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Amygdalin

Amygdalin

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Amygdalin C20H27NO11, is a glycoside
Glycoside
In chemistry, a glycoside is a molecule in which a sugar is bound to a non-carbohydrate moiety, usually a small organic molecule. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. These can be activated by enzyme...

 initially isolated from the seeds of the tree Prunus dulcis, also known as bitter almonds, by Pierre-Jean Robiquet
and A. F. Boutron-Charlard in 1830, and subsequently investigated by Liebig
Justus von Liebig
Justus von Liebig was a German chemist who made major contributions to agricultural and biological chemistry, and worked on the organization of organic chemistry. As a professor, he devised the modern laboratory-oriented teaching method, and for such innovations, he is regarded as one of the...

 and Wöhler in 1830. Several other related species in the genus of Prunus
Prunus
Prunus is a genus of trees and shrubs, which includes the plums, cherries, peaches, apricots and almonds. There are around 430 species spread throughout the northern temperate regions of the globe. Many members of the genus are widely cultivated for fruit and ornament.-Botany:Members of the genus...

, including apricot (Prunus armeniaca) and black cherry (Prunus serotina), also contain amygdalin.

Since the early 1950s, a modified form of amygdalin has been promoted under the names laetrile and "Vitamin B17" as a cancer cure, but it is not a vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...

, and studies have found it to be ineffective and potentially toxic as a possible cause of cyanide
Cyanide
A cyanide is a chemical compound that contains the cyano group, -C≡N, which consists of a carbon atom triple-bonded to a nitrogen atom. Cyanides most commonly refer to salts of the anion CN−. Most cyanides are highly toxic....

 poisoning. The promotion of laetrile to treat cancer has been described in the scientific literature as a canonical example of quackery
Quackery
Quackery is a derogatory term used to describe the promotion of unproven or fraudulent medical practices. Random House Dictionary describes a "quack" as a "fraudulent or ignorant pretender to medical skill" or "a person who pretends, professionally or publicly, to have skill, knowledge, or...

, with Irving Lerner of the University of Minnesota
University of Minnesota
The University of Minnesota, Twin Cities is a public research university located in Minneapolis and St. Paul, Minnesota, United States. It is the oldest and largest part of the University of Minnesota system and has the fourth-largest main campus student body in the United States, with 52,557...

 describing it as "the slickest, most sophisticated, and certainly the most remunerative cancer quack promotion in medical history."

Chemistry


Amygdalin is extracted from almond or apricot kernel cake by boiling in ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...

; on evaporation of the solution and the addition of diethyl ether
Diethyl ether
Diethyl ether, also known as ethyl ether, simply ether, or ethoxyethane, is an organic compound in the ether class with the formula . It is a colorless, highly volatile flammable liquid with a characteristic odor...

, amygdalin is precipitated as white minute crystals. Liebig and Wöhler were already able to find three decomposition products of the newly discovered amygdalin: sugar, benzaldehyde, and prussic acid (hydrogen cyanide). Later research showed that sulfuric acid
Sulfuric acid
Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...

 decomposes it into D-glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

, benzaldehyde
Benzaldehyde
Benzaldehyde is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. This colorless liquid has a characteristic pleasant almond-like odor...

, and prussic acid; while hydrochloric acid
Hydrochloric acid
Hydrochloric acid is a solution of hydrogen chloride in water, that is a highly corrosive, strong mineral acid with many industrial uses. It is found naturally in gastric acid....

 gives mandelic acid
Mandelic acid
Mandelic acid is an aromatic alpha hydroxy acid with the molecular formula C6H5CHCO2H. It is a white crystalline solid that is soluble in water and polar organic solvents. It is a useful precursor to various drugs...

, D-glucose, and ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...

.

Several glucosidase enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

s are known to act on amygdalin, leading to its decomposition by various pathways. Maltase
Maltase
Maltase is an enzyme that breaks down the disaccharide maltose. Maltase is an enzyme that catalyzes the hydrolysis of the disaccharide maltose to the simple sugar glucose. This enzyme is found in plants, bacteria, and yeast. Then there is what is called Acid maltase deficiency...

 causes partial degradation, giving D-glucose and mandelic nitrile glucoside, C6H5CH(CN)O·C6H11O5. Emulsin, on the other hand, decomposes it into benzaldehyde
Benzaldehyde
Benzaldehyde is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. This colorless liquid has a characteristic pleasant almond-like odor...

, cyanide
Cyanide
A cyanide is a chemical compound that contains the cyano group, -C≡N, which consists of a carbon atom triple-bonded to a nitrogen atom. Cyanides most commonly refer to salts of the anion CN−. Most cyanides are highly toxic....

, and two molecules of glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

; this enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 occurs in the bitter almond, and consequently the seeds invariably contain free cyanide and benzaldehyde. An "amorphous
Amorphous solid
In condensed matter physics, an amorphous or non-crystalline solid is a solid that lacks the long-range order characteristic of a crystal....

 amygdalin" is said to occur in the cherry laurel (Prunus laurocerasus). Lastly, amygdalin beta-glucosidase
Amygdalin beta-glucosidase
In enzymology, an amygdalin beta-glucosidase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are -amygdalin and H2O, whereas its two products are -prunasin and D-glucose....

 and prunasin beta-glucosidase
Prunasin beta-glucosidase
In enzymology, a prunasin beta-glucosidase is an enzyme that catalyzes the chemical reaction-prunasin + H2O \rightleftharpoons D-glucose + mandelonitrile...

 consecutively catalyze loss of the two glucose units to yield mandelonitrile
Mandelonitrile
Mandelonitrile is a chemical compound of the cyanohydrin class. Small amounts of mandelonitrile occur in the pits of some fruits.-Occurrence:...

, which can then decompose to form free cyanide and benzaldehyde.

Natural amygdalin has the R configuration at the chiral
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....

 benzyl
Benzyl
In organic chemistry, benzyl is the term used to describe the substituent or molecular fragment possessing the structure C6H5CH2-. Benzyl features a benzene ring attached to a CH2 group.-Nomenclature:...

 center. Under mild basic conditions, this stereogenic center epimerizes; the S epimer is called neoamygdalin.

Laetrile



Amygdalin is sometimes confused with laevomandelonitrile, also called laetrile for short; however, amygdalin and laetrile are different chemical compound
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...

s. Laetrile, which was patented in the United States, is a semi-synthetic molecule sharing part of the amygdalin structure, while the "laetrile" made in Mexico is usually amygdalin, the natural product
Natural product
A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design...

 obtained from crushed apricot pits, or neoamygdalin.

Laetrile has a melting point
Melting point
The melting point of a solid is the temperature at which it changes state from solid to liquid. At the melting point the solid and liquid phase exist in equilibrium. The melting point of a substance depends on pressure and is usually specified at standard atmospheric pressure...

 of 214 to 216 degrees Celsius. Its Chemical Abstracts Service Registry Number is 1332-94-1 and its International Union of Pure and Applied Chemistry nomenclature name is (2S,3S,4S,5R,6R)-6-[(R)-cyano(phenyl)methoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid. Laetrile's chemical formula
Chemical formula
A chemical formula or molecular formula is a way of expressing information about the atoms that constitute a particular chemical compound....

 is C14H15NO7 and its PubChem
PubChem
PubChem is a database of chemical molecules and their activities against biological assays. The system is maintained by the National Center for Biotechnology Information , a component of the National Library of Medicine, which is part of the United States National Institutes of Health . PubChem can...

 number is 5484354. Its molecular weight is 309.2714 grams/mole
Mole (unit)
The mole is a unit of measurement used in chemistry to express amounts of a chemical substance, defined as an amount of a substance that contains as many elementary entities as there are atoms in 12 grams of pure carbon-12 , the isotope of carbon with atomic weight 12. This corresponds to a value...

. Laetrile is also classified as a cyanogenic glycoside.

Though it is sometimes sold as "Vitamin B17", it is not a vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...

. Amygdalin/laetrile was claimed to be a vitamin by chemist Ernst T. Krebs
Ernst T. Krebs
Ernst T. Krebs, Jr. was an American biochemist. He is known for promoting various substances as alternative cures for cancer, including pangamic acid and amygdalin. He also co-patented the semi-synthetic chemical compound closely related to amygdalin named Laetrile, which was also promoted as a...

 in the hope that if classified as a nutritional supplement it would escape the federal legislation regarding the marketing of drugs. He could also capitalise on the public fad for vitamins at that time.

Toxicity


The metabolism of amygdalin produces hydrogen cyanide, a potent toxin. Beta-glucosidase
Amygdalin beta-glucosidase
In enzymology, an amygdalin beta-glucosidase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are -amygdalin and H2O, whereas its two products are -prunasin and D-glucose....

, one of the enzymes that catalyzes the release of cyanide from amygdalin, is present in the human small intestine and in a variety of common foods. This leads to an unpredictable and potentially lethal toxicity when amygdalin or laetrile is taken orally. Ingestion of purified amygdalin or apricot seeds can cause severe toxicity and death due to cyanide poisoning. Numerous case reports in the medical literature describe serious cyanide poisoning in patients who ingested laetrile as a cancer treatment. Blood cyanide concentrations may be measured as a means of confirming the diagnosis in hospitalized patients or to assist in the forensic investigation of a fatal overdose.

Some laetrile promoters have claimed that the cyanide generated by laetrile is harmlessly detoxified by the mitochondrial
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...

 enzyme rhodanese. However, these claims are false, as regardless of the level of rhodanese present, the body's available stores of cystine
Cystine
Cystine is a dimeric amino acid formed by the oxidation of two cysteine residues that covalently link to make a disulfide bond. This organosulfur compound has the formula 2. It is a white solid, and melts at 247-249 °C...

, cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

, and other sulfur compounds necessary to detoxify cyanide are rapidly depleted in laetrile poisoning.

Cancer treatment


Amygdalin was first isolated in 1830. In 1845 it was used as a cancer treatment in Russia, and in the 1920s in the United States, but it was considered too poisonous. In the 1950s, a purportedly non-toxic, synthetic form was patented for use as a meat preservative, and later marketed as laetrile for cancer treatment.

The U.S. Food and Drug Administration prohibited the interstate shipment of amygdalin and laetrile in 1977. Thereafter, 27 U.S. states legalized the use of amygdalin within those states.

Initial studies at Sloan-Kettering


In 1972, Memorial Sloan-Kettering Cancer Center
Memorial Sloan-Kettering Cancer Center
Memorial Sloan–Kettering Cancer Center is a cancer treatment and research institution founded in 1884 as the New York Cancer Hospital...

 (MSKCC) board member Benno C. Schmidt, Sr.
Benno C. Schmidt, Sr.
Benno Charles Schmidt, Sr. was an American lawyer and venture capitalist who was active in New York City civic affairs and played an important role in the initiation of the War on Cancer....

 convinced the hospital to test laetrile so that he could assure others of its ineffectiveness "with some conviction." Kanematsu Sugiura
Kanematsu Sugiura
Kanematsu Sugiura was a cancer researcher who spent his career at the Memorial Sloan-Kettering Cancer Center. He has been called "one of the true pioneers in cancer research", and completed over 250 papers before his death. He received a number of awards and prizes throughout his life, and...

, the scientist who performed the requested tests, found that laetrile inhibited secondary tumors in mice, though it did not destroy the primary tumors. He repeated the experiment several times with the same results. However, three other researchers were unable to confirm
Reproducibility
Reproducibility is the ability of an experiment or study to be accurately reproduced, or replicated, by someone else working independently...

 Sugiura's results. While these uncontrolled and inconclusive results were considered too preliminary to publish, they were leaked to laetrile advocates, resulting in significant public attention.

To expand on Sugiura's results, MSKCC researchers conducted a controlled
Scientific control
Scientific control allows for comparisons of concepts. It is a part of the scientific method. Scientific control is often used in discussion of natural experiments. For instance, during drug testing, scientists will try to control two groups to keep them as identical and normal as possible, then...

 experiment in which they injected some mice with laetrile (as Sugiura had done) and others with placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...

. Sugiura, who was unaware of which mice had received laetrile, performed the pathologic analysis. In this controlled, blinded follow-up of Sugiura's initial uncontrolled experiment, laetrile showed no more activity than placebo.

Subsequently, laetrile was tested on 14 tumor systems without evidence of effectiveness. Given this collection of results, MSKCC concluded that "laetrile showed no beneficial effects." Mistakes in the MSKCC press release were highlighted by a group of laetrile proponents led by Ralph Moss
Ralph W. Moss (science writer)
Ralph Walter Moss is an American author who advocates for alternative medicine, especially in its use in cancer treatments.- Career :...

, former public affairs official of MSKCC who was fired following his appearance at a press conference accusing the hospital of covering up the benefits of laetrile. These mistakes were considered scientifically inconsequential, but Nicholas Wade in Science stated that "even the appearance of a departure from strict objectivity is unfortunate." The results from these studies were published all together.

Subsequent clinical studies


A 2006 systematic review
Systematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...

 by the Cochrane Collaboration
Cochrane Collaboration
The Cochrane Collaboration is a group of over 28,000 volunteers in more than 100 countries who review the effects of health care interventions tested in biomedical randomized controlled trials. A few more recent reviews have also studied the results of non-randomized, observational studies...

 concluded: "The claim that [l]aetrile has beneficial effects for cancer patients is not supported by data from controlled clinical trials. This systematic review has clearly identified the need for randomised or controlled clinical trials assessing the effectiveness of [l]aetrile or amygdalin for cancer treatment." Given the lack of evidence, laetrile has not been approved by the U.S. Food and Drug Administration.

The U.S. National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...

 evaluated the evidence separately and concluded that clinical trials of amgydalin showed little or no effect against cancer. For example, a 1982 trial of 175 patients found that tumor size had increased in all but one patient. The authors reported that "the hazards of amygdalin therapy were evidenced in several patients by symptoms of cyanide toxicity or by blood cyanide levels approaching the lethal range."

The study concluded "Patients exposed to this agent should be instructed about the danger of cyanide poisoning, and their blood cyanide levels should be carefully monitored. Amygdalin (Laetrile) is a toxic drug that is not effective as a cancer treatment".

Advocacy and legality


Although laetrile is widely considered quackery
Quackery
Quackery is a derogatory term used to describe the promotion of unproven or fraudulent medical practices. Random House Dictionary describes a "quack" as a "fraudulent or ignorant pretender to medical skill" or "a person who pretends, professionally or publicly, to have skill, knowledge, or...

 in the medical community
Consensus (medical)
Medical consensus is a public statement on a particular aspect of medical knowledge available at the time it was written, and that is generally agreed upon as the evidence-based, state-of-the-art knowledge by a representative group of experts in that area...

, advocates for laetrile dispute this label, asserting that there is a conspiracy
Conspiracy theory
A conspiracy theory explains an event as being the result of an alleged plot by a covert group or organization or, more broadly, the idea that important political, social or economic events are the products of secret plots that are largely unknown to the general public.-Usage:The term "conspiracy...

 between the U.S. Food and Drug Administration, the pharmaceutical industry and the medical community, including the American Medical Association
American Medical Association
The American Medical Association , founded in 1847 and incorporated in 1897, is the largest association of medical doctors and medical students in the United States.-Scope and operations:...

 and the American Cancer Society
American Cancer Society
The American Cancer Society is the "nationwide community-based voluntary health organization" dedicated, in their own words, "to eliminating cancer as a major health problem by preventing cancer, saving lives, and diminishing suffering from cancer, through research, education, advocacy, and...

, to exploit the American people, and especially cancer patients. Some North American cancer patients have traveled to Mexico
Mexico
The United Mexican States , commonly known as Mexico , is a federal constitutional republic in North America. It is bordered on the north by the United States; on the south and west by the Pacific Ocean; on the southeast by Guatemala, Belize, and the Caribbean Sea; and on the east by the Gulf of...

 for treatment with the substance, allegedly under the auspices of Dr. Ernesto Contreras. Actor Steve McQueen died in Mexico following cancer treatment with laetrile and surgery to remove a stomach tumor while undergoing treatment for peritoneal mesothelioma
Peritoneal mesothelioma
Peritoneal mesothelioma is the name given to the cancer that attacks the lining of the abdomen. This type of cancer affects the lining that protects the contents of the abdomen and which also provides a lubricating fluid to enable the organs to move and work properly.The peritoneum is made of two...

 (a cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

 that attacks the lining of the abdomen
Abdomen
In vertebrates such as mammals the abdomen constitutes the part of the body between the thorax and pelvis. The region enclosed by the abdomen is termed the abdominal cavity...

) under the care of William D. Kelley, a dentist and orthodontist who devised a supposed cancer treatment based on laetrile.

Laetrile advocates in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

 include Dean Burk
Dean Burk
Dean Burk was an American biochemist: a co-discoverer of biotin, medical researcher, and a cancer researcher at the Kaiser Wilhelm Institute and the National Cancer Institute...

 (now deceased), a former chief chemist of the National Cancer Institute
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...

 cytochemistry
Cytochemistry
Cytochemistry is the biochemistry of cells, especially that of the macromolecules responsible for cell structure and function...

 laboratory, and national arm wrestling
Arm wrestling
Arm wrestling is a sport with two participants. Each participant places one arm on a surface with their elbows bent and touching the surface, and they grip each other's hand...

 champion Jason Vale, who claimed that his kidney
Kidney cancer
Kidney cancer is a type of cancer that starts in the cells in the kidney.The two most common types of kidney cancer are renal cell carcinoma and urothelial cell carcinoma of the renal pelvis...

 and pancreatic
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...

 cancers were cured by eating apricot
Apricot
The apricot, Prunus armeniaca, is a species of Prunus, classified with the plum in the subgenus Prunus. The native range is somewhat uncertain due to its extensive prehistoric cultivation.- Description :...

 seeds. Vale was convicted in 2003 for, among other things, marketing laetrile. The court also found that Vale, who had made at least $500,000 from his illegal sales of laetrile, had fraudulently marketed the substance.

The US Food and Drug Administration continues to seek jail sentences for vendors marketing laetrile for cancer treatment, calling it a "highly toxic product that has not shown any effect on treating cancer."

See also

  • United States v. Rutherford, . Finding: The Federal Food, Drug, and Cosmetic Act makes no express exception for drugs used by the terminally ill and no implied exemption is necessary to attain congressional objectives or to avert an unreasonable reading of the terms "safe" and "effective" in 201 (p) (1).

External links