Amygdalin

Amygdalin
Names
IUPAC name
[(6-O-β-D-Glucopyranosyl-β-D-glucopyranosyl)oxy](phenyl)acetonitrile
Identifiers
29883-15-6 N
3D model (Jmol) Interactive image
Interactive image
ChEBI CHEBI:17019 YesY
ChEMBL ChEMBL461727 YesY
ChemSpider 570897 YesY
ECHA InfoCard 100.045.372
MeSH Amygdalin
PubChem 34751
UNII 214UUQ9N0H YesY
Properties
C20H27NO11
Molar mass 457.429
Melting point 223-226 °C(lit.)
H2O: 0.1 g/mL hot, clear to very faintly turbid, colorless
Hazards
Safety data sheet A6005
GHS pictograms
GHS signal word Warning
H302
P264, P270, P301+312, P330, P501
NFPA 704
Flammability code 0: Will not burn. E.g., water Health code 1: Exposure would cause irritation but only minor residual injury. E.g., turpentine Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
0
1
0
Related compounds
Related compounds
 Vicianin, laetrile, prunasin, sambunigrin
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

Amygdalin (from Ancient Greek: ἀμυγδαλή amygdálē "almond"), is a poisonous cyanogenic glycoside found in many plants, but most notably in the seeds (kernels) of apricot, bitter almonds, apple, peach, and plum.

Since the early 1950s, both amygdalin and a modified form named laetrile have been promoted as alternative cancer treatments, often using the misnomer Vitamin B17.[1] But studies have found them to be clinically ineffective in the treatment of cancer, as well as potentially toxic or lethal when taken by mouth, due to cyanide poisoning. Neither amygdalin nor laetrile is a vitamin.

The promotion of laetrile to treat cancer has been described in the medical literature as a canonical example of quackery,[2][3] and as "the slickest, most sophisticated, and certainly the most remunerative cancer quack promotion in medical history."[1]

Chemistry

Amygdalin is a cyanogenic glycoside derived from the aromatic amino acid phenylalanine. Amygdalin and prunasin are very common among plants of the Rosaceae family, particularly the Prunus genus, Poaceae (grasses), Fabaceae (legumes), and in other food plants, including linseed and manioc. Sambunigrin, obtained from leaves of the elder tree (Sambucus nigra), is isomeric to prunasin.[4] Within these plants, amygdalin and the enzymes necessary to hydrolyze them are stored in separate locations so that they will mix in response to tissue damage. This provides a natural defense system[5]

Amygdalin is contained in stone fruit kernels, such as apricot (8%), peach (6%), bitter almond (5%), and plum (2.5%); amygdalin is also found in the seeds of the apple.[6] The stones are taken out of the fruit and cracked to obtain the kernels, which are dried in the sun or in ovens. The kernels are boiled in ethanol; on evaporation of the solution and the addition of diethyl ether, amygdalin is precipitated as white minute crystals. Natural amygdalin has the R configuration at the chiral phenyl center. Under mild basic conditions, this stereogenic center isomerizes; the S epimer is called neoamygdalin. Although the synthesized version of amygdalin is the R-epimer, the stereogenic center attached to the nitrile and phenyl groups easily epimerizes if the manufacturer does not store the compound correctly.[7]

Amygdalin is hydrolyzed by intestinal β-glucosidase, emulsin,[8] and amygdalase to gentiobiose and L-mandelonitrile. Gentiobiose is further hydrolyzed to glucose, whereas mandelonitrile is hydrolyzed to benzaldehyde and hydrogen cyanide. Hydrogen cyanide in sufficient quantities (allowable daily intake: ~0.6 mg) causes cyanide poisoning (fatal oral dose: 0.6-1.5 mg/kg). Apricot pits contain 89-2,170 mg/kg hydrogen cyanide (wet weight).

In small quantities these glycosides do exhibit expectorant, sedative and digestive properties. Wild cherry bark (Prunus serotina) is an excellent cough remedy and tonic, as well as a flavouring agent used in cough syrups. It is of benefit as a tea for bronchitis. The main antitussive principle is prunasin.[4] In Chinese medicine, apricot seeds (杏仁, xìngrén) are used against cough and constipation (4.5-9 g).[9]

Laetrile

Laetrile
Names
IUPAC name
(2S,3S,4S,5R,6R)-6-[(R)-cyano(phenyl)methoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid
Other names
L-mandelonitrile-β-D-glucuronide, Vitamin B₁₇
Identifiers
1332-94-1
ECHA InfoCard 100.045.372
PubChem 5484354
Properties
C14H15NO7
Molar mass 309.2714
Melting point 214 to 216 °C (417 to 421 °F; 487 to 489 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Laetrile (patented 1961) is a simpler semisynthetic version of amygdalin. Laetrile is synthesized from amygdalin by hydrolysis. The usual preferred commercial source is from apricot kernels (Prunus armeniaca). The name is derived from the separate words "laevarotatory" and "mandelonitrile". Laevarotatory describes the stereochemistry of the molecule, while mandelonitrile refers to its chemical identity[10]

A 500 mg laetrile tablet may contain between 5–51 mg of hydrogen cyanide per gram.[11]

Like amygdalin, laetrile is hydrolyzed in the duodenum (alkaline) and in the intestine (enzymatically) to D-glucuronic acid and L-mandelonitrile; the latter hydrolyzes to benzaldehyde and hydrogen cyanide, that in sufficient quantities causes cyanide poisoning. Intravenous laetrile does not result in cyanide exposure. This is due to the fact that the necessary enzymes are released either upon chewing the plant material or are provided by bacteria residing in the human gastrointestinal system.[12]

Claims for laetrile were based on three different hypotheses:[13]

Ernst T. Krebs branded laetrile as a vitamin in order to have it classified as a nutritional supplement rather than as a pharmaceutical.[1]

History of laetrile

Early usage

Amygdalin was first isolated in 1830 from bitter almond seeds (Prunus dulcis) by Pierre-Jean Robiquet and Antoine Boutron-Charlard.[14] Liebig and Wöhler found three hydrolysis products of amygdalin: sugar, benzaldehyde, and prussic acid (hydrogen cyanide).[15] Later research showed that sulfuric acid hydrolyzes it into D-glucose, benzaldehyde, and prussic acid; while hydrochloric acid gives mandelic acid, D-glucose, and ammonia.[16]

In 1845 amygdalin was used as a cancer treatment in Russia, and in the 1920s in the United States, but it was considered too poisonous.[17] In the 1950s, a purportedly non-toxic, synthetic form was patented for use as a meat preservative,[18] and later marketed as laetrile for cancer treatment.[17]

The U.S. Food and Drug Administration prohibited the interstate shipment of amygdalin and laetrile in 1977.[19][20] Thereafter, 27 U.S. states legalized the use of amygdalin within those states.[21]

Initial positive results

In 1972, Memorial Sloan-Kettering Cancer Center (MSKCC) board member Benno C. Schmidt, Sr. convinced the hospital to test laetrile. Kanematsu Sugiura, the scientist who performed the 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 Sugiura's results. Sugiura's results were leaked to laetrile advocates, resulting in significant public attention.

Subsequent results

In 1977 a controlled, blinded follow-up experiment, laetrile showed no more activity than placebo.[22]

Subsequently, laetrile was tested on 14 tumor systems without evidence of effectiveness. MSKCC concluded that "laetrile showed no beneficial effects."[22] Mistakes in the MSKCC press release were highlighted by a group of laetrile proponents led by Ralph Moss, 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.[23] These mistakes were considered scientifically inconsequential, but Nicholas Wade in Science stated that "even the appearance of a departure from strict objectivity is unfortunate."[22] The results from these studies were published all together.[24]

A 2011 systematic review from the Cochrane Collaboration found:

The claims that laetrile or amygdalin have beneficial effects for cancer patients are not currently supported by sound clinical data. There is a considerable risk of serious adverse effects from cyanide poisoning after laetrile or amygdalin, especially after oral ingestion. The risk–benefit balance of laetrile or amygdalin as a treatment for cancer is therefore unambiguously negative.[25]

The authors also recommended, on ethical grounds, that no further clinical research into laetrile or amygdalin be conducted.[25]

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 evaluated the evidence separately and concluded that clinical trials of amygdalin showed little or no effect against cancer.[17] For example, a 1982 trial by the Mayo Clinic of 175 patients found that tumor size had increased in all but one patient.[26] 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".

Additionally, "No controlled clinical trials (trials that compare groups of patients who receive the new treatment to groups who do not) of laetrile have been reported." [27]

The side effects of laetrile treatment are the symptoms of cyanide poisoning. These symptoms include: nausea and vomiting, headache, dizziness, cherry red skin color, liver damage, abnormally low blood pressure, droopy upper eyelid, trouble walking due to damaged nerves, fever, mental confusion, coma, and death.

Advocacy and legality of laetrile

Advocates for laetrile assert that there is a conspiracy between the US Food and Drug Administration, the pharmaceutical industry and the medical community, including the American Medical Association and the American Cancer Society, to exploit the American people, and especially cancer patients.[28]

Advocates of the use of laetrile have also changed the rationale for its use, first as a treatment of cancer, then as a vitamin, then as part of a "holistic" nutritional regimen, or as treatment for cancer pain, among others, none of which have any significant evidence supporting its use.[28]

Despite the lack of evidence for its use, laetrile developed a significant following due to its wide promotion as a "pain-free" treatment of cancer as an alternative to surgery and chemotherapy that have significant side effects. The use of laetrile led to a number of deaths.[28] The FDA and AMA crackdown, begun in the 1970s, effectively escalated prices on the black market, played into the conspiracy narrative and enabled unscrupulous profiteers foster multimillion-dollar smuggling empires.[29]

Some North American cancer patients have traveled to Mexico for treatment with the substance, for example at the Oasis of Hope Hospital in Tijuana.[30] The actor Steve McQueen died in Mexico following surgery to remove a stomach tumor having previously undergone extended treatment for pleural mesothelioma (a cancer associated with asbestos exposure) under the care of William D. Kelley, a de-licensed dentist and orthodontist who claimed to have devised a cancer treatment involving pancreatic enzymes, 50 daily vitamins and minerals, frequent body shampoos, enemas, and a specific diet as well as laetrile.[31]

Laetrile advocates in the United States include Dean Burk, a former chief chemist of the National Cancer Institute cytochemistry laboratory,[32] and national arm wrestling champion Jason Vale, who claimed that his kidney and pancreatic cancers were cured by eating apricot seeds. Vale was convicted in 2004 for, among other things, fraudulently marketing laetrile as a cancer cure.[33] The court also found that Vale had made at least $500,000 from his fraudulent sales of laetrile.[34]

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."[35]

See also

References

  1. 1 2 3 Lerner IJ (1981). "Laetrile: a lesson in cancer quackery". CA Cancer J Clin. 31 (2): 91–5. doi:10.3322/canjclin.31.2.91. PMID 6781723.
  2. ↑ Lerner IJ (February 1984). "The whys of cancer quackery". Cancer. 53 (3 Suppl): 815–9. doi:10.1002/1097-0142(19840201)53:3+<815::AID-CNCR2820531334>3.0.CO;2-U. PMID 6362828.
  3. ↑ Nightingale SL (1984). "Laetrile: the regulatory challenge of an unproven remedy". Public Health Rep. 99 (4): 333–8. PMC 1424606Freely accessible. PMID 6431478.
  4. 1 2 Andrew Pengelly (2004), The Constituents of Medicinal Plants (2nd ed.), Allen & Unwin, pp. 44–45, ISBN 1-74114-052-8
  5. ↑ Mora, Carlos A.; Halter, Jonas G.; Adler, Cornel; Hund, Andreas; Anders, Heidrun; Yu, Kang; Stark, Wendelin J. (2016-05-11). "Application of the Prunus spp. Cyanide Seed Defense System onto Wheat: Reduced Insect Feeding and Field Growth Tests". Journal of Agricultural and Food Chemistry. 64 (18): 3501–3507. doi:10.1021/acs.jafc.6b00438. ISSN 0021-8561.
  6. ↑ Bolarinwa, Islamiyat F.; Orfila, Caroline; Morgan, Michael R.A. (2014). "Amygdalin content of seeds, kernels and food products commercially-available in the UK". Food Chemistry. 152: 133–139. doi:10.1016/j.foodchem.2013.11.002.
  7. ↑ Wahab, Farooq (2015). "Problems and Pitfalls in the Analysis of Amygdalin and its Epimer". Journal of Agricultural and Food Chemistry. 63: 8966–8973.
  8. ↑ George Mann, Frederick; Charles Saunders, Bernard (1975). Practical Organic Chemistry (4th ed.). London: Longman. pp. 509–517. ISBN 9788125013808. Retrieved 1 February 2016.
  9. ↑ Medicinal Plants in China (2nd ed.), World Health Organization, 1997, p. 233, ISBN 92-9061-102-2
  10. ↑ "Laetrile/Amygdalin". National Cancer Institute. Retrieved 2016-11-16.
  11. ↑ Jerrold B. Leikin; Frank P. Paloucek, eds. (2008), "Laetrile", Poisoning and Toxicology Handbook (4th ed.), Informa, p. 950, ISBN 978-1-4200-4479-9
  12. ↑ Rietjens, Ivonne M. C. M.; Martena, Martijn J.; Boersma, Marelle G.; Spiegelenberg, Wim; Alink, Gerrit M. (2005-02-01). "Molecular mechanisms of toxicity of important food-borne phytotoxins". Molecular Nutrition & Food Research. 49 (2): 131–158. doi:10.1002/mnfr.200400078. ISSN 1613-4133.
  13. 1 2 James A. Duke (2003), CRC Handbook of Medicinal Spices, CRC Press, pp. 261–262, ISBN 0-8493-1279-5
  14. ↑ "A chronology of significant historical developments in the biological sciences". Botany Online Internet Hypertextbook. University of Hamburg, Department of Biology. 18 August 2002. Archived from the original on 20 August 2007. Retrieved 6 August 2007.
  15. ↑ F. Wöhler; J. Liebig (1837). "Ueber die Bildung des Bittermandelöls". Annalen der Pharmacie. 22 (1): 1–24. doi:10.1002/jlac.18370220102.
  16. ↑ J. W. Walker; V. K. Krieble (1909). "The hydrolysis of amygdalin by acids. Part I". Journal of the Chemical Society. 95 (11): 1369–77. doi:10.1039/CT9099501369.
  17. 1 2 3 "Laetrile/Amygdalin". National Cancer Institute.
  18. ↑ US 2985664, Krebs, Ernst T. & Ernst T. Krebs, Jr., "Hexuronic acid derivatives"
  19. ↑ Carpenter, Daniel (2010). Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA. Princeton: Princeton University Press. Princeton: Princeton University Press. ISBN 0-691-14180-0.
  20. ↑ Kennedy, Donald (1977). "Laetrile: The Commissioner's Decision" (PDF). Federal Register. Docket No. 77-22310.
  21. ↑ American Cancer Society (1991). "Unproven methods of cancer management. Laetrile". CA Cancer J Clin. 41 (3): 187–92. doi:10.3322/canjclin.41.3.187. PMID 1902140.
  22. 1 2 3 Wade N (December 1977). "Laetrile at Sloan-Kettering: A Question of Ambiguity". Science. 198 (4323): 1231–4. doi:10.1126/science.198.4323.1231. PMID 17741690.
  23. ↑ Budiansky, Stephen (9 July 1995). "Cures or Quackery: How Senator Harkin shaped federal research on alternative medicine". U.S. News & World Report. Archived from the original on 3 September 2011. Retrieved 7 November 2009.
  24. ↑ Stock CC, Tarnowski GS, Schmid FA, Hutchison DJ, Teller MN (1978). "Antitumor tests of amygdalin in transplantable animal tumor systems". J Surg Oncol. 10 (2): 81–8. doi:10.1002/jso.2930100202. PMID 642516.
    Stock CC, Martin DS, Sugiura K (1978). "Antitumor tests of amygdalin in spontaneous animal tumor systems". J Surg Oncol. 10 (2): 89–123. doi:10.1002/jso.2930100203. PMID 347176.
  25. 1 2 Milazzo S, Ernst E, Lejeune S, Boehm K, Horneber M (2011). "Laetrile treatment for cancer". Cochrane Database Syst Rev (Systematic review) (11): CD005476. doi:10.1002/14651858.CD005476.pub3. PMID 22071824.
  26. ↑ "Laetrile (amygdalin, vitamin B17)". cancerhelp.org.uk.
  27. ↑ "Laetrile/Amygdalin". National Cancer Institute.
  28. 1 2 3 Editors of Consumer Reports Books (1980). "Laetrile: the Political Success of a Scientific Failure". Health Quackery. Vernon, New York: Consumers Union. pp. 16–40. ISBN 0-89043-014-4
  29. ↑ Laetrile: The Cult of Cyanide Poisoning; Promoting Poison for Profit, American Journal of Clinical Nutrition, May 1979, pp. 1121–1158. http://www.ajcn.org/content/32/5/1121.full.pdf retrieved: Jan. 2012.
  30. ↑ Moss RW (March 2005). "Patient perspectives: Tijuana cancer clinics in the post-NAFTA era". Integr Cancer Ther. 4 (1): 65–86. doi:10.1177/1534735404273918. PMID 15695477.
  31. ↑ Lerner, Barron H. (15 November 2005). "McQueen's Legacy of Laetrile". New York Times. Retrieved 23 April 2010.
  32. ↑ "Dean Burk, 84, Noted Chemist At National Cancer Institute, Dies". Washington Post. 9 October 1988.
  33. ↑ Brian S. McWilliams (2005). Spam kings: the real story behind the high-rolling hucksters pushing porn, pills and @*#?% enlargements. Sebastopol, CA: O'Reilly. ISBN 0-596-00732-9.
  34. ↑ "New York Man Sentenced to 63 Months for Selling Fake Cancer Cure". Medical News Today. 22 June 2004. Retrieved 8 July 2010.
  35. ↑ US FDA (22 June 2004). Lengthy Jail Sentence for Vendor of Laetrile – A Quack Medication to Treat Cancer Patients. FDA News

External links

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