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AMYGDALIN
(LAETRILE) B-17
MONOGRAPHIC SUMMARY
Edited by Dr. Jose Ernesto Contreras Pulido
Clinical Research of the Hospital Ernesto Contreras In
Collaboration
with: KEM S.A. Laboratories and Hospital Oasis
In spite of
the great advances in the diagnosis and treatment of
malignant tumors, cancer continues be one of the principal
causes of death in the highly industrialized countries. It
is calculated that one out of four persons will eventually
die from some form of cancer. Since it is true that surgery
and radiotherapy are capable of curing some patients with
localized tumors and that chemotherapy has achieved cures in
some ten types of malignant tumors, the general mortality
rate from cancer has not improved substantially in the last
25 years and nearly 60 percent of the patients, upon being
diagnosed, find that their disease is so widespread that the
chemotherapy drugs currently being used, due to their high
toxicity, cannot be given in dosages sufficient to destroy
the large tumoral mass present in patients. Many cannot be
exposed to therapy, surgery or radiotherapy because of the
undesirable effects. There are several types of tumors for
which there is no effective treatment yet known.
All this justifies, and even makes imperative, the
search for new substances with anti-tumor effect and
ideally, with little or no toxicity in therapeutic doses. In
the last ten years, several vegetable and hormonal
substances have been discovered with such characteristics
and, therefore, many patients who formerly could not be
benefited or alleviated medicinally may now be exposed to
useful , antineoplastic treatments.
KEM S.A. Laboratories, with great satisfaction, is able to
present a vegetable agent whose anti-tumor action was known
empirically for many years, but in the last twenty years has
been scientifically proven, primarily through the clinical
studies directed by Dr. Ernesto Contreras Rodriguez and
carried out in the Centro Medico y Hospital Del Mar at
Playas de Tijuana, B.C.N. Mexico.
This anti-tumor agent is AMYGDALIN
(commonly known as Laetrile).
AMYGDALIN is a natural substance that can be found in a
variety of species in the vegetable kingdom. The greatest
concentration is found in the seeds of the rosaceous fruits,
such as the apricot pits and other biter nuts. There are
many seeds, cereals and vegetables that contain minimal
quantities of Amygdalin and form part of our daily diet.
Various documents from the oldest civilizations such as
Egypt at the time of the Pharaohs and from China 2,500 years
before Christ mention the therapeutic use of derivatives of
bitter almonds. Egyptian papyri from 5,000 years ago mention
the use of "aqua amigdalorum"
for the treatment of some tumors of the skin. The Greeks and
Romans also attributed therapeutic properties to that
extract in low doses. But the systematized study of
AMYGDALIN really did not begin until the first half of the
past century, when the chemist Bohn discovered in 1802 that
during the distillation of the water from bitter almonds
hydrocyanic acid was released.
Soon many researchers became interested in analyzing this
extract and so Robiquet and Boutron isolated, for the first
time, a white crystalline substance which they called
AMYGDALIN (from amygdala = almond)
Leiberg and Wholler in 1937 isolated an enzymatic compound
from sweet almonds, also present in the biter ones, which
they called emulsin. They later reported that emulsin broke
AMYGDALIN down into three compounds: glucose, hydrocyanic
acid, and benzaldehyde.
Studies from that time, performed by several authors, can
summarize the declaration made by Otto Jacobsen in his book
"Die Glucoside" in 1887: "AMYGDALIN is
not toxic," and gives 99 references from studies made
within the 20 years prior to his publication.
Extraction Methods
The source for obtaining AMYGDALIN which use most currently
utilized use the apricot kernel. The method for its
extraction and refining has only been standardized in the
last five years, thanks to the multiple research projects
completed primarily by KEM S.A. Laboratories. The main steps
to follow in the extraction of AMYGDALIN are summarized
below :
1. Selection of kernels.
2. Cleaning the Kernels.
Keeping as the principal objective the elimination of
shells, husks, rock and leaves which might damage the mills.
3. Milling the kernels. With
this, it is possible to separate most of the oil from the
initial milling and the remainder in the subsequent
millings. The product from the milling is a fine, brownish
powder with a bitter odor which, upon letting it sit,
ferments spontaneously, which is desirable, because with it
the yield from the extraction is increased.
4. Dissolving the powder. A
stainless steel digester is used in the presence of
isopropyl alcohol at a constant temperature and with
constant reflux of the alcohol, for a period of 2 1/2 hours.
5. Filtering. One uses filters
on very fine cloth so as to avoid the passage of particles
of the powder which are not digested. The resulting product
is allowed to sit for 72 hours, and is then washed with
ethylic ether eliminate the isopropyl alcohol.
6. Drying the AMYGDALIN. The
dry, white powder, product of the filtering, is spread out
on stainless steel dishes and is exposed for eight hours to
temperatures between 50 and 60 degrees C. The project is 65
through 80% percent pure AMYGDALIN.
7. Crystallization. This is
completed in closed, glass, vacuum receptacles after
exposing the AMYGDALIN to a mixture of activated carbon and
ionized earth which act as a filter. The final product is
AMYGDALIN with a purity of no less than 96%.
Physical and chemical properties
Although the identification of the majority of the physical
and chemical characteristics of AMYGDALIN have been known
since the beginning of our century, it was not until the
second half of this century that Ernest T. Krebs Jr.
(biochemist) and Ernest T. Krebs Sr. (doctor) isolated
Amygdalin with a purity of practically 100%, enabling all
the physical and chemical characteristics peculiar to
AMYGDALIN to be ascertained. Listed below are the majority
of these:
1. Amygdalin is a white, crystalline,
inodorous powder with an intensely bitter taste, slightly
soluble in cold water, alcohol and acetone, very soluble in
hot water, alcohol and acetone. Insoluble in ether.
2. It has a pH of 7 (neutral) in a saturated, aqueous
solution. its point of fusion is between 210 and 218 degrees
Celsius and its loss upon drying is less than 12%.
3. Its optical rotation is levogyrous or negative: between
-37 and 42 degrees. It has a maximum absorbency of
ultraviolet light of 262 microns and a minimum of 250
microns.
4. Its stability is complete in crystalline form as well as
in saturated , aqueous solution in which the loss is less
than 2.5% after 5 years.
5. Chemically, it is cyanogenic diglucoside, with a
condensed formula C20H27NO11, with a molecular weight of
457.42 g., a chemical name of D (1)
Mandelonetrile-betaglucoside-6 beta-D-glucoside.
6. If it is mixed with concentrated, hydrochloric acid, it
gives positive reactions characteristic of benzaldehyde, of
the reducing sugars and the hydrocyanic acid.
Evaluation Test
It is considered to be specific and, therefore, useful in
determining the purity of the AMYGDALIN product.
Method
1. Measure out a volume equivalent to 100mg of AMYGDALIN and
transfer it to a volumetric matrass.
2. Add distilled water to complete 100 ml. solution.
3. Measure the absorbency of the solution in ultraviolet
light at 230 u and up to 280 u, using a spectrophotometer
with a quartz cell of 1 cm.
4. Graph the curve of the absorbency of the solution in
ultraviolet light.
5. Determine the tangent between the minimum absorbency
(near 230 u) and the final inflection (at 280 u).
6. Designate at point A the maximum absorbency in the curve,
and at point B the corresponding absorbency of the traced
tangent.
7. Formula and calculation. A constant equivalent to 595
will be utilized as divisor, and the following operation
will be performed:
A-B x 100 = PERCENTAGE OF AMYGDALIN IN
SAMPLE 595
Click To see Picture
PRECLINICAL STUDIES WITH AMYGDALIN
It is accepted that every scientific study of a substance
that is intended for human use should include toxicology
studies with laboratory animals, in order to predict safe
dosages for humans in a more rapid and rational manner than
if it id calculated solely in an empirical fashion.
Generally, toxicology studies should include the
determination of the LD50 (lethal dosage for 50% of those
exposed) in mice and other mammiferous rodents, specially by
intravenous, intraperitoneal, intramuscular, subcutaneous
and occasionally tumorally or intra-cavity applications if
the product is intended for use in this form. It is also
indispensable to calculate the Minimum Toxic Dosage and the
Minimum Lethal dosage in rodents as well as in dogs, in
those in which also should be studied the histopathological
changes that the exposure to the substance caused in at
least six organs considered to be vital. Oral toxicity is
also studied in dogs.
Since it is true that there is no animal that reacts to
medicaments exactly like man, it is know that by using a
rodent, or a dog, in the toxicology tests, very likely one
can predict the majority of the pharmacological effects of
said substance in a human being. There are few cases in
which it is better to use monkeys rather than dogs for these
studies. AMYGDALIN has been subject to these studies under
the sponsorship of foreign investigators as well as KEM S.A.
LABORATORIES.
We shall make mention of only the results in the following
pages. Other studies not included in this summary include
experiments for antigenicity in guinea pigs which were
reported as negative (not antigenic); experiments for
teratogenicity in rats and dogs in which there were found no
alterations in the progeny which could be attributed to the
use of AMYGDALIN; Studies of subacute toxicity from various
application methods and in several rodents which show a very
low toxicity orally and practically none by intravenous or
intraperitoneal application.
LD50 for Various Species and By
Different Methods of Application
Click to see Picture
STUDIES OF TOXICITY IN DOGS BY VARIOUS
METHODS OF ADMINISTRATION
Acute Toxicity by Intravenous
Application:
At dosages up to 3,000 mg/kg/B.W. (or 54,000mg total
dosages), it was not possible to achieve the minimum lethal
dosage. There was only slight arterial hypotension and
hyposphygamia which normalized before concluding the 30
minute infusion. The monitored blood flow and cardiac
contractility showed no changes.
Acute Toxicity Through I.V.
Application:
The minimum lethal dose was not achieved in dosages up to
15,000 mg/kg/B.W. (or 120,000mg total dosages). The general
symptoms were slight arterial hypotension and fleeting
adipsia, which appeared after the minimum toxic dosage of
3,750 mg/kg/B.W.
Subacute Intravenous Toxicity:
There were no undesirable effects up to daily dosages of
1,000 mg/kg/B.W. for eight weeks.
Chronic Intravenous Toxicity:
Dosages up to 15 mg/kg/B.W. five days per week, for six
consecutive months, did not cause clinical or
histopathological alterations in necropsy studies of the
exposed dogs.
Acute Oral Toxicity:
The minimal lethal dose was 14,318 mg/kg/B.W. and the
minimum toxic dose was 400 mg/kg/B.W. The symptoms that were
observed were apathy, anorexia, adipsia, and loss of hair.
These symptoms disappeared in less than 48 hours in the dogs
in which AMYGDALIN was discontinued. The dog that received
the minimum lethal dosage developed convulsions and typical
cyanide poisoning shock which evolved into coma and death by
cardiac arrest.
Oral Toxicity:
By calculation, some authors suggested as the minimum lethal
dosage 2,000 to 2,500 mg/kg/B.W.
All these findings coincide with that mentioned by Otto
Jacobsen in 1887, Davidson in 1944, and Dr. Dean Burk
(National Cancer Institute of the USA) in 1968. "AMYGDALIN
is impressively atoxic (non-toxic) from the pharmacological
point of view," and that "Non-hydrolyzed AMYGDALIN is
less toxic than glucose." On the other hand, our studies
proved that KEMDALIN in dosages of 100 to 120 mg/kg/B.W.
(unusual dosage for humans) by intravenous application
corresponds to a dosage of AMYGDALIN 30 to 40 times less
than the minimum toxic dosage in dogs and that KEMDALIN in
dosages of 20 to 40 mg/kg/B.W. orally, used in humans, is
some 10 to 20 times less than the minimum toxic dosage,
orally, in dogs.
ANTINEOPLASTIC ACTIVITY OF AMYGDALIN
IN THE CULTIVATION OF TUMOR CELLS AND IN VARIOUS TUMOR
MODELS IN ANIMALS
With the purpose of exploring the antineoplastic activity of
AMYGDALIN, several pre-clinical studies have been completed.
There have been some in which the results have been
negative, but this does not invalidate for AMYGDALIN or for
other substances analyzed by a similar method, the positive
anti-tumor findings reported in this study. These are listed
by author or responsible institution.
Pre-clinical Studies to Demonstrate
the Antineoplastic Activity of AMYGDALIN
Mark Paulic:
A study sponsored by the American Lung Association of
Indiana, USA. With pulmonary tumor cells kept in ascitic
liquid of mice, AMYGDALIN caused a statistically,
significant increase in the mice inoculated and exposed to
AMYGDALIN.
SCIND Laboratories:
In two studies using Carcinoma Walker 256 in rats, a
statistically significant increase in the survival of rats
exposed to AMYGDALIN was proved.
Harold Manner:
Several studies of mice with spontaneous breast cancer, type
C3H/HEJ, have shown a statistically significant increase in
the life span of those exposed to AMYGDALIN with proteolytic
enzymes and mega-doses of Vitamin-A.
K. Sugiura:
Sponsored by the Sloan-Kettering Institute of New York, USA.
Studies with spontaneous CD8F1 and Swiss albino mice, breast
tumors, showed in five separate studies that AMYGDALIN has
clear, anti-tumor effect demonstrated by the regression of
the primary tumors and the retardance caused in the
appearance of pulmonary metastasis in the mice exposed to
AMYGDALIN.
SCIND Laboratories:
Using cancer cells from human, mammary melanoma exposed to
AMYGDALIN, it was proved by the polarographic method of
oxygen consumption, inhibition in activity and respiration.
We believe that these studies
adequately justify the study of the toxicity, tolerance, and
anti-tumor effect of AMYGDALIN in humans.
CLINICAL EXPERIENCE WITH THE USE OF
AMYGDALIN
Like many other substances, AMYGDALIN was initially employed
empirically on patients with malignant tumors. Inozensov, a
Russian doctor, used it with this purpose at the beginning
of our century. Dr. Ernest T. Krebs Sr., Dr. Manuel Navarro
and Dr. Ernesto Contreras Rodriguez and their collaborators
have published their experiences since the 1950s.
All agree that it is a characteristically harmless substance
when administered intravenously under medical supervision
and that orally, therapeutic dosages can be tolerated. On
the other hand, they all report definite palliative and
anti-tumor effects even in patients with cancer in terminal
stages. Already mentioned are the great numbers of
scientific studies which, in animals, have shown the
antineoplastic effect of AMYGDALIN during the last 25 years.
In this section, summaries of the results of the clinical
studies performed by Dr. Ernesto Contreras Rodriguez and his
associates at the Centro Medico y Hospital Del Mar, Playas
de Tijuana, B.C.N., Mexico, are included.
These studies were sponsored by KEM S.A. LABORATORIES,
taking into account that Dr. Contreras and his staff have
the greatest experience with the use of AMYGDALIN in humans:
Nearly 30,000 patients treated. Phase
I, II and III studies were completed.
Phase I Study
These studies were conducted to determine the minimum toxic
dosage in humans. Some 420 patients with cancer in advanced
stages and 90 healthy volunteers were exposed to AMYGDALIN
in intravenous dosages of up to 21g, or 2g orally, per day,
tolerated perfectly without evidence of toxicity, acute or
chronic (six month study). The palliative effect was
apparent in those patients who were not able to tolerate any
kind of conventional treatment.
Phase II Study
The Phase II studies were designed to demonstrate the
antitumoral effect of AMYGDALIN. The files of 1,200 patients
with advanced malignant neoplasms exposed to AMYGDALIN in
varying dosages were reviewed. Intravenously and orally,
AMYGDALIN demonstrated to have anti-tumor effects. Complete
remissions, partial remissions and prolonged stabilizations
(objective responses) were seen in almost 33% of the
patients, who were no longer candidates for conventional
treatment in more than 70% of the cases. Subjective
responses (responses of the patient rather than the
malignancy) were observed in more than 45% of the cases.
There was improvement in the general condition of the
patient, improvement in appetite and in diminishing pain.
We should emphasize that practically
100% of the patients using morphine derivatives to control
their pain were able to substitute these for non-narcotic
analgesics in less than four weeks after the initial dose of
AMYGDALIN.
Phase II and III studies were sponsored to demonstrate the
therapeutic value of AMYGDALIN upon specific types of
tumors.
Currently, Phase III studies have been completed on patients
with inoperable lung cancer of all types (four studies on
previously or simultaneously exposed to conventional
treatments and AMYGDALIN and one study on virgin patients
treated only with AMYGDALIN) and in patients with
Glioblastoma Multiform. Studies will soon be completed on
patients with breast cancer, prostate, stomach, pancreas,
and other malignant tumors who are not candidates for
conventional treatments.
The findings from one of the Phase III studies (patients
with inoperable lung cancer) are included in this summary.
Phase III Study
This study included 257 patients with inoperable lung
cancer, in its different histopathologic types and stages of
diffusion. It was possible to prove that there was complete
or partial remission from the disease in 12.45% of the
patients and, at least, stabilization of the disease for a
minimum of six months in 55.25% of the patients. It was
concluded that more than half of the patients experienced
subjective improvement.
Survival to twelve months and the median survival were
better than those of the historic controls used for
comparative analysis, both from the diagnosis and from the
date of first treatment. When the results were compared with
some of the better series reported using of radiotherapy
and/or chemotherapy, the results with AMYGDALIN were as
good, or better, according to the histopathologic type,
stage and functional capacity (Karnofsky Performance
Status). The survival to twelve months from the diagnosis
was 55.25% (142 of 257 patients) and 34.63% from the first
use of AMYGDALIN (89 of 257 patients). The median survival
was 59.45 weeks from the diagnosis and 35.76% from the first
dose of AMYGDALIN. Most other literature reports a median
survival of 25 weeks for patients with inoperable lung
cancer.
There was not one case reported with
morbidity or mortality attributable to the use of AMYGDALIN.
All this in contrast to the frequent side effects reported
with the use of radiotherapy in high dosages and/or multiple
chemotherapy, mortality of 3 to 4% and a significant or
severe morbidity in more than 30% of the patients who
frequently discontinue their treatment.
It was also proven that AMYGDALIN combines perfectly with
conventional therapy, helpfully influencing in the tolerance
and response to it, chiefly by diminishing the severity of
the side effects caused by chemotherapy.
AMYGDALIN is proposed to be used:
1. As an alternative on those patients who are not
candidates for other methods of conventional treatment.
2. As a simultaneous treatment with conventional therapy.
3. As a helpful treatment for those patients in remission.
4. As one more palliative for cancer patients in advanced
stages.
Conclusion
With all that which has been previously exposed, we can
conclude that AMYGDALIN has an anti-tumor effect, even in
those patients in poor condition and/or with an extensively
disseminated disease. Non-toxic dosages, whether alone or in
combination with other methods of conventional treatment,
are useful. At KEM S.A. Laboratories we believe that, with
the studies already conducted by the Centro Medico and
Hospital Del Mar, and the ones still pending, we shall soon
see the greater value of AMYGDALIN as an antineoplastic
agent alone or associated with other conventional cancer
treatments.
AMYGDALIN (or Laetrile) as an
antineoplastic agent is no longer a dream to be proven, but
rather, a demonstrated reality with scientific evidence
confirmed each time that it is prescribed.
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