Semen Armeniacae, Herbal Medicine. - Herbal Medicine Plants

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Tuesday, September 11, 2012

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).
Semen Armeniacae
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).

Semen Armeniacae
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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
Semen Armeniacae
70

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
71
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).
Semen Armeniacae

72

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.
73

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).

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