Hoek,TLet al,null).
    b) PROCAINAMIDE/ADULT LOADING DOSE
    1) 20 to 50 milligrams/minute IV until dysrhythmia is suppressed or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%), or a total dose of 17 milligrams/kilogram is given (1.2 grams for a 70 kilogram person) (Neumar et al, 2010).
    2) ALTERNATIVE DOSING: 100 mg every 5 minutes until dysrhythmia is controlled, or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%) or 17 mg/kg have been given (Neumar et al, 2010).
    3) MAXIMUM DOSE: 17 milligrams/kilogram (Neumar et al, 2010).
    c) PROCAINAMIDE/CONTROLLED INFUSION
    1) In conscious patients, procainamide should be administered as a controlled infusion (20 milligrams/minute) because of the risk of QT prolongation and its hypotensive effects (Link et al, 2015)
    d) PROCAINAMIDE/ADULT MAINTENANCE DOSE
    1) 1 to 4 milligrams/minute via an intravenous infusion (Neumar et al, 2010).
    e) PROCAINAMIDE/PEDIATRIC LOADING DOSE
    1) 15 milligrams/kilogram IV/Intraosseously over 30 to 60 minutes; discontinue if hypotension develops or the QRS widens by 50% (Kleinman et al, 2010).
    f) PROCAINAMIDE/PEDIATRIC MAINTENANCE DOSE
    1) Initiate at 20 mcg/kg/minute and increase in 10 mcg/kg/minute increments every 15 to 30 minutes until desired effect is achieved; up to 80 mcg/kg/minute (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    g) PROCAINAMIDE/PEDIATRIC MAXIMUM DOSE
    1) 2 grams/day (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    h) MONITORING PARAMETERS
    1) ECG, blood pressure, and blood concentrations (Prod Info procainamide HCl IV, IM injection solution, 2011). Procainamide can produce hypotension and QT prolongation (Link et al, 2015).
    i) AVOID
    1) Avoid in patients with QT prolongation and CHF (Neumar et al, 2010).

Enhanced Elimination

    A) SUMMARY
    1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Abstracts

Case Reports

    A) ADULT
    1) A 36-year-old male, with severe vomiting and diarrhea of 3 days duration, was admitted to the hospital. He was hypotensive (BP 74/44 mmHg), and had lost an estimated 4000 to 5000 mL of fluid. The profuse vomiting and diarrhea began about 10 hours following the ingestion of an extract of Tripterygium wilfordii, which the authors later determined was probably a toxic dose (Chou et al, 1995).
    a) CBC revealed granulocytopenia (WBC 1000/mcL, with 4% bands, 18% segmented cells, and 71% lymphocytes), thrombocytopenia (118,000/mcL), hemoconcentration (Hgb 20.5 g/dL), and mild elevation of hepatic and cardiac enzymes. Other laboratory parameters showed azotemia (BUN 32 mg/dL and creatinine 2.7 mg/dL), hypocalcemia (total Ca 1.83 mmol/L), and metabolic acidosis (arterial blood pH 7.335, PO2 140 mmHg, PCO2 21 mmHg and bicarbonate 11.0 mmol/L). An ECG showed sinus tachycardia, widened QRS complex with ST elevation and low voltage. Echocardiogram revealed global hypokinesis. An ECG several years prior to admission was normal except for an incomplete right bundle branch block.
    b) His metabolic acidosis and hypocalcemia progressively worsened despite bicarbonate and calcium gluconate therapy. Ventricular tachyarrhythmias developed which did not respond to cardiac massage and cardioversion. The patient died as a result of hypovolemic shock with possible contributory cardiac damage.

Range Of Toxicity

Summary

    A) Human toxicity reports are limited. Dosage is variable due to the nature of the plant, with extracts derived from the root. Other parts of the plant are highly toxic, and if ingested may cause more toxic effects. It is reported that the margin of safety of this herbal is narrow.
    B) A home-made extract from the plant roots was reported to cause death as a result of hypovolemic shock.

Therapeutic Dose

    7.2.1) ADULT
    A) DISEASE STATE
    1) RHEUMATOID ARTHRITIS - Tripterygium extract 1.0 milligram/kilogram per day has been reported as a therapeutic dose (Asano et al, 1998).
    2) INFLAMMATORY CONDITIONS - Lipsky & Tao (1997) report a methanol-chloroform extract of the woody portion of the roots, referred to as T2, is manufactured as a 20 milligram dose, to be taken 3 times daily.

Minimum Lethal Exposure

    A) ACUTE
    1) MOUSE - A lethal oral dose of Tripterygium wilfordii extract has been reported to be 500 micrograms/kilogram in the mouse. Since an oral effective dose in humans is reported to be 1 milligram/kilogram/day, the metabolic pathway of the effective components of this herbal extract may be different between humans and mice (Asano et al, 1998).
    2) LD50 studies of the ethanol/ethyl acetate extract of Tripterygium in mice showed a lethal dose range in 50% of the animals to be 608 to 858 milligrams/kilogram, which varied with the source of the plant and season of harvest (Lipsky & Tao, 1997).
    3) LD50 studies in mice using the chloroform/methanol extract revealed an LD50 for acute toxicity of 160 +/-14 milligrams/kilogram (Lipsky & Tao, 1997).
    4) IN-VITRO - Studies have shown a dose-toxicity relationship with extracts of Tripterygium (Li & Weir, 1990).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Lipsky & Tao (1997) reported adverse effects of a methanol-chloroform extract of Tripterygium, given for 12 weeks in a dosage of 20 milligrams 3 times daily. The most common effects were gastric disturbances. Transient effects of leukopenia and thrombocytopenia were reported in several patients. Within days of starting therapy, some of the gastric effects, including anorexia, abdominal pain, vomiting, diarrhea, and esophageal burning occurred. All adverse effects appeared to be dose-related and were reversible.
    a) Effects occurring after several weeks or months of therapy included oral ulcers, skin pigmentation, and menstrual disturbances. Amenorrhea was reported to be related to cumulative dosing.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) TRIPTERYGIUM HYPOGLAUCUM HUTCH, EXTRACT
    1) LD50- (ORAL)MOUSE:
    a) 3496 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)RAT:
    a) 3975 mg/kg (RTECS, 2001)
    B) TRIPTERYGIUM WILFORDII HOOK F, ROOT EXTRACT
    1) LD50- (ORAL)MOUSE:
    a) 158 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Anti-inflammatory actions of Tripterygium may be due to a direct effect. Inhibition of production of arachidonic acid metabolites may contribute to the anti-inflammatory effects (Tao et al, 1998). A methanol-chloroform extract of Tripterygium (T2) was demonstrated to preferentially inhibit the expression of an inducible COX-2 mRNA, which in turn reduced the production of prostaglandin E2. The constitutive COX-1 mRNA was not affected by T2.
    1) Asano et al (1998) demonstrated the suppressive effects of Tripterygium on collagen arthritis in mice. Extracts appeared to inhibit the ability of inguinal lymph node cells to produce T cell cytokines interleukin-2 and interferon-gamma. The production of macrophage cytokines interleukin -1 beta and tumor necrosis factor were also inhibited. The authors showed that Tripterygium can inhibit the onset and development of arthritis and immune responses to collagen, but cannot alter the severity of established disease.
    2) Chang et al (1997) have demonstrated in-vitro inhibition of interleukin-2 and interleukin-4 production from lymphocytes, and prostaglandin E secretion from monocytes by Tripterygium wilfordii Hook-f, thus concluding that this herbal exerts a strong suppressive effect on human immune responses. Kao et al (1993) attribute the success of this herbal in a patient to potentiating the effects of prednisone, another immunosuppressive agent, in resolving a case of severe lupus nephritis associated with severe proteinuria.
    B) Tripterygium wilfordii multiglycoside inhibits glomerular albumin permeability in vitro. This may be due to a direct stabilization of the glomerular permeability barrier by increasing or maintaining the anionic charges on the filtration barrier. Another mechanism may be the stabilization of actin cytoskeletal proteins or the actin binding proteins of the podocytes (Sharma et al, 1997).
    C) The male anti-fertility effects of Tripterygium appear to be the result of an effect on metamorphosing spermatids and testicular and epididymal spermatozoa. It causes exfoliation and inhibition of basic nuclear protein turnover of late spermatids. The extracts of this herbal may also create delayed spermiation and sperm head-tail separation, and damage microtubules, microfilaments and membranes. The immunosuppressive doses are approximately 5 to 12 times the anti-fertility doses (Zhen et al, 1995).

Toxicologic Mechanism

    A) Tripterygium wilfordii may cause leukopenia and thrombocytopenia due to its cytotoxicity. It inhibits antigen- and mitogen-induced proliferation of T and B cells, IL-2 production by T cells, and immunoglobulin production by B cells, leading to immunosuppression (Tao et al, 1991; Li & Weir, 1990; Shamon et al, 1997). Prostaglandin E2 (PGE2) in peripheral blood mononuclear cells (PBMC) from normal persons and from rheumatoid arthritis (RA) patients were strongly suppressed by Tripterygium and dexamethasone (Tao et al, 1998). Triptolide, a major active component of the plant, is known to be immunosuppressive on T cells and B cells. The suppression of PGE2 by Tripterygium was weaker than indomethacin but the anti-inflammatory effect of Tripterygium was stronger and more persistent, most likely through additional inhibition of lymphocyte proliferation, interleukin production, and immunoglobulin production.
    1) A methanol-chloroform extract of Tripterygium (T2) does not appear to be directly cytotoxic to bone marrow cells, even at the highest doses tested. Studies using human CD34-positive human bone marrow cells have shown that T2 directly blocks the ability of very early multilineage as well as lineage-specific committed HPC to respond to growth factors and form colonies. This suppression may manifest as a loss of hematopoietic regenerative potential in patients receiving T2 and may result in aplastic anemia (Pyatt et al, 2000). The two glycosides thought responsible for T2-induced immunosuppression are triptolide and tripdiolide, which make up about 0.1% of T2 extract.
    B) Higher or toxic doses of Tripterygium have been reported to cause damage to the CNS, including necrosis of the midbrain, medulla, and cerebellum, and cause gastric ulcerations, cardiac muscle necrosis, and hepatocellular necrosis. When taken by mothers during the period of organogenesis, anomalies may occur, as reported in toxicity studies of mouse embryos (Chan & Ng, 1995).

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