Semen Armeniacae, Herbal Medicine.

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Definition

Semen Armeniacae consists of the dried ripe seeds of Prunus armeniaca

L., Prunus armeniaca L. var. ansu Maxim. or allied species (Rosaceae)

(1–4).

Synonyms

Armeniaca vulgaris Lam. (5).

Selected vernacular names

Abricotier, anzu, apricot, Aprikose, Aprikosenbaum, barqouq, bitter

apricot, chuli, cuari, culu, elk mesmas, haeng-in, Himalayan wild apricot,

hsing, ku-xinggren, kurbani, mao, michmich, mouchmouch, o mai,

sal-goo, touffah armani, wild apricot, xing ren, zardalou, zardalu (3, 5–8).

Geographical distribution

Indigenous to the Korean peninsula and to China, India and Japan (9, 10).

Cultivated in Asia, North Africa and United States of America (11).

Description

A medium-sized, deciduous tree, with reddish bark and glabrous twigs.

Leaves convoluted in bud, blade broadly ovate, 5–7 cm long, 4–5 cm wide,

acuminate, crenate-glandular, hairy on the veins of the underside when

young, glabrous when mature, except for the axils of the underside veins.

Petiole approximately 2.5 cm long, glandular; stipules, lanceolate, glandular

on the margins. Flowers appearing before the leaves, bisexual, pinkish

to white, solitary or fascicled, pedicels very short; calyx-tube campanulate,

puberulent, 5 mm long; surrounding lobes, pubescent, half the length

of the tube; petals suborbicular, 7–13 mm long; stamens inserted with the

petals at the mouth of the calyx-tube; ovary and base of the style hairy.

Fruit a downy or glabrous, yellow-tinged, red drupe with a fl eshy outer

layer surrounding a hard stone containing the seed (9, 10).

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Plant material of interest: dried ripe seeds

General appearance

Flattened, cordate, 1.1–1.9 cm long, 0.8–1.5 cm wide, 0.4–0.8 cm thick,

acute at one end, plump, unsymmetrical, rounded at the other. Seed coat

yellowish-brown to deep brown; short linear hilum situated at the acute

end; chalaza at the rounded end, with numerous, deep-brown veins radiating

upwards. Testa, thin; two cotyledons (1, 3, 4).

Organoleptic properties

Odourless; taste: bitter (1, 3, 4).

Microscopic characteristics

Epidermal surface has stone cells, 60–90 μm in diameter, on veins protruded

by vascular bundles, which appear as angular circles–ellipses, approximately

uniform in shape, with uniformly thickened walls. In lateral

view, stone cells appear obtusely triangular, walls extremely thickened at

the apex (1, 2).

Powdered plant material

See characteristic features under Microscopic characteristics (1, 2).

General identity tests

Macroscopic and microscopic examinations, and microchemical tests

(1, 2, 4).

Purity tests

Microbiological

Tests for specifi c microorganisms and microbial contamination limits are

as described in the WHO guidelines on quality control methods for medicinal

plants (12).

Pesticide residues

The recommended maximum limit of aldrin and dieldrin is not more than

0.05 mg/kg (13). For other pesticides, see the European pharmacopoeia

(13), and the WHO guidelines on quality control methods for medicinal

plants (12) and pesticide residues (14).

Heavy metals

For maximum limits and analysis of heavy metals, consult the WHO

guidelines on quality control methods for medicinal plants (12).

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66

Radioactive residues

Where applicable, consult the WHO guidelines on quality control methods

for medicinal plants (12) for the analysis of radioactive isotopes.

Other purity tests

Chemical, foreign organic matter, total ash, acid-insoluble ash, sulfated

ash, alcohol-soluble extractive, water-soluble extractive and loss on drying

tests to be established in accordance with national requirements.

Chemical assays

Contains not less than 3.0% amygdalin determined by titrimetric assay

with silver nitrate (4). A high-performance liquid chromatography

method is also available (15).

Major chemical constituents

The major constituent is amygdalin (up to 4.9%), a cyanogenic glycoside

(a plant compound that contains sugar and produces cyanide). Other cyanogenic

compounds present are prunasin and mandelonitrile. Also present

are the amygdalin-hydrolysing enzyme, emulsin, and fatty acids and

sitosterols (8, 16). The structure of amygdalin is presented below.

Medicinal uses

Uses supported by clinical data

None.

Uses described in pharmacopoeias and well established documents

Internally as a decoction, after processing by dipping in boiling water and

stir-frying until yellow (4), for symptomatic treatment of asthma, cough

with profuse expectoration and fever. The seed oil is used for treatment of

constipation (3, 4).

Pharmacology

Experimental pharmacology

Analgesic and antipyretic activity

Intragastric administration of 46.32 mg/kg body weight (bw) of amygdalin

to rats induced a small increase in body temperature, and prevented

ephedrine-induced hyperthermia (18). In the hot plate and acetic acidinduced

writhing tests in mice, the analgesic median effective doses (ED50)

were 457.0 mg/kg and 288.0 mg/kg bw, respectively. However, at these

doses, amygdalin could not substitute for morphine in morphine-addicted

rats in relieving withdrawal syndrome. No anti-infl ammatory effects

were observed in the animals treated with amygdalin (19).

Antitumour activity

Intragastric administration of 200.0 mg/kg–2.0 g/kg bw of amygdalin to

mice with P388 lymphocytic leukaemia or P815 mast-cell leukaemia on

days 1 and 5, or days 1, 5 and 9. Despite treatment with high doses of

amygdalin there was no prolongation in the lifespan of mice in either

group (20).

Antitussive activity

Amygdalin, 30.0 mg, had antitussive effects in the sulfur dioxide gasinduced

cough model in mice (21, 22). The enzymes amygdalase and

prunase, along with gastric juice, hydrolyse amygdalin to form small

amounts of hydrocyanic acid, thereby stimulating the respiratory refl ex

and producing antitussive and antiasthmatic effects (19).

Metabolism and pharmacokinetics

After intragastric administration of 30.0 mg of amygdalin or prunasin to

rats, capacity for hydrolysing these compounds was greatest in the organs

of 15-day-old animals, most of the activity being concentrated in the tissues

of the small and large intestines. The activity decreased with age. In

adult rats, hydrolysis of prunasin was greater than that of amygdalin and

was concentrated in the spleen, large intestine and kidney (35.0 μg, 15.0 μg

and 8.9 μg of prunasin hydrolysed per hour per gram of tissue, respectively).

Minced liver, spleen, kidney and stomach tissue had a greater hydrolytic

capability than the homogenate of these organs, while the reverse

was the case with the small and large intestines. Following oral administration

of 30.0 mg of amygdalin to adult rats, distribution after the fi rst

hour was as follows: stomach 0.89 mg, small intestine 0.78 mg, spleen

0.36 mg, large intestine 0.30 mg, kidney 0.19 mg, liver 0.10 mg and serum

5.6 μg/ml. At the end of the second hour, the highest amygdalin content,

0.79 mg, was found in the large intestine (23, 24).

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Toxicology

Intragastric administration of 125.0 mg/kg bw of powdered defatted Semen

Armeniacae per day for 7 days to mice or rabbits produced no behavioural,

histological or microscopic toxic effects (25). Intragastric administration

of 250.0 mg/kg bw of an aqueous suspension of the powdered

defatted seeds to mice had no toxic effects within a 24-hour period (25).

The median lethal dose (LD50) of amygdalin in rats was 880.0 mg/kg bw

after intragastric administration. However, when a dose of 600.0 mg/kg

bw was administered by the same route, together with β-glucosidase, all

animals died. Total and magnesium adenosine triphosphatase activities in

the heart decreased with increasing levels of administered amygdalin (23,

24).

Diets containing 10% ground seeds were fed to young and breeding

male and female rats. The seeds were obtained from 35 specifi c apricot

cultivars and divided into groups containing low amygdalin (cyanide

< 50.0 mg/100 g), moderate amygdalin (cyanide 100–200.0 mg/100 g), or

high amygdalin (cyanide > 200.0 mg/100 g). Growth of young male rats

was greatest in the low and moderate amygdalin groups, indicating that

the animals were more sensitive to the bitter taste of the kernels with high

amygdalin content. In female rats, but not males, liver rhodanase activity

and blood thiocyanate levels were increased with the high-amygdalin diet,

but both males and females effi ciently excreted thiocyanate, indicating effi

cient detoxifi cation and clearance of cyanide hydrolysed from the dietary

amygdalin. No other changes in blood chemistry were observed (26).

Toxic amounts of cyanide were released into the blood of rats following

intragastric administration of amygdalin (proprietary laetrile) (dose not

specifi ed); cyanide blood concentrations and toxicity were lower when

amygdalin was given intravenously (dose not specifi ed). Analysis of the

time course of cyanogenesis suggests that cyanide could accumulate in

blood after repeated oral doses of amygdalin (27). Following intraperitoneal

administration of 250.0 mg/kg bw, 500.0 mg/kg bw or 750.0 mg/kg

bw of amygdalin per day to rats for 5 days, mortalities were 30.8%, 44.1%

and 56.8%, respectively. The mode of death and the elevated serum cyanide

levels in the dying animals strongly suggested cyanide poisoning as

the cause of death (28).

The systemic effects of an oil prepared from the seeds containing 94%

unsaturated fatty acids, and oleic and linoleic acids were assessed in a 13-

week feeding study in rats. The animals were fed a diet containing 10% oil.

No toxic effects were observed and no macroscopic or microscopic lesions

in any of the organs were found (29). External applications of 0.5 ml of the

seed oil to rabbits did not produce any observable toxic effects (25).

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Clinical pharmacology

Antitumour activity

The term “laetrile” is an acronym used to describe a purifi ed form of

amygdalin, a cyanogenic glucoside found in the pits of many fruits and

raw nuts and in other plants, such as lima beans, clover and sorghum (30).

However, the chemical composition of a proprietary laetrile preparation

patented in the United States of America (LaetrileR), which comprises

mandelonitrile-β-glucuronide, a semisynthetic derivative of amygdalin, is

different from that of natural laetrile/amygdalin, which consists of mandelonitrile

β-d-gentiobioside and is made from crushed apricot pits. Mandelonitrile,

which contains cyanide, is a structural component of both

products. It has been proposed that the cyanide is an active anticancer

ingredient in laetrile, but two other breakdown products of amygdalin,

prunasin (which is similar in structure to the proprietary product) and

benzaldehyde, have also been suggested. The studies discussed in this

summary used either Mexican laetrile/amygdalin or the proprietary formulation.

Laetrile can be administered orally as a pill, or it can be given

by injection (intravenous or intramuscular). It is commonly given intravenously

over a period of time followed by oral maintenance therapy. The

incidence of cyanide poisoning is much higher when laetrile is taken orally

because intestinal bacteria and some commonly eaten plants contain

enzymes (β-glucosidases) that activate the release of cyanide following

laetrile ingestion (31). Relatively little breakdown to yield cyanide occurs

when laetrile is injected (32).

Laetrile has been used as an anticancer treatment in humans worldwide.

While many anecdotal reports and case reports are available, results

from only two clinical trials have been published (33, 34). No controlled

clinical trial (a trial including a comparison group that receives no additional

treatment, a placebo, or another treatment) of laetrile has ever been

conducted. Case reports and reports of case series have provided little

evidence to support laetrile as an anticancer treatment (35). The absence

of a uniform documentation of cancer diagnosis, the use of conventional

therapies in combination with laetrile, and variations in the dose and duration

of laetrile therapy complicate evaluation of the data. In a published

case series, fi ndings from ten patients with various types of metastatic

cancer were reported (36). These patients had been treated with a wide

range of doses of intravenous proprietary laetrile (total dose range 9–

133 g). Pain relief (reduction or elimination) was the primary benefi t reported.

Some responses, such as decreased adenopathy (swollen lymph

nodes) and decreased tumour size, were noted. Information on prior or

concurrent therapy was provided; however, patients were not followed

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long-term to determine whether the benefi ts continued after treatment

ceased. Another case series, published in 1953, included 44 cancer patients

and found no evidence of objective response that could be attributed to

laetrile (37). Most patients with reported cancer regression in this series

had recently received or were receiving concurrent radiation therapy or

chemotherapy. Thus, it is impossible to determine which treatment produced

the positive results.

In 1978, the United States National Cancer Institute (NCI), at the

National Institutes of Health, requested case reports from practitioners

who believed their patients had benefi ted from laetrile treatment (38). Of

the 93 cases submitted, 67 were considered suitable for evaluation. An

expert panel concluded that only two of the 67 patients had complete responses,

and that four others had partial responses while using laetrile.

On the basis of these six responses, NCI agreed to sponsor phase I and

phase II clinical trials. The phase I study was designed to test the doses,

routes of administration and schedule of administration. Six patients with

advanced cancer were treated with amygdalin given intravenously at

4.5 g/m2 per day. The drug was largely excreted unchanged in the urine

and produced no clinical or laboratory evidence of a toxic reaction.

Amygdalin given orally, 0.5 g three times daily, produced blood cyanide

levels of up to 2.1 μg/ml. No clinical or laboratory evidence of toxic reaction

was seen in the six patients taking the drug at this dosage. However,

two patients who ate raw almonds while undergoing oral treatment developed

symptoms of cyanide poisoning (33).

In the phase II clinical trial, 175 patients with various types of cancer

(breast, colon, lung) were treated with amygdalin plus a “metabolic therapy”

programme consisting of a special diet, with enzymes and vitamins.

The great majority of these patients were in good general condition before

treatment. None was totally disabled or in a preterminal condition.

One-third had not received any previous chemotherapy. The amygdalin

preparations were administered by intravenous injection for 21 days, followed

by oral maintenance therapy, dosages and schedules being similar

to those evaluated in the phase I study. Vitamins and pancreatic enzymes

were also administered as part of a metabolic therapy programme that

included dietary changes to restrict the use of caffeine, sugar, meats, dairy

products, eggs and alcohol. A small subset of patients received higherdose

amygdalin therapy and higher doses of some vitamins as part of the

trial. Patients were followed until there was defi nite evidence of cancer

progression, elevated blood cyanide levels or severe clinical deterioration.

Among 175 patients suitable for assessment, only one met the criteria for

response. This patient, who had gastric carcinoma with cervical lymph

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node metastasis, experienced a partial response that was maintained for

10 weeks while on amygdalin therapy. In 54% of patients there was measurable

disease progression at the end of the intravenous course of treatment,

and all patients had progression 7 months after completing intravenous

therapy; 7% reported an improvement in performance status

(ability to work or to perform routine daily activities) at some time during

therapy, and 20% claimed symptomatic relief. In most patients, these

benefi ts did not persist. Blood cyanide levels were not elevated after intravenous

amygdalin treatment; however, they were elevated after oral therapy

(34). On the basis of this phase II study, NCI concluded that no further

investigation of laetrile was warranted.

Adverse reactions

The side-effects associated with amygdalin treatment are the same as the

symptoms of cyanide poisoning. Cyanide is a neurotoxin that initially

causes nausea and vomiting, headache and dizziness, rapidly progressing

to cyanosis (bluish discoloration of the skin due to oxygen-deprived haemoglobin

in the blood), liver damage, marked hypotension, ptosis (droopy

upper eyelid), ataxic neuropathies (diffi culty in walking due to damaged

nerves), fever, mental confusion, convulsions, coma and death. These

side-effects can be potentiated by the concurrent administration of raw

almonds or crushed fruit pits, eating fruits and vegetables that contain β-

glucosidase, such as celery, peaches, bean sprouts and carrots, or high

doses of vitamin C (35).

Numerous cases of cyanide poisoning from amygdalin have been reported

(39–42). After ingestion, amygdalin is metabolized in the gastrointestinal

tract to produce prunasin and mandelonitrile, which are further

broken down to benzaldehyde and hydrocyanic acid, the latter of which

is highly toxic. Overdose causes dizziness, nausea, vomiting and headache,

which may progress to dyspnoea, spasms, dilated pupils, arrhythmias

and coma. A 65-year-old woman with cirrhosis and hepatoma lapsed

into deep coma, and developed hypotension and acidosis after ingestion

of 3 g of amygdalin. After initial treatment, the patient regained consciousness,

but massive hepatic damage led to her death (42). A 67-yearold

woman with lymphoma suffered severe neuromyopathy following

amygdalin treatment, with elevated blood and urinary thiocyanate and

cyanide levels. Sural nerve biopsy revealed a mixed pattern of demyelination

and axonal degeneration, the latter being prominent. Gastrocnemius

muscle biopsy showed a mixed pattern of denervation and myopathy

with type II atrophy (41).

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Contraindications

Semen Armeniacae should not be administered during pregnancy or

nursing, or to children (43, 44).

Warnings

Overdose may cause fatal intoxication (4, 43, 44). The lethal dose is

reported to be 7–10 kernels in children and 50–60 kernels (approximately

30 g) in adults (45).

Precautions

Carcinogenesis, mutagenesis, impairment of fertility

No effects on fertility were observed in rats fed a diet containing 10%

Semen Armeniacae for 5 weeks (26). An aqueous extract of the seeds was not

mutagenic in the Salmonella/microsome assay using S. typhimurium strains

TA98 and TA100, or in the Bacillus subtilis H-17 recombinant assay at concentrations

of up to 100.0 mg/ml (46). However, a hot aqueous extract of the

seeds was mutagenic in the Salmonella/microsome assay in S. typhimurium

strains TA98 and TA100 at a concentration of 12.5 mg/plate (47).

Pregnancy: teratogenic effects

Intragastric administration of amygdalin (dose not specifi ed) to pregnant

hamsters induced skeletal malformations in the offspring, and intravenous

administration resulted in embryopathic effects. Oral laetrile increased in

situ cyanide concentrations, while intravenous laetrile did not. Thiosulfate

administration protected embryos from the teratogenic effects of oral

laetrile. The embryopathic effects of oral laetrile appear to be due to cyanide

released by bacterial β-glucosidase activity (48). A pregnant woman

who took laetrile as daily intramuscular injections (dose not specifi ed) during

the last trimester gave birth to a live infant at term. There was no laboratory

or clinical evidence of elevated cyanide or thiocyanate levels (49).

Pregnancy: non-teratogenic effects

Offspring of breeding rats fed a high-amygdalin diet (cyanide > 200.0 mg/

100 g) for 18 weeks had lower 3-day survival indices, lactation indices and

weaning weights than those in a low-amygdalin group (cyanide < 50.0 mg/

100 g). This may indicate that the cyanide present in the milk may not be

effi ciently detoxifi ed to thiocyanate and excreted by neonates (26).

Nursing mothers

See Contraindications.

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Paediatric use

See Contraindications.

Other precautions

No information available on general precautions or on precautions concerning

drug interactions; or drug and laboratory test interactions.

Dosage forms

Processed (see Posology) dried ripe seeds (4); seed oil. Store in a cool, dry

place, protected from moths (4).

Posology

(Unless otherwise indicated)

Average daily dose: 3.0–9.0 g of dried ripe seeds processed by breaking

into pieces, rinsing in boiling water and stir-frying until yellow, then adding

to a decoction when nearly fi nished (4).