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PLANTS-PASSIFLORA

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) There are approximately 400 species of the genus Passiflora. They are primarily vines. The term "Passion Flower" denotes many of the Passiflora species, but is primarily associated with Passiflora incarnata, which is used medicinally in the United States and Europe.
    B) Passiflora incarnata is a flowering vine from which passionflower extract, used in homeopathic medicine, is derived. The plant extract contains alkaloids (harman or passiflorin), flavonoids, and other constituents (maltol and ethylmaltol). The Council of Europe lists Passion Flower as a natural source of food flavoring.

Specific Substances

    A) PASSIFLORA INCARNATA
    1) Apricot vine
    2) Granadilla
    3) Grenadille
    4) Harman
    5) Maypop
    6) Maracuja
    7) Pasionari
    8) Passiflora extract
    9) Passiflorae herba
    10) Passiflorin
    11) Passion Flower
    12) Passion vine
    13) Wild Passion Flower
    14) CAS 8057-62-3 (Passion Flower Extract)
    15) CAS 486-84-0 (harman)
    RELATED SPECIES
    1) PASSIFLORA ALATA
    2) PASSIFLORA ANTIOQUIENSIS
    3) PASSIFLORA CAERULEA
    4) PASSIFLORA COCCINEA
    5) PASSIFLORA CORIACEA
    6) PASSIFLORA EDULIS
    7) PASSIFLORA INVOLUCRATA
    8) PASSIFLORA LAURIFOLIA
    9) PASSIFLORA LIGULARIS
    10) PASSIFLORA MACROCARPA
    11) PASSIFLORA MALIFORMIS
    12) PASSIFLORA MOLLISSIMA
    13) PASSIFLORA QUADRANGULARS
    14) PASSIFLORA VAN-VOLXEMII

Available Forms Sources

    A) FORMS
    1) The herbal extract of this plant may be found in tablet forms (500 mg), dried herb for oral use, or by infusion, liquid extract, or tincture (Fisher et al, 2000; Newall, 1996). An oral tablet contains an extract of Passiflora incarnata L. equivalent to 500 milligrams of the active ingredients.
    B) SOURCES
    1) The extract is prepared from the dried leaves, stems, and flowers of the plant (Fisher et al, 2000). The roots have much less, if any, anxiolytic activity. Methanol extracts are more potent than water extracts (Dhawan et al, 2001a).
    C) USES
    1) Traditional medicinal uses of Passiflora incarnata have included a sedative in neurasthenia, neurovegetative dystonia, insomnia, anxiety states, restlessness, and nervous disorders (Dhawan et al, 2001; Bisset, 1994). Other historic uses have included compresses for burns and against inflammation, inflamed hemorrhoids, climacteric complaints, and pediatric attention disorders, nervousness and excitability (Dhawan et al, 2001a; Anon, 1999). The most common folk medicine use has been as a sedative and anxiolytic agent (Buchbauer et al, 1992).
    2) All species do not have equal therapeutic effect. Variations in toxic effects are unknown. In mice, at a dose of 125 milligrams/kilogram, the anxiolytic activity of P. incarnata was significant while that of P. edulis was absent (Dhawan et al, 2001).
    3) Opiate Withdrawal: Passiflora extract, given concurrently with clonidine, was effective in managing the mental symptoms (anxiety and insomnia) of opiate withdrawal. In a study of 65 opiate-dependent subjects, randomly selected to receive clonidine plus Passiflora extract (60 drops daily) or clonidine plus placebo, Akhondzadeh et al (2001) reported both protocols were equally effective for treatment of physical withdrawal symptoms; however, a significant improvement of mental symptoms with Passiflora extract was seen as compared to placebo (Akhondzadeh et al, 2001a).
    4) Anxiety: Passiflora extract has been shown, in human clinical trials and animal studies, to reduce anxiety. It has been reported that no significant difference between anxiety scores after 14 days of therapy with either oxazepam (30 milligrams/day) or Passiflora extract (45 drops/day) in a double-blind randomized trial on 36 outpatients diagnosed with general anxiety disorder (Akhondzadeh et al, 2001a).
    a) Using the plus-maze model of anxiety in mice, a methanol extract of P. incarnata showed significant anti-anxiety activity. Preliminary information would indicate the activity due to a benzoflavone (Dhawan et al, 2001b).

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: There are approximately 400 species of the genus Passiflora. They are primarily vines found in Central or South America.
    B) USES: The herbal extract has been used in American traditional medicine for many years for sedative effect, to treat insomnia, anxiety, restlessness, analgesic action and nervous disorders.
    C) PHARMACOLOGY: PLANT: The aerial parts of Passiflora incarnata have several primary constituents that include: flavonoids, maltol, cyanogenic glycosides, and indole alkaloids. The indole alkaloids occur in small amounts and include: harman, harmin, harmalin, harmol, and harmalol which act as monoamine-oxidase inhibitors. It is predicted that similar alkaloids exist within other Passiflora species. HERBAL EXTRACT: The extract from Passiflora incarnata has been reported to contain flavonoids and their glycosides, beta-carboline alkaloids (harman or passiflorin), cyanogenic glycosides, benzopyrone derivatives, gamma-aminobutyric acid, volatile constituents, and terpene derivatives.
    D) TOXICOLOGY: The pharmacological profile of the extracts of this plant suggests that large doses may result in CNS depression and potentially conduction disturbances.
    E) EPIDEMIOLOGY: Exposures have occurred, but appear infrequent. Significant human toxicity is very rare.
    F) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: The herbal extract (containing Passiflora incarnata) can produce sedation and drowsiness in large doses. Bradycardia may also occur following a large ingestion of the extract. Other adverse effects include dizziness and allergic reaction. LESS FREQUENT: Confusion, ataxia, anorexia, diarrhea, and fatigue have also been reported. CASE REPORT: In one case, a woman taking a therapeutic dose of Passiflora incarnata extract developed severe nausea, vomiting, drowsiness, prolonged QT and episodes of non-sustained ventricular tachycardia.
    G) WITH POISONING/EXPOSURE
    1) TOXICITY: Limited human data. There have been no reports of human overdose. However, it is anticipated that large doses of the herbal extract could produce CNS depression, bradycardia, and potentially QT prolongation and non-sustained ventricular tachycardia.
    0.2.20) REPRODUCTIVE
    A) No adverse fetal effects were found in rat dams fed the plant extract on days 7 through 17 of gestation.

Laboratory Monitoring

    A) Monitor fluid and electrolytes in patients with prolonged vomiting, QT prolongation or cardiac dysrhythmias.
    B) Monitor for CNS depression.
    C) Institute continuous cardiac monitoring and obtain and ECG in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor neuro status; large doses may result in CNS depression. Rehydrate patients that have lost fluids through vomiting; treat with IV fluids if significant GI loss occurs.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Limited human data. Severe toxicity is not anticipated. Obtain a baseline ECG and continuous cardiac monitoring following a significant exposure. Evaluate for hypoxia or electrolyte disorders in patients that develop conduction disturbances. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Treat Torsades de pointes with IV magnesium, overdrive pacing.
    C) DECONTAMINATION
    1) PREHOSPITAL: GI decontamination is unlikely to be necessary following a minor (ie, 1 herbal supplement) or "taste" ingestion due to a lack of toxicity.
    2) HOSPITAL: Activated charcoal may be indicated following a recent very large ingestion.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary unless the patient develops severe CNS depression requiring airway support or ventilation.
    E) ENHANCED ELIMINATION
    1) The role of hemodialysis in the removal of Passiflora extract is not yet known.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic child or a child with mild gastrointestinal symptoms following a minor exposure (eg, one herbal supplement) can be managed at home with adult supervision. An adult with inadvertent overdose and mild symptoms can be managed at home.
    2) OBSERVATION CRITERIA: Patients with persistent clinical effects (eg, vomiting or diarrhea) or more than mild toxicity should be referred to a healthcare facility. They may require supportive measures including IV fluids, electrolyte replacement and antiemetics.
    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 Passiflora exposure. Patients with evidence of significant neurologic toxicity (i.e., drowsiness, CNS depression) or cardiac conduction disturbances should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    G) PITFALLS
    1) Toxicity is limited, do not over treat. Limited clinical information available in the literature. Other potential unknown ingestions in a young child.

Range Of Toxicity

    A) TOXICITY: Acute toxicity of Passiflora incarnata appears to be minimal. ADULT: A woman developed severe nausea, vomiting and drowsiness and an ECG revealed bradycardia, prolonged QTc interval, and episodes of nonsustained ventricular tachycardia after ingesting Passiflora incarnata at therapeutic doses (3500 mg total) over 2 days.

Clinical Effects

Summary Of Exposure

    A) BACKGROUND: There are approximately 400 species of the genus Passiflora. They are primarily vines found in Central or South America.
    B) USES: The herbal extract has been used in American traditional medicine for many years for sedative effect, to treat insomnia, anxiety, restlessness, analgesic action and nervous disorders.
    C) PHARMACOLOGY: PLANT: The aerial parts of Passiflora incarnata have several primary constituents that include: flavonoids, maltol, cyanogenic glycosides, and indole alkaloids. The indole alkaloids occur in small amounts and include: harman, harmin, harmalin, harmol, and harmalol which act as monoamine-oxidase inhibitors. It is predicted that similar alkaloids exist within other Passiflora species. HERBAL EXTRACT: The extract from Passiflora incarnata has been reported to contain flavonoids and their glycosides, beta-carboline alkaloids (harman or passiflorin), cyanogenic glycosides, benzopyrone derivatives, gamma-aminobutyric acid, volatile constituents, and terpene derivatives.
    D) TOXICOLOGY: The pharmacological profile of the extracts of this plant suggests that large doses may result in CNS depression and potentially conduction disturbances.
    E) EPIDEMIOLOGY: Exposures have occurred, but appear infrequent. Significant human toxicity is very rare.
    F) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: The herbal extract (containing Passiflora incarnata) can produce sedation and drowsiness in large doses. Bradycardia may also occur following a large ingestion of the extract. Other adverse effects include dizziness and allergic reaction. LESS FREQUENT: Confusion, ataxia, anorexia, diarrhea, and fatigue have also been reported. CASE REPORT: In one case, a woman taking a therapeutic dose of Passiflora incarnata extract developed severe nausea, vomiting, drowsiness, prolonged QT and episodes of non-sustained ventricular tachycardia.
    G) WITH POISONING/EXPOSURE
    1) TOXICITY: Limited human data. There have been no reports of human overdose. However, it is anticipated that large doses of the herbal extract could produce CNS depression, bradycardia, and potentially QT prolongation and non-sustained ventricular tachycardia.

Vital Signs

    3.3.3) TEMPERATURE
    A) Hypothermia has been reported in animal studies following large doses (RTECS , 2002; Anon, 1999).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) Decreased or irregular pulse was reported in one adult following therapeutic use of an herbal supplement containing Passiflora incarnata (Fisher et al, 2000).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Bradycardia (43-52 bpm) developed in a 34-year-old woman following a therapeutic ingestion of 7 tablets (3500 mg) of Passiflora incarnata herbal supplement over a 2-day period. The ECG normalized over a 3-day period following antiemetics and intravenous fluids (Fisher et al, 2000).
    2) WITH POISONING/EXPOSURE
    a) Large doses of the extract may result in reduced heart rate (Anon, 1999).
    B) VENTRICULAR TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: ECG revealed bradycardia associated with ventricular bigeminy and episodes of nonsustained ventricular tachycardia in a 34-year-old woman after a therapeutic ingestion of 3500 mg of Passiflora incarnata extract tablets over a 2-day period. Her QTc interval was prolonged (0.539 seconds) with nonspecific ST-T wave changes and U waves more prominent in anterolateral leads. The ECG normalized over a 3-day period following antiemetics and intravenous fluids (Fisher et al, 2000).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ARRHYTHMIA VENTRICULAR
    a) In one study, epinephrine precipitated serious cardiac dysrhythmias, including ventricular fibrillation, when harman methosulfate (an alkaloid salt found in Passiflora) was injected into cats and dogs. Dysrhythmias ranging from nodal rhythm and ventricular extrasystoles to ventricular tachycardia and fibrillation were noted. The incidence of ventricular fibrillation was dose-dependent on harman methosulfate and epinephrine. Bradycardia was commonly observed following the injection of harman methosulfate (Scriabine & Hutcheon, 1956).
    2) BRADYCARDIA
    a) Cardiovascular actions of 3 harmala alkaloids (harmine, harmaline, and harmalol) were studied in isolated perfused rat hearts and in the intact dog. Dose-related bradycardia was observed; neither vagotomy nor atropinization affected the alkaloid-induced bradycardia in the dog. A direct negative chronotropic effect of the alkaloids was suggested (Aarons et al, 1977).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) BRONCHOSPASM
    1) Occupational respiratory allergic disease has been reported following a 6-month exposure to Passiflora alata. IgE-mediated occupational asthma and rhinitis occurred in a pharmacy worker preparing medications from the plant. Confirmation was reported with skin testing and Western blot analysis as well as bronchial challenge (Giavina-Bianchi et al, 1997).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH THERAPEUTIC USE
    a) The herbal extract is a sedative with depressant actions (Duke et al, 2002; Speroni & Minghetti, 1988; Aoyagi et al, 1974). In a meta analysis of passiflora use for anxiety disorders, confusion and ataxia were reported infrequently with therapeutic use of the herbal extract (Miyasaka et al, 2007).
    b) CASE REPORT: Drowsiness and fatigue, as well as severe nausea and vomiting and dysrhythmias were reported in a 34-year-old woman following therapeutic ingestion of 7 tablets (3500 mg) of Passiflora incarnata herbal supplements over a 2-day period. The patient recovered following antiemetics and IV fluid therapy (Fisher et al, 2000).
    2) WITH POISONING/EXPOSURE
    a) Although significant human toxicity is uncommon, it might be expected that large doses would result in CNS depression. Five patients required hospitalization for reduced levels of consciousness following ingestion of an herbal remedy for insomnia and restlessness containing Passiflora incarnata (Solbakken et al, 1997).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In a meta analysis of passiflora use for anxiety disorders, dizziness was reported infrequently with therapeutic use of the herbal extract (Miyasaka et al, 2007).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) LACK OF EFFECT: In a meta analysis of passiflora use for anxiety disorders, there were no reports of seizure activity with therapeutic use (Miyasaka et al, 2007).
    2) WITH POISONING/EXPOSURE
    a) Although not likely following an overdose, seizures may occur if the concentration of harmala alkaloids in the Passiflora extract is excessively high, and the dose ingested is massive. Seizures would NOT be expected with standardized herbal preparations following overdose.
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CNS DEPRESSION
    a) The predominant effect of Passiflora incarnata and Passiflora alata doses in mouse and rat studies, approaching the LD50, were CNS depression, with general depressed activity, prolonged sleeping time, and decreased locomotor activity (RTECS , 2002; Speroni & Minghetti, 1988; Oga et al, 1984). Death in animals was due to CNS depressant effects, and in lethal doses, death occurred within 24 hours.
    b) Buchbauer et al (1992) demonstrated in mice that inhalation of essential oils of Herba Passiflora resulted in decreased motility in caffeine-stimulated animals, confirming a sedative action of the plant oils (Buchbauer et al, 1992).
    c) Following 3 weeks of oral treatment of rats with Passiflora incarnata, a diminished general activity in the one-arm radial maze was noted (Sopranzi et al, 1990).
    2) SEIZURES
    a) The harmala alkaloid portion of Passiflora incarnata has been studied in animals and has been shown to have a stimulant effect, possibly as a result of monoamine oxidase inhibition. When injected into animals, harmala alkaloids have caused seizures. However, when the total extract is administered, maltol alkaloid caused CNS depression and was felt to counteract the stimulant action of harmala alkaloids (Tyler, 1993; Aoyagi et al, 1974).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Based on limited human data, nausea and vomiting may occur following an overdose.
    b) CASE REPORT: Severe nausea and profuse and prolonged vomiting resulted in mild dehydration in a 34-year-old woman following therapeutic ingestion of 7 tablets (3500 mg) of Passiflora incarnata extract over 2 days (Fisher et al, 2000).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In a meta-analysis of passiflora use for anxiety disorders, diarrhea developed with therapeutic use of the herbal extract (Miyasaka et al, 2007).
    C) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) In a meta-analysis of passiflora use for anxiety disorders, anorexia was reported infrequently with therapeutic use of the herbal extract (Miyasaka et al, 2007).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) VASCULITIS
    1) WITH THERAPEUTIC USE
    a) Urticaria and cutaneous vasculitis due to an idiosyncratic hypersensitivity reaction following 3 weeks of alternate day ingestions of an herbal preparation of a Passiflora plant has been reported. Blisters, papules and purpura developed over the chest, shoulder, ankles and thumb. Symptoms cleared after discontinuance of the herbal product (Smith et al, 1993).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH POISONING/EXPOSURE
    a) IgE-mediated occupational asthma and rhinitis have been reported in a pharmacy worker following 6 months exposure to Passiflora alata while preparing medicinal products from the plant. Skin testing and Western blot confirmed sensitization of the patient to the plant extracts. Bronchial challenge confirmed a cause-and-effect relationship (Giavina-Bianchi et al, 1997).
    b) A case of idiosyncratic hypersensitivity reaction to the plant extract resulting in urticaria and cutaneous vasculitis has been reported An herbal preparation of the plant extract was taken orally on alternate days for 3 weeks prior to symptoms. Following herbal discontinuation, symptoms cleared (Smith et al, 1993).

Reproductive

    3.20.1) SUMMARY
    A) No adverse fetal effects were found in rat dams fed the plant extract on days 7 through 17 of gestation.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) No adverse fetal effects were found when rat dams were fed up to 400 milligrams/kilogram of the extract on days 7 through 17 of gestation (Hirakawa et al, 1981).

Genotoxicity

    A) The harmanal flavonoid portion of Passiflora incarnata extracts has been shown to be genotoxic in bacterial, murine, and human assays (AR Scialli , 2000).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor fluid and electrolytes in patients with prolonged vomiting, QT prolongation or cardiac dysrhythmias.
    B) Monitor for CNS depression.
    C) Institute continuous cardiac monitoring and obtain and ECG in symptomatic patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolyte levels, particularly in symptomatic patients with prolonged vomiting and/or cardiac dysrhythmias.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Monitor ECG and initiate continuous cardiac monitoring in symptomatic patients.
    2) MONITORING
    a) Monitor for central nervous system depression.

Methods

    A) SPECTROMETRY/SPECTROSCOPY
    1) Li et al (1991) described a mass spectral and C NMR method for the determination of the four major C-glycosidic flavonoids isolated from Passiflora incarnata. The data from this spectrometry method corresponded to the four major flavonoids found on reversed-phase HPLC of crude extracts of the plant (Qimin et al, 1991).
    B) CHROMATOGRAPHY
    1) An isocratic high performance liquid chromatographic method is described for the determination of Passiflora incarnata flavonoids in drugs used as sedatives (Pietta et al, 1986).
    2) A GC-MS procedure has been described for the quantification of the volatile components of Passiflora and the plant constituents, maltol and 2-phenylethanol, in the blood of mice following inhalation of the essential plant oils (Buchbauer et al, 1992).

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 Passiflora exposure. Patients with evidence of significant neurologic toxicity (i.e., drowsiness, CNS depression) or cardiac conduction disturbances 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, one herbal supplement) can be managed at home with adult supervision. Adults with mild symptoms after inadvertent overdose can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with persistent clinical effects (eg, vomiting or diarrhea) or more than mild toxicity should be referred to a healthcare facility. They may require supportive measures including IV fluids, electrolyte replacement and antiemetics.

Monitoring

    A) Monitor fluid and electrolytes in patients with prolonged vomiting, QT prolongation or cardiac dysrhythmias.
    B) Monitor for CNS depression.
    C) Institute continuous cardiac monitoring and obtain and ECG in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) GI decontamination is generally not recommended as acute toxicity is limited.
    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) Treatment is symptomatic and supportive. Rehydrate patients as necessary.
    2) Continuous cardiac monitoring should be instituted and an ECG obtained in all symptomatic patients.
    3) Monitor serum electrolytes in patients with protracted vomiting or QT prolongation.
    4) Monitor for CNS depression. In very rare cases, seizures may occur if ingestion of haramala alkaloids is excessively high. Note: This is unlikely to occur following ingestion of the herbal extract; it may be more likely to occur following the ingestion of a Passiflora plant species.
    5) In the unusual event of seizures (only reported in animal studies secondary to haramala alkaloid exposure), treat with standard anticonvulsants.
    B) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Vomiting may be prolonged with large ingestions, resulting in fluid and electrolyte loss. Monitor and replace fluids as necessary. Treat with antiemetics.
    C) VENTRICULAR ARRHYTHMIA
    1) Based on limited data, severe symptomatic conduction disturbances have not been reported in humans.
    2) Asymptomatic ventricular dysrhythmias (ie, non-sustained ventricular tachycardia) were reported in one adult following therapeutic use of a herbal extract containing Passiflora incarnata. She was monitored for several days but did not require any pharmacologic interventions. Therapy was limited to Intravenous fluids and antiemetics to control GI symptoms (Fisher et al, 2000).
    3) 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.
    4) LIDOCAINE/INDICATIONS
    a) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    5) LIDOCAINE/DOSE
    a) 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.
    1) 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).
    b) 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).
    6) LIDOCAINE/MAJOR ADVERSE REACTIONS
    a) 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).
    7) LIDOCAINE/MONITORING PARAMETERS
    a) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    8) AMIODARONE/INDICATIONS
    a) 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).
    9) AMIODARONE/ADULT DOSE
    a) 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).
    10) AMIODARONE/PEDIATRIC DOSE
    a) 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).
    11) ADVERSE EFFECTS
    a) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    D) TORSADES DE POINTES
    1) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    2) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    3) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    4) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    5) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    6) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    7) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

Enhanced Elimination

    A) HEMODIALYSIS
    1) The role of hemodialysis in the removal of Passiflora extract is not yet known.

Range Of Toxicity

Summary

    A) TOXICITY: Acute toxicity of Passiflora incarnata appears to be minimal. ADULT: A woman developed severe nausea, vomiting and drowsiness and an ECG revealed bradycardia, prolonged QTc interval, and episodes of nonsustained ventricular tachycardia after ingesting Passiflora incarnata at therapeutic doses (3500 mg total) over 2 days.

Therapeutic Dose

    7.2.1) ADULT
    A) DISEASE STATE
    1) SEDATIVE (Passiflora incarnata) -
    a) Dried herb: 0.25 to 1.0 gram orally or by infusion (as a tea) 3 times daily
    b) Liquid extract (1:1 in 25% alcohol): 0.5 to 1.0 milliliter 3 times daily
    c) Tincture (1:8 in 45% alcohol): 0.5 to 2.0 milliliter 3 times daily
    d) Tablets: 500 to 1000 milligrams 3 times daily
    e) References: Duke et al, 2002; Blumenthal, 1998; Bisset, 1994; Newell et al, 1996

Maximum Tolerated Exposure

    A) ADULT
    1) Following therapeutic ingestion of 7 tablets (3500 mg) of Passiflora incarnata as an herbal supplement over 2 days, a 34-year-old woman developed severe nausea, vomiting and drowsiness and was admitted to the ED. ECG revealed bradycardia, prolonged QTc interval, and episodes of nonsustained ventricular tachycardia (Fisher et al, 2000).
    B) ANIMAL DATA
    1) MICE: In studies determining the pharmacological activity of the herbal extract, no acute toxicity was observed after intraperitoneal injection of doses greater than 900 mg/kg in mice (Speroni & Minghetti, 1988).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA (Passiflora incarnata extract)
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 3140 mg/kg (RTECS, 2002)
    2) LD50- (ORAL)MOUSE:
    a) Greater than 15 grams/kg (RTECS, 2002)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 8300 mg/kg (RTECS, 2002)
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 3510 mg/kg (RTECS, 2002)
    5) LD50- (ORAL)RAT:
    a) Greater than 15 grams/kg (RTECS, 2002)
    6) LD50- (SUBCUTANEOUS)RAT:
    a) Greater than 10 grams/kg (RTECS, 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The exact mechanism of action of Passiflora incarnata extract has NOT yet been determined. Neuropharmacological studies in animals have shown a complex activity on the CNS, inducing dose-dependent stimulation and depression. The extract causes a rise in the nociceptive threshold which may be due to motor impairment induced by the extract. In rats, locomotor activity was significantly affected, as was pentobarbital-induced sleeping time, which was prolonged. Rats were protected from the convulsive effects of pentylenetetrazole. Further studies are needed to assess possible relationships with CNS neurotransmitters (Speroni & Minghetti, 1988). The plant flavonoids may act on central benzodiazepine receptors (Bourin et al, 1997) Wolfman et al, 1994). After fractionating and testing in mice, the active constituent remains unidentified, but appears to be a benzoflavone moiety (Dhawan et al, 2001b).
    B) Low doses (3 to 6 milligrams) of the harman alkaloid have produced CNS effects similar to those of coffee or tea, while higher doses of 15 to 35 mg have caused strong motor unrest, followed by drowsiness. Higher doses have caused hallucinations, severe motor unrest, and vomiting. Harmala alkaloids have been shown to inhibit monoamine oxidase, which may account for some of their pharmacological effect (Anon, 1999).
    C) When the maltol fraction of the Passiflora incarnata extract was administered to mice (400 milligrams/kilogram SC), reduced spontaneous activity, bradycardia, hypothermia, relaxation of skeletal muscle, and diminished pinna, corneal and ipsilateral flexor reflexes were noted. It is suggested that maltol and ethyl maltol may mask the stimulant effects of harmala alkaloids in Passiflora incarnata (Aoyagi et al, 1974).
    D) Passiflora incarnata extract is known to contain flavonoids, beta-carboline alkaloids, and terpene derivatives. It is unknown which agent in the extract is responsible for the herbal drugs sedative-like actions. Speroni & Minghetti (1988) found two different products within the extract that chemically appeared to be responsible for the biologic activity. One behaved similar to a very lipophilic compound, which did NOT correspond to either aromatic or heterocyclic structures due to its low absorbance in the UV region. The other compound behaved like a very polar compound, with similar chemical characteristics as the first compound. This compound contained a great majority of flavonoid derivatives, but were ruled out as being responsible for the biologic activity. The first compound was an aglycone and the other its hydroxylated or glycosylated derivative.
    E) Studies on the effects of harmaline and other harmala alkaloids on contractions induced in the vascular smooth muscle of rabbit aorta and guinea pig intestinal smooth muscle have suggested an inhibition of contractile response due to inhibition of calcium channels. The potency and selectivity of inhibitory effects varies by modification of the alkaloid structure (Karaki et al, 1986).
    1) Harmaline inhibited the sustained contraction in the aorta induced by high concentrations of potassium and by noradrenaline. The inhibitory effects of harmaline on potassium-induced contractions were antagonized by external calcium concentrations, but the harmaline inhibition of noradrenaline contractions were NOT antagonized by external calcium. This suggests that harmaline inhibits the pathways of calcium influx which are activated by high potassium and receptor agonists.
    2) Scriabine & Hutcheon (1956) reported that epinephrine precipitated serious cardiac dysrhythmias, including ventricular fibrillation, when harman methosulfate was injected into cats and dogs. Dysrhythmias ranging from nodal rhythm and ventricular extrasystoles to ventricular tachycardia and fibrillation were noted. The incidence of ventricular fibrillation was dose-dependent on harman methosulfate and epinephrine. Bradycardia was commonly observed following the injection of harman methosulfate.

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