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ARISTOLOCHIC ACID

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Aristolochic acid, derived from the alkaloid aristolochine, is principally found in members of the Aristolochiaceae plant family. It consists of a group of related nitrophenanthrene carboxylic acid derivatives, appearing in two major forms, aristolochic acid I and aristolochic acid II. These acids are nephrotoxic, carcinogenic, mutagenic, and genotoxic, and are found in some herbal preparations, particularly Aristolochia fang chi, which is particularly aristolochic-acid rich.

Specific Substances

    1) Aristolochic acid
    2) Aristolactone
    3) Aristolochic acid-I
    4) Aristolochic acid-II
    5) Aristolochic acid A
    6) Aristolochine
    7) Aristored
    8) 8-Methoxy-6-nitrophenanthro-(3,4-d)-1,3-dioxole-
    9) 5-carboxylic acid
    10) 3,4-Methylenedioxy-8-methoxy-10-nitro-1-
    11) phenanthrenecarboxylic acid
    12) Molecular formula C17-H11-N-O7
    13) CAS 313-67-7
    14) CAS 61117-05-3
    15) CAS 313-67-7 (ARISTOLOCHIC ACID)

Available Forms Sources

    A) FORMS
    1) Aristolochine is a yellow, amorphous substance which has a bitter and slightly acrid taste ((Grieve, 1998)). Aristolochic acids are slightly soluble in water and soluble in alcohol (Budavari, 1996).
    B) USES
    1) Plants containing aristolochic acid have been used as anti-inflammatories, antivirals, immune system stimulants, and in herbal drugs. Most recently, slimming herbal regimens containing Aristolochia fang chi have been associated with Chinese herb nephropathy. Other herbals have been used for the treatment of snake bites. In Germany and other countries, plants containing aristolochic acid are no longer recommended for human use (McGuffin et al, 1997).
    2) As a stimulant, tonic roots promote perspiration. Choctaw Indians use it to alleviate stomachache. It supposedly promotes appetite, tones the digestive organs and serves as a cardiac stimulant. It is used an adjunct to quinine in malaria. In larger doses, it is used to promote diaphoresis and diuresis. It is also reported to be useful in amenorrhea, bilious fever, dyspepsia, erysipelas, pneumonia, smallpox, typhoid and typhus (Millspaugh, 1974).
    3) Mose et al (1980) applied aristolochic acid to the eyes of rabbits infected with herpes simplex, which lead to a more rapid healing of the lesions as compared to an untreated control group.

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: Aristolochic acid, derived from the alkaloid aristolochine, is principally found in members of the Aristolochiaceae plant family. It consists of a group of related nitrophenanthrene carboxylic acid derivatives, appearing in two major forms, aristolochic acid I and aristolochic acid II. These acids are nephrotoxic, carcinogenic, mutagenic, and genotoxic, and are found in some herbal preparations, particularly Aristolochia fang chi, which is particularly aristolochic-acid rich.
    B) USES: Plants containing aristolochic acid have been used as anti-inflammatories, antivirals, immune system stimulants, and in herbal drugs as slimming agents. As a stimulant, tonic roots promote perspiration. Choctaw Indians use it to alleviate stomachache. It supposedly promotes appetite, tones the digestive organs and serves as a cardiac stimulant. It is used as an adjunct to quinine in malaria. In larger doses, it is used to promote diaphoresis and diuresis. It is also reported to be useful in amenorrhea, bilious fever, dyspepsia, erysipelas, pneumonia, smallpox, typhoid and typhus.
    C) TOXICOLOGY: Slimming herbal regimens containing Aristolochia fang chi have been associated with Chinese herb nephropathy. A possible mechanism is that a DNA mutation is responsible for kidney-destructive fibrotic processes in patients with aristolochia nephropathy. Persistence of specific DNA adducts months following discontinuation of aristolochia herbs suggests non-repairable lesions in a number of tissues exposed to carcinogens. Interindividual variability in aristolochia metabolism and batch-to-batch differences of aristolochic acid content in herbal capsules are major factors influencing DNA adduct levels.
    D) EPIDEMIOLOGY: Acute exposure is rare. Toxicity appears to be related to chronic use.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild to moderate hypertension, metabolic acidosis, and electrolyte depletion (eg, hypokalemia, hypophosphatemia, hypouricemia) have been reported and may be secondary to aristolochic acid-induced renal failure.
    2) SEVERE TOXICITY: Chronic use of aristolochic acid, particularly the herbal preparation, Aristolochia fang chi, has been associated with a rapidly progressive fibrosing interstitial nephritis, termed "Chinese herb nephropathy" or "aristolochia herb nephropathy" which may progress to terminal renal failure. Other toxic effects that have been reported include severe anemia secondary to the development of nephropathy, Fanconi's syndrome, muscle weakness, and paralysis. Valvular heart disease has been reported in some patients following concomitant administration of appetite suppressants and herbal supplements, including aristolochic acid; however, a specific causal relationship with aristolochic acid consumption has not been established.
    0.2.20) REPRODUCTIVE
    A) Certain members of the Aristolochiaceae family are classified as 2b by the American Herbal Products Association Standards Committee. Those herbal medicines in class 2b should NOT be used during pregnancy .
    0.2.21) CARCINOGENICITY
    A) Aristolochic acid is a known human and animal carcinogen.

Laboratory Monitoring

    A) Monitor renal function and serum electrolytes, and obtain a urinalysis in all symptomatic patients.
    B) Monitor vital signs.
    C) Obtain a CBC and arterial blood gases in patients with evidence of renal insufficiency.
    D) Monitor liver function tests as indicated.
    E) Obtain an echocardiogram in patients with a murmur or suspected valvular disease after chronic ingestion.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Most reported cases of toxicity have involved chronic ingestion of aristolochic acid contained in herbal medicines. Treatment is symptomatic and supportive. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Correct electrolyte abnormalities as indicated.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate 1 to 2 mEq/kg. Use of steroid therapy may slow the progression of renal failure in aristolochic acid related interstitial fibrosis.
    C) DECONTAMINATION
    1) PREHOSPITAL: Toxicity after an acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary.
    2) HOSPITAL: Toxicity after acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary. Consider activated charcoal only if coingestants with significant toxicity are involved.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been administered concurrently.
    E) ANTIDOTE
    1) None.
    F) CORTICOSTEROID
    1) During a clinical trial, prednisolone 1 mg/kg was administered for 1 month, tapering off 0.1 mg/kg every 2 weeks, to a maintenance dose of 0.15 mg/kg, to patients with moderate renal failure and with biopsy-proven renal fibrosis associated with the consumption of Chinese herbs containing aristolochic acid. The steroid therapy appeared to slow the progression of renal failure.
    G) ENHANCED ELIMINATION
    1) In patients that develop renal failure despite supportive care, hemodialysis may be indicated.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients who are asymptomatic or with minimal symptoms after exposure to aristolochic acid and are otherwise improving may be managed at home.
    2) OBSERVATION CRITERIA: Patients who are symptomatic need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment 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.
    I) PITFALLS
    1) Missing an ingestion of another chemical or other possible etiologies for a patient’s symptoms. History of exposure may be difficult to obtain in some settings.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause renal insufficiency.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. During a clinical trial, 20 patients were administered IV infusions of aristolochic acid in doses ranging from 0.1 mg/kg/day for 5 days up to a single dose of 2 mg/kg. Acute toxic nephrosis was the cause of death in several of the patients; toxicity appeared to be dose and time related. An adult developed Fanconi's syndrome with hypokalemic paralysis and nephropathy after ingesting 7 g/day of a Chinese herb mixture (containing approximately 50 mcg of aristolochic acid-I) for 2 months. The patient recovered with supportive therapy.

Clinical Effects

Summary Of Exposure

    A) BACKGROUND: Aristolochic acid, derived from the alkaloid aristolochine, is principally found in members of the Aristolochiaceae plant family. It consists of a group of related nitrophenanthrene carboxylic acid derivatives, appearing in two major forms, aristolochic acid I and aristolochic acid II. These acids are nephrotoxic, carcinogenic, mutagenic, and genotoxic, and are found in some herbal preparations, particularly Aristolochia fang chi, which is particularly aristolochic-acid rich.
    B) USES: Plants containing aristolochic acid have been used as anti-inflammatories, antivirals, immune system stimulants, and in herbal drugs as slimming agents. As a stimulant, tonic roots promote perspiration. Choctaw Indians use it to alleviate stomachache. It supposedly promotes appetite, tones the digestive organs and serves as a cardiac stimulant. It is used as an adjunct to quinine in malaria. In larger doses, it is used to promote diaphoresis and diuresis. It is also reported to be useful in amenorrhea, bilious fever, dyspepsia, erysipelas, pneumonia, smallpox, typhoid and typhus.
    C) TOXICOLOGY: Slimming herbal regimens containing Aristolochia fang chi have been associated with Chinese herb nephropathy. A possible mechanism is that a DNA mutation is responsible for kidney-destructive fibrotic processes in patients with aristolochia nephropathy. Persistence of specific DNA adducts months following discontinuation of aristolochia herbs suggests non-repairable lesions in a number of tissues exposed to carcinogens. Interindividual variability in aristolochia metabolism and batch-to-batch differences of aristolochic acid content in herbal capsules are major factors influencing DNA adduct levels.
    D) EPIDEMIOLOGY: Acute exposure is rare. Toxicity appears to be related to chronic use.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild to moderate hypertension, metabolic acidosis, and electrolyte depletion (eg, hypokalemia, hypophosphatemia, hypouricemia) have been reported and may be secondary to aristolochic acid-induced renal failure.
    2) SEVERE TOXICITY: Chronic use of aristolochic acid, particularly the herbal preparation, Aristolochia fang chi, has been associated with a rapidly progressive fibrosing interstitial nephritis, termed "Chinese herb nephropathy" or "aristolochia herb nephropathy" which may progress to terminal renal failure. Other toxic effects that have been reported include severe anemia secondary to the development of nephropathy, Fanconi's syndrome, muscle weakness, and paralysis. Valvular heart disease has been reported in some patients following concomitant administration of appetite suppressants and herbal supplements, including aristolochic acid; however, a specific causal relationship with aristolochic acid consumption has not been established.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) Asymptomatic diastolic murmur and in some cases valvular heart disease have been associated with Aristolochia fang chi ingestion in patients with Chinese herb nephropathy. However, it appears that all the patients had also been taking concomitant appetite suppressants, including fenfluramine, dexfenfluramine, or phentermine, which most likely contributed to the heart murmurs (Van Ypersele de Strihou C, 1998; Vanherweghem, 1997) .
    2) Kurz & Van Ermen (1997) reported 12 cases of valvular heart disease in women taking combinations of fenfluramine, phentermine, diethylpropion, and herbal medicines. It is suggested that herbal medicines may contribute to, or be synergistic with the adverse cardiac effects of these appetite suppressants. An actual causal relationship, however, has not been established (Kurz & Van Ermen, 1997).
    3) A higher prevalence of aortic insufficiency (42% versus 0%, P<0.05) was evident in 15 cases of Chinese herb nephropathy as compared to a control group of 15 females with interstitial nephropathies of other origins (Reginster et al, 1997).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Mild to moderate hypertension has been reported in 80% of females with Chinese herb nephropathy in one study (Reginster et al, 1997).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) TACHYCARDIA
    a) The pure alkaloid, aristolochine, has been reported to cause tachycardia, weak pulse, and decreased heart tonus in animals following toxic doses (Watthim & Breyer-Brandwijk, 1962).

Respiratory

    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RESPIRATORY DEPRESSION
    a) Toxicity studies in rats and mice have shown respiratory depression or dyspnea when LD50 doses were administered (RTECS , 2000).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) PARALYSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 60-year-old man presented to the emergency department with a 2-day history of muscle weakness and an inability to walk after waking up in the morning. Interview of the patient revealed that he had been consuming 4 g of a Chinese herb powdered mixture 4 times daily to treat leg edema for 5 months prior to presentation. Neurologic examination demonstrated paralysis with areflexia of the lower extremities and decreased strength (2/5 normal) in his upper extremities with decreased bicep reflexes. Laboratory data revealed hypokalemia (plasma potassium 1.8 mEq/L), hypophosphatemia (plasma phosphate 0.9 mg/dL), hypouricemia (plasma uric acid 1.3 mg/dL), hyperphosphaturia, hyperuricosuria, and glycosuria, all of which was consistent with a diagnosis of Fanconi's syndrome. A renal biopsy showed acellular interstitial fibrosis indicative of aristolochic acid associated nephropathy. With supportive therapy, including potassium supplementation, the patient's potassium concentration increased (3.6 mEq/L) and his muscle strength improved; however, the patient's renal dysfunction persisted. Analysis of the herb mixture, via high performance liquid chromatography, revealed that the herb powder contained aristolochic acids (Yang et al, 2002).
    b) CASE REPORT: A 41-year-old man presented to the emergency department with a sudden onset of bilateral lower limb weakness and an inability to walk after waking up in the morning. Neurologic exam revealed symmetrical flaccid paralysis of the lower extremities with hyporeflexia in the upper and lower extremities. Laboratory data revealed serum creatinine level of 1.6 mg/dL, severe hypokalemia (serum potassium 1.6 mmol/L), and hypophosphatemia with hyperphosphaturia, hypouricemia with hyperuricosuria, and glycosuria, indicative of Fanconi's syndrome. Arterial blood gas analysis demonstrated hyperchloremic metabolic acidosis. Interview of the patient revealed that he had been consuming a Chinese herb mixture, later determined to contain aristolochic acid-I, daily for 2 months prior to presentation. His daily intake of the mixture was 7 g (approximately 50 mcg of aristolochic acid-I). Following supportive therapy, including oral potassium supplementation and vitamin D3, and cessation of the Chinese herb mixture, the patient completely recovered 2 months later (Tsai et al, 2005).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SOMNOLENCE
    a) Somnolence, with general depressed activity, has been demonstrated in rat and mouse studies of aristolochic acid toxicity (RTECS , 2000).
    2) ATAXIA
    a) Rat and mouse studies of aristolochic acid toxicity have resulted in ataxia (RTECS , 2000).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Reversible acute hepatitis has been reported in an adult following the use of herbal teas containing aristolochic acid. A 49-year-old woman presented with jaundice, hepatomegaly, and elevated serum liver function tests. No clear cause, other than consumption of herbal teas, could be found. A definite causal relationship was not established, but several constituents of the tea were suspected of causing the hepatitis (Levi et al, 1998).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FIBROSIS
    1) WITH THERAPEUTIC USE
    a) A rapidly progressive interstitial renal fibrosis (Chinese herb nephropathy), progressing to terminal renal failure, has been reported in patients following prolonged use of herbs containing aristolochic acid. Renal lesions consist primarily of tubular atrophy and interstitial fibrosis (Lee et al, 2004; Cosyns et al, 1994; Ono et al, 1998; Vanherweghem, 1993; Vanherweghem, 1994; Vanherweghem et al, 1996; Tanaka et al, 1997; Tanaka et al, 1997a; Van Ypersele de Strihou & Vanherweghem, 1995; Vanherweghem, 1993; Depierreux et al, 1994; (Anon, 2000); Lord et al, 1999; (Breckenridge, 1999); Cosyns et al, 1999).
    1) Cortical fibrosis without primary glomerular abnormalities has been observed in nephroureterectomy specimens from patients suffering from Chinese herb nephropathy (Cosyns et al, 1994; Depierreux et al, 1994).
    2) Changes in renal tubules, with acute renal failure and acute tubular necrosis, has been demonstrated as toxic human effects at intravenous intermittent doses of 3 mg/kg/2D (RTECS , 2000).
    3) The pattern of cortical fibrosis is homogeneous and follows a marked corticomedullary gradient, with minimal sparing of the medulla. The topography of significant vascular lesions involves mainly interlobular arteries, the presence of atypia and metaplasia of the urothelium, and in one case, a severe pelviureteral fibrosis (Cosyns et al, 1994).
    4) Renal biopsy samples from these patients showed similar histological findings. Extensive hypocellular interstitial fibrosis and atrophy and loss of tubules was consistently seen (Yang et al, 2000; (Lord et al, 1999).
    b) Progressive interstitial renal fibrosis occurred in Belgium from Aristolochia fang chi which was accidentally substituted for Stephania tetrandra and Magnolia officinalis. Seventy cases were identified, with 30 of these experiencing terminal renal failure (Vanhaelen et al, 1994; Vanherweghem, 1993).
    c) Cosyns et al (1994) reported many similarities with Balkan endemic nephropathy and Chinese herbs nephropathy, based on clinical and morphological grounds. A common etiologic agent, aristolochic acid was suspected (Cosyns et al, 1994).
    1) Stefanovic & Polenakovic (1991) described Balkan nephropathy and suggest one possible causative factor to be aristolochic acid which was found in wheat contaminated with Aristolochia clematis seeds in the endemic area. The exact causal relationship was not established (Stefanovic & Polenakovic, 1991).
    d) Van Ypersele de Strihou (1998) and Schmeiser et al (1996) have demonstrated DNA adducts formed by aristolochic acid in renal tissue from patients with aristolochia nephropathy. Control patients with renal diseases other than Chinese herb nephropathy had an absence of this DNA adduct (Van Ypersele de Strihou C, 1998; Schmeiser et al, 1996).
    e) Five female patients, who had taken slimming herbals containing aristolochic acid for 13 to 23 months, all developed renal failure due to interstitial fibrosis, tubular atrophy, and fibrosis of mainly interlobular arteries. All required kidney transplantations (Schmeiser et al, 1996).
    f) Death due to acute toxic nephrosis occurred in several patients in a clinical trial with intravenous doses ranging from 0.1 mg/kg/day for 5 days to a single dose of 2 mg/kg (Jackson et al, 1964).
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 69-year-old man presented with fatigue and nausea following a trip to China where he consumed, on three occasions, Dutchman's pipe root, a member of the Aristolochia family, that was boiled in water. Laboratory data revealed mild proteinuria and a serum creatinine concentration of 643 mcmol/L (eGFR of 8), indicating acute renal failure. A renal biopsy demonstrated tubulotoxic injury. Following treatment with prednisolone, the patient's renal function improved with a repeat serum creatinine concentration of 150 mcmol/L (eGFR of 40) (Hutton et al, 2012).
    C) FANCONI SYNDROME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 60-year-old man presented to the emergency department with a 2-day history of muscle weakness and an inability to walk after waking up in the morning. Interview of the patient revealed that he had been consuming 4 g of a Chinese herb powdered mixture 4 times daily to treat leg edema for 5 months prior to presentation. Neurologic examination demonstrated paralysis with areflexia of the lower extremities and decreased strength (2/5 normal) in his upper extremities with decreased bicep reflexes. Laboratory data revealed hypokalemia (plasma potassium 1.8 mEq/L), hypophosphatemia (plasma phosphate 0.9 mg/dL), hypouricemia (plasma uric acid 1.3 mg/dL), hyperphosphaturia, hyperuricosuria, and glycosuria, all of which was consistent with a diagnosis of Fanconi's syndrome. A renal biopsy showed acellular interstitial fibrosis indicative of aristolochic acid associated nephropathy. With supportive therapy, including potassium supplementation, the patient's potassium concentration increased (3.6 mEq/L) and his muscle strength improved; however, the patient's renal dysfunction persisted. Analysis of the herb mixture, via high performance liquid chromatography, revealed that the herb powder contained aristolochic acids (Yang et al, 2002).
    b) CASE REPORT: A 41-year-old man presented to the emergency department with a sudden onset of bilateral lower limb weakness and an inability to walk after waking up in the morning. Neurologic exam revealed symmetrical flaccid paralysis of the lower extremities with hyporeflexia in the upper and lower extremities. Laboratory data revealed serum creatinine level of 1.6 mg/dL, severe hypokalemia (serum potassium 1.6 mmol/L), and hypophosphatemia with hyperphosphaturia, hypouricemia with hyperuricosuria, and glycosuria, indicative of Fanconi's syndrome. Arterial blood gas analysis demonstrated hyperchloremic metabolic acidosis. Interview of the patient revealed that he had been consuming a Chinese herb mixture, later determined to contain aristolochic acid-I, daily for 2 months prior to presentation. His daily intake of the mixture was 7 g (approximately 50 mcg of aristolochic acid-I). Following supportive therapy, including oral potassium supplementation and vitamin D3, and cessation of the Chinese herb mixture, the patient completely recovered 2 months later (Tsai et al, 2005).
    c) CASE REPORT: A 41-year-old woman presented with polydipsia and polyuria. Interview of the patient revealed that she had been taking a Chinese herb mixture, later identified to contain aristolochic acids, for 10 days approximately 20 days prior to presentation. Based on her laboratory results of decreased potassium, phosphorus and uric acid concentrations in her blood and the presence of glucose and protein in her urine, a diagnosis of Fanconi's syndrome was made. With supportive therapy, including potassium supplementation, the patient recovered after 3 weeks; however, 3 months later, she presented to the hospital with anorexia, nausea, generalized edema and weakness. Laboratory data revealed serum creatinine concentration of 1334.8 mcmol/L. A renal biopsy demonstrated tubular atrophy and severe interstitial fibrosis, consistent with a diagnosis of aristolochic acid-induced nephropathy. The patient required ongoing hemodialysis (Lee et al, 2004).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RENAL FIBROSIS
    a) RATS: Aristolochic acid, given in single oral doses of 10, 50 or 100 mg/kg, caused dose related renal lesions. Histological results showed evidence of renal tubular necrosis. Rises in plasma creatinine and urea and urinary glucose and protein were also evident (Mengs & Stotzem, 1993).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) Hypochloremic metabolic acidosis has been reported in patients who developed Fanconi's syndrome and nephropathy associated with chronic ingestion of Chinese herbs containing aristolochic acids (Tsai et al, 2005; Yang et al, 2002).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Early and severe anemia, associated with renal insufficiency from Chinese herb nephropathy, has been reported (Vanherweghem, 1993; Cosyns et al, 1994; Tanaka et al, 1997; Reginster et al, 1997).
    B) LEUKOCYTIC PHAGOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) In 2 clinical studies, aristolochic acid was given to 12 healthy subjects in a dose of 0.9 mg/day for 10 days. Phagocytic activity of peripheral granulocytes was increased after the third day of therapy, and returned to normal following discontinuation of the drug (Kluthe et al, 1982).

Musculoskeletal

    3.15.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) MUSCLE WEAKNESS
    a) Muscle weakness occurred in rabbit studies following intraperitoneal doses of 1500 mcg/kg of aristolochine (RTECS , 2000).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DISORDER OF IMMUNE FUNCTION
    1) WITH THERAPEUTIC USE
    a) Use of steroid therapy has been shown to slow the progression of renal failure in aristolochic acid related interstitial fibrosis, supporting a hypothesis that renal interstitial fibrosis may be an immune-mediated process (Yang et al, 2014; Vanherweghem et al, 1996).

Reproductive

    3.20.1) SUMMARY
    A) Certain members of the Aristolochiaceae family are classified as 2b by the American Herbal Products Association Standards Committee. Those herbal medicines in class 2b should NOT be used during pregnancy .
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Certain members of the Aristolochiaceae family are classified as 2b by the American Herbal Products Association Standards Committee. Those herbal medicines in class 2b should NOT be used during pregnancy (McGuffin et al, 1997).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Aristolochic acid is a known human and animal carcinogen.
    3.21.3) HUMAN STUDIES
    A) SUMMARY
    1) The International Agency for Research on Cancer (IARC) has determined that aristolochic acid is carcinogenic to humans (Group I) after a systematic review and evaluation of the scientific evidence by leading independent experts (International Agency for Research on Cancer, 2015).
    2) Aristolochic acid has been shown to have carcinogenic properties (RTECS , 2000; Nortier et al, 2000; Fernando et al, 1993) and was removed from the German national market due to the demonstration of a carcinogenic potential in a three month oral toxicity study in rats (Lewis, 1996).
    B) UROTHELIAL AND RENAL CARCINOMA
    1) A cohort study found an association between consumption of Chinese herbal products containing aristolochic acid and an increased risk of developing urothelial cancer in patients with end-stage renal disease (Wang et al, 2014).
    2) Urothelial changes, characterized by extensive atypia and atypical hyperplasia of the epithelial lining of collecting ducts, calyces, pelves, and ureter, were found in several female patients following several months of use of a slimming herbal regimen containing aristolochic acid. Aristolochic acid DNA adducts have been demonstrated in tissue samples (Schmeiser et al, 1996; Cosyns et al, 1999). A case-control study of 6564 Chinese herbalists who were employed between 1985 and 1998 showed that processing, selling, or dispensing fangchi (an herb containing aristolochic acid) significantly increased the risk of developing urothelial carcinoma (hazard ratio, 2.4; 95% CI, 1.1 to 5.3; p=0.03). Twenty-four cases of urothelial carcinoma and 140 controls were identified and included in the analysis; of these subjects, 3 died (2 cases and 1 control) during follow-up. The association between fangchi exposure and increased risk of urothelial carcinoma was independent of cigarette smoking or potential arsenic exposure from drinking well water (Yang et al, 2013). Urothelial carcinoma associated with Aristolochia fangchi use has been reported in a dose-related manner (Nortier et al, 2000). In-situ carcinomas and urothelial cellular atypias may be a causal effect of aristolochic acid (Van Ypersele de Strihou, 1998) (Cosyns et al, 1994; Bieler et al, 1997; Nortier et al, 2000). Cosyns et al (1999) have suggested a role for a p53 gene mutation resulting in urothelial atypia. This proposed molecular mechanism is supported by the finding of aristolochic acid DNA adducts on the p53 gene in malignant urothelial cells from a 53-year-old woman who developed urothelial cancer 6 years after developing aristolochic acid-associated nephropathy (Lord et al, 2004; Cosyns et al, 1999).
    3) ANIMALS: Mengs & Stotzem (1993) have shown that aristolochic acid induced multiple tumors in rats and mice, which were dose and time dependent. Tumors were found in the kidneys and urinary bladder. Doses of 0.1 mg/kg and higher also resulted in papillomatosis in the forestomach, followed later by keratinizing squamous cell carcinomas.
    a) In an investigation in rats given single doses of 10, 50 or 100 mg/kg by gastric tube, renal lesions, which were dose dependent, developed within 3 days (Mengs & Stotzem, 1993).
    C) LYMPHOMA
    1) Following aristolochic acid administration to rodents, lymphomas as well as renal, bladder, stomach, and lung carcinomas have been reported ((Anon, 2000)).

Genotoxicity

    A) Aristolochic acid has shown weak mutagenic activity in the Ames test (Lewis, 1996; McGuffin et al, 1997; RTECS , 2000), in mammalian somatic cells (RTECS , 2000) and in Salmonella typhimurium strains and Chinese hamster ovary cells (Pezzuto et al, 1988).
    B) In vitro tests with aristolochic acid have produced induction of structural chromosome aberrations and sister chromatid exchanges in human lymphocytes (Abel & Schimmer, 1983).
    C) Researchers have demonstrated DNA adducts formed by aristolochic acid in renal tissue from patients with aristolochia nephropathy (Schmeiser et al, 1996; Bieler et al, 1997) (Van Ypersele de Strihou, 1998) (Nortier et al, 2000).
    D) Fernando et al (1993) have demonstrated the formation and persistence of specific purine DNA adducts in target and non-target organs of rats administered single oral doses of aristolochic acid I (Fernando et al, 1993).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor renal function and serum electrolytes, and obtain a urinalysis in all symptomatic patients.
    B) Monitor vital signs.
    C) Obtain a CBC and arterial blood gases in patients with evidence of renal insufficiency.
    D) Monitor liver function tests as indicated.
    E) Obtain an echocardiogram in patients with a murmur or suspected valvular disease after chronic ingestion.
    4.1.2) SERUM/BLOOD
    A) Monitor renal function and serum electrolytes in all symptomatic patients.
    B) Obtain a CBC and arterial blood gases in patients with evidence of renal insufficiency.
    C) Monitor liver function tests as indicated.
    4.1.3) URINE
    A) URINALYSIS
    1) Urine should be monitored for signs of renal dysfunction, which may include proteinuria, hematuria, glycosuria, and aminoaciduria (Tanaka et al, 1997).
    4.1.4) OTHER
    A) OTHER
    1) ECHOCARDIOGRAM
    a) Obtain an echocardiogram in patient with heart murmurs and those with suspected valvular disease.

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) Patients who remain symptomatic despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients who are asymptomatic or with minimal symptoms after exposure to aristolochic acid and are otherwise improving may be managed at home.
    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.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients who are symptomatic need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Monitor renal function and serum electrolytes, and obtain a urinalysis in all symptomatic patients.
    B) Monitor vital signs.
    C) Obtain a CBC and arterial blood gases in patients with evidence of renal insufficiency.
    D) Monitor liver function tests as indicated.
    E) Obtain an echocardiogram in patients with a murmur or suspected valvular disease after chronic ingestion.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Toxicity after an acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Toxicity after acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary. Consider activated charcoal only if coingestants with significant toxicity are involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Most reported cases of toxicity have involved chronic ingestion of aristolochic acid contained in herbal medicines. Treatment is symptomatic and supportive. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Correct electrolyte abnormalities as indicated.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate 1 to 2 mEq/kg. Use of steroid therapy has been shown to slow the progression of renal failure in aristolochic acid related interstitial fibrosis.
    B) MONITORING OF PATIENT
    1) Monitor renal function and serum electrolytes, and obtain a urinalysis in all symptomatic patients.
    2) Monitor vital signs.
    3) Obtain a CBC and arterial blood gases in patients with evidence of renal insufficiency.
    4) Monitor liver function tests as indicated.
    5) Obtain an echocardiogram in patients with a murmur or suspected valvular disease after chronic ingestion.
    C) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    3) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    4) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) PHENTOLAMINE/INDICATIONS
    a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
    9) PHENTOLAMINE/ADULT DOSE
    a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
    b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
    10) PHENTOLAMINE/PEDIATRIC DOSE
    a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
    11) PHENTOLAMINE/ADVERSE EFFECTS
    a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
    12) CAUTION
    a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
    13) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    14) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    15) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    D) 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.
    E) CORTICOSTEROID
    1) A retrospective study was conducted to evaluate the efficacy of steroid therapy in patients with Chinese herb nephropathy. The study consisted of a total of 35 female patients who were exposed to Aristolochia fang chi at an approximate dose of 900 mg/day. Of the 35 patients, 12 patients with moderate renal failure and biopsy-proven renal fibrosis were administered prednisolone 1 mg/kg for 1 month, tapering off 0.1 mg/kg every 2 weeks to a maintenance dose of 0.15 mg/kg. The other 23 patients did not receive steroid therapy due to several factors, including refusal to enter the trial (n=6), late presentation of the disease (n=6), and steroid therapy was not offered at the nephrology center treating the patient (n=11), and, therefore, were considered the control group. Laboratory data of the steroid group revealed that the mean plasma creatinine level was stable from the time that steroids were initiated (t=0; 2.8 +/-0.2 mg/dL) to 6 months later (t=6; 2.9 +/- 0.3 mg/dL), then increased to 4 +/- 0.7 mg/dL at 12 months (t=12), indicating slow progression of renal failure, compared to the control group that demonstrated rapid and severe deterioration of kidney function, with mean plasma creatinine levels of 2.6 +/- 0.1 mg/dL, 5.3 +/- 0.5 mg/dL, and 7.1 +/- 0.5 mg/dL, at t=0, t=6, and t=12, respectively. Based on these lab results, steroid therapy appeared to slow the progression of renal failure, suggesting that renal interstitial fibrosis may be an immune-mediated process (Vanherweghem et al, 1996).

Enhanced Elimination

    A) SUMMARY
    1) In patients that develop renal failure despite supportive care, hemodialysis may be indicated.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. During a clinical trial, 20 patients were administered IV infusions of aristolochic acid in doses ranging from 0.1 mg/kg/day for 5 days up to a single dose of 2 mg/kg. Acute toxic nephrosis was the cause of death in several of the patients; toxicity appeared to be dose and time related. An adult developed Fanconi's syndrome with hypokalemic paralysis and nephropathy after ingesting 7 g/day of a Chinese herb mixture (containing approximately 50 mcg of aristolochic acid-I) for 2 months. The patient recovered with supportive therapy.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) ARISTOLOCHIA SERPENTARIA - Powdered root: 10 to 30 grains; fluid extract: 0.5 to 1.0 drachm; tincture: 0.5 to 1.0 drachm; infusion: 0.5 to 1.0 ounce; concentrated solution: 0.5 to 2.0 drachms ((Grieve, 1998)).
    2) ARISTOLOCHIC ACID - The pure form in a dose of 0.9 milligrams/day orally has been used for immune stimulating action (McGuffin et al, 1997) and in a clinical trial assessing phagocytic action on peripheral granulocytes (Kluthe et al, 1982).

Minimum Lethal Exposure

    A) Twenty patients were administered intravenous infusions of aristolochic acid (AA) in doses ranging from 0.1 mg/kg/day for 5 days up to a single dose of 2 mg/kg in a clinical trial evaluating the anti-cancer effects of AA. Lack of anti-tumor effect and kidney toxicity precluded AA from further testing. Acute toxic nephrosis was the cause of death in several of the patients; toxicity appeared to be dose and time related (Jackson et al, 1964).

Maximum Tolerated Exposure

    A) ADULT
    1) Twenty patients were administered intravenous infusions of aristolochic acid (AA) in doses ranging from 0.1 mg/kg/day for 5 days up to a single dose of 2 mg/kg in a clinical trial evaluating the anti-cancer effects of AA. Lack of anti-tumor effect and kidney toxicity precluded AA from further testing. Acute toxic nephrosis was the cause of death in several of the patients; toxicity appeared to be dose and time related. Nine of 10 patients who received daily doses of less than 1 mg/kg did not experience renal toxicity (Jackson et al, 1964).
    2) CASE REPORT: A 41-year-old man presented to the emergency department with a sudden onset of bilateral lower limb weakness and an inability to walk after waking up in the morning. Neurologic exam revealed symmetrical flaccid paralysis of the lower extremities with hyporeflexia in the upper and lower extremities. Laboratory data revealed serum creatinine level of 1.6 mg/dL, severe hypokalemia (serum potassium 1.6 mmol/L), and hypophosphatemia with hyperphosphaturia, hypouricemia with hyperuricosuria, and glycosuria, indicative of Fanconi's syndrome. Arterial blood gas analysis demonstrated hyperchloremic metabolic acidosis. Interview of the patient revealed that he had been consuming a Chinese herb mixture, later determined to contain aristolochic acid-I, daily for 2 months prior to presentation. His daily intake of the mixture was 7 g (approximately 50 mcg of aristolochic acid-I). Following supportive therapy, including oral potassium supplementation and vitamin D3, and cessation of the Chinese herb mixture, the patient completely recovered 2 months later (Tsai et al, 2005).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (ORAL)MOUSE:
    a) 55900 mcg/kg (RTECS , 2000a)
    2) LD50- (ORAL)RAT:
    a) 184 mg/kg (RTECS , 2000a)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) External application of aristolochic acid was shown to increase the number of micro- and macrophages in the cornea and in the vitreous body, respectively, of rabbit eyes infected with herpes simplex, and lead to a more rapid healing of the lesions as compared to an untreated control group (Mose et al, 1980).

Toxicologic Mechanism

    A) Schmeiser et al (1997) suggested the possibility that a DNA mutation is responsible for kidney-destructive fibrotic processes in patients with aristolochia nephropathy. Persistence of specific DNA adducts months following discontinuation of aristolochia herbs suggests non-repairable lesions in a number of tissues exposed to carcinogens. A correlation between adduct levels and the duration of herbal intake was not found in human studies. Interindividual variability in aristolochia metabolism and batch-to-batch differences of aristolochic acid content in herbal capsules are major factors influencing DNA adduct levels.
    1) The authors further suggested the possibility that aristolochic acid I DNA adducts also initiated a renal fibrotic process which destroyed the kidney in a human study. The fibrotic process extended from the kidney to the pelvis and ureter in one patient and perhaps contributed to an occurrence of aortic valvular lesions in 40% of patients with Chinese herb nephropathy (CHN). The quantities of aristolochia used in herbal medicines appear to be capable of altering DNA to a significant extent, and could possibly have a synergistic effect with other agents used as slimming cures.
    2) The presence of aristolochic acid metabolites as DNA adducts in patients with CHN has been demonstrated. This also suggests that dA-AA-IDNA adducts may be responsible for urothelial cancers observed in patients with CHN.

Physicochemical

Physical Characteristics

    A) Aristolochine is a yellow, amorphous substance which has a bitter and slightly acrid taste ((Grieve, 1998)). Aristolochic acids are slightly soluble in water and soluble in alcohol, chloroform, ether, acetone, acetic acid, aniline, and alkalies (Budavari, 1996).

Molecular Weight

    A) 341.29

References

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