Why sudden death from cyanide poisoning

Cyanide intoxication after oral amygdalin treatment (from the ADR database)

Amygdalin occurs in the nuclei of e.g. B. peaches or apricots. The semi-synthetic Laevo mandelic acid nitrile β-glucuroniside (Laetrile) is structurally very similar. Cyanide (hydrogen cyanide) can be released from both compounds. Although authorities and scientific institutions rate amygdalin and laetrile as ineffective and toxic or questionable (1-5), bitter apricot kernels or finished preparations containing amygdalin / laetrile are heavily advertised on the Internet for alternative medical prophylaxis and treatment of cancer.

The AkdÄ was reported the case of a four-year-old boy (110 cm, 18 kg) with cyanide intoxication after treatment with amygdalin (AkdÄ case number 163180): The child had an anaplastic ependymoma (WHO grade 3), which was initially resected. After six months, a recurrence of the tumor made another operation necessary. Six months later, a recurrence of the tumor and spinal metastasis were diagnosed again and treated with radiation. Approximately one and a half years after the initial diagnosis, an alternative medical treatment with amygdalin took place in the palliative situation: The boy had received "vitamin B17" (amygdalin) intravenously and an additional ten bitter apricot kernels per day orally. He was also given numerous vitamin preparations, trace elements and micro-green algae. Five days after starting this treatment, he took 500 mg of an amygdalin preparation orally for the first time. Fifteen minutes later, the boy was suddenly agitated, cramping arms and hands and rolling his eyes. The vigilance was variable, there was no cyanosis. The child was hospitalized by the emergency doctor on suspicion of cyanide intoxication. Laboratory tests showed lactic acidosis (pH 7.13; lactate 11.8 mmol / l). The cyanide blood level was 514 µg / l (toxic range:> 200 µg / l). After administration of the antidote sodium thiosulfate, the boy's condition improved. He was discharged after two days of inpatient treatment.

Effects of amygdalin

The terms amygdalin and laetrile are often used synonymously or the term "vitamin B17" is used. However, the latter is misleading as neither amygdalin nor laetrile meet the criteria for a vitamin (5-7).

Amygdalin / Laetril is a cyanogenic glycoside and contains the cyanide structure. Specific enzymes, which are found in the microbial intestinal flora, are required for the release of cyanide (8). After intravenous application of amygdalin, the cyanide level in the blood does not rise because the enzymes required for release are missing (9). After oral ingestion, the release of cyanide and an increase in blood levels can occur (8). The fact that the kernels of bitter apricots, almonds and others also contain cyanide-releasing enzymes in addition to amygdalin also contribute to the release of cyanide after oral ingestion (5).

Amygdalin / Laetrile is ascribed an effectiveness against cancer in alternative medicine. In malignant cells, their changed enzyme equipment leads to an increased release and reduced breakdown of cyanide, which is held responsible for the cytotoxic effect. Another unsubstantiated claim is to compensate for a postulated deficiency in "vitamin B17" that causes cancer (5, 7, 10).

Cyanide is a toxic substance and can lead to life-threatening poisoning by blocking the mitochondrial respiratory chain and the formation of the intracellular energy supplier adenosine triphosphate (ATP). Typical symptoms of cyanide intoxication are headache, nausea, dizziness, tachy- or dyspnea, hyper- or hypotension, arrhythmias, loss of consciousness, convulsions, cardiovascular failure and death, depending on the severity. Laboratory tests often show metabolic acidosis and increased lactate (11).

effectiveness

The scientific evidence for the effectiveness of amygdalin / laetrile in cancer must be considered disproved (5). Although there are a large number of anecdotal case reports on the supposed effectiveness of amygdalin / laetrile, methodologically high-quality, randomized controlled studies in humans are not available. According to a 2011 Cochrane review, most publications refer to consecutive and non-consecutive case series (10). In a current Medline research, we could not identify any other relevant studies.

A much-cited study on 178 patients with histologically proven cancer did not provide any proof of the effectiveness of amygdalin (12). The patients were initially treated intravenously with amygdalin and then received oral maintenance therapy. This study did not have an amygdalin-free control group. Only one patient experienced a partial remission of his disease, but died 37 weeks after the start and continued treatment after clear progression of the disease. The median survival for all patients was 4.8 months. Despite monitoring the cyanide blood level, toxic symptoms occurred. The authors conclude that amygdalin is a toxic substance with no effect in cancer treatment (12). The US National Cancer Institute initiated a retrospective case evaluation (13). Over 450,000 doctors and other health professionals were asked to report positive outcomes after treatment with Laetrile. These cases as well as "control cases" from the institute's register were then assessed by twelve oncologists who did not know which treatment (Laetrile, no or conventional treatment) the patients had received. Although it was estimated that there were around 70,000 Laetrile-treated patients in the United States at the time, only 93 cases were submitted for evaluation. Of these, 26 could not be assessed due to insufficient documentation. Despite the selection bias, a response was found in only six of the fully recorded cases. Although the questionnaire was only asked about positive results with Laetrile, 220 doctors also reported a total of more than 1000 patients who had experienced no benefit from the Laetrile treatment (13).

toxicity

The lack of proof of effectiveness is offset by the toxicity of amygdalin / laetrile. In one study, amygdalin was administered intravenously and later orally to six cancer patients (9). While no cyanide was detectable in the blood after intravenous administration of amygdalin, the cyanide level in the blood increased after oral administration. This increase varied significantly between study participants. Of the six patients, only one patient developed clinical symptoms of cyanide intoxication. However, she had consumed a large amount of raw almonds in addition to amygdalin (9). However, proof of the safety and tolerability of amygdalin cannot be derived from this study on only six patients in a defined setting. In the case series of 178 patients (12) already mentioned, the blood levels of cyanide measured varied greatly between individuals. Observed toxic symptoms such as nausea, vomiting, headache, drowsiness, and impaired consciousness were not always associated with high levels (12). In the literature, there are some cases of cyanide intoxication after accidental or "therapeutic" ingestion of amygdalin, some with fatal results (5, 14-18). The toxicity is particularly increased after oral ingestion (10).

According to research by the NDR, the packaging of bitter apricot kernels indicates a dosage of up to eight kernels per day (19). However, in its opinion on bitter apricot kernels, the Federal Institute for Risk Assessment advises that adults should not consume more than one or two kernels per day (corresponding to around 0.5–1 mg hydrogen cyanide) or should not eat them at all. About 0.5–3.5 mg of cyanide per kilogram of body weight are fatal for humans (2). In the present case, the boy had taken 500 mg amygdalin orally, which corresponds to about 28 mg bound cyanide (1.6 mg / kg body weight). If the cyanide is released rapidly, this dosage is sufficient to cause the toxic symptoms.

Current assessments

The Federal Institute for Drugs and Medical Devices (BfArM) recently made it clear that "amygdalin-containing products that are offered for the treatment of tumor diseases [...] according to Section 2 (1) of the German Medicines Act (AMG) are medicinal products and therefore require authorization as finished medicinal products [...] are] "(5). However, amygdalin is not approved as a finished medicinal product. The BfArM also states that the use of amygdalin is fraught with considerable risks, but that its effectiveness in the treatment of tumor diseases must be considered refuted. According to the BfArM, amygdalin is to be classified as a "questionable drug" within the meaning of Section 5 AMG. "According to this, questionable drugs must not be placed on the market or used on other people. A dispensing of amygdalin is therefore inadmissible even if a doctor's prescription is available" (5).

In the event of a lack of effectiveness and considerable toxicity, the AkdÄ advises against the use of amygdalin-containing finished medicinal products and other amygdalin-containing products.


literature
  1. Drug Commission of the German Pharmacists (AMK: Dubious Prescription Drugs: http://www.akdae.de/Arzneimittelsicherheit/Weiter/Bedenkliche-Rezepturarzneimittel.pdf. Information from the Drugs Commission of the German Pharmacists (AMK) from September 2013. Last checked: August 15, 2014 .
  2. Federal Institute for Risk Assessment (BfR): Consumption of bitter apricot kernels is a health hazard: http://www.bfr.bund.de/cm/343/verzehr_von_bitteren_aprikosenkernen_ist_gesundheitlich_bedenklich.pdf. Opinion No. 014/2007 of May 3, 2007. Last checked: August 15, 2014.
  3. Drug Commission of the German Medical Association: Warning of Laetrile. Dtsch Arztebl 1978; 75: 362.
  4. Kennedy D, Whitehorn WV, Martin EW: Toxicity of laetrile. FDA Drug Bulletin 1977; 26-32.
  5. Lilienthal N: Amygdalin - lack of effectiveness and harmful side effects. Drug Safety Bulletin 2014; 5 (3): 7-13.
  6. Unproven methods of cancer management. Laetrile. CA Cancer J Clin 1991; 41: 187-92.
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  8. Carter JH, McLafferty MA, Goldman P: Role of the gastrointestinal microflora in amygdalin (laetrile) -induced cyanide toxicity. Biochem Pharmacol 1980; 29: 301-4.
  9. Moertel CG, Ames MM, Kovach JS, et al .: A pharmacologic and toxicological study of amygdalin. JAMA 1981; 245: 591-4.
  10. Milazzo S, Ernst E, Lejeune S, et al .: Laetrile treatment for cancer. Cochrane Database Syst Rev 2011; Issue 11: CD005476.
  11. Lawson-Smith P, Jansen EC, Hyldegaard O: Cyanide intoxication as part of smoke inhalation - a review on diagnosis and treatment from the emergency perspective. Scand J Trauma Resusc Emerg Med 2011; 19:14.
  12. Moertel CG, Fleming TR, Rubin J, et al .: A clinical trial of amygdalin (Laetrile) in the treatment of human cancer. N Engl J Med 1982; 306: 201-6.
  13. Ellison NM, Byar DP, Newell GR: Special report on Laetrile: the NCI Laetrile Review. Results of the National Cancer Institute's retrospective Laetrile analysis. N Engl J Med 1978; 299: 549-52.
  14. Smith FP, Butler TP, Cohan S, Schein PS: Laetrile toxicity: a report of two cases. JAMA 1977; 238: 1361.
  15. O'Brien B, Quigg C, Leong T: Severe cyanide toxicity from 'vitamin supplements'. Eur J Emerg Med 2005; 12: 257-8.
  16. Beamer WC, Shealy RM, Prough DS: Acute cyanide poisoning from laetrile ingestion. Ann Emerg Med 1983; 12: 449-51.
  17. Braico KT, Humbert JR, Terplan KL, Lehotay JM: Laetrile intoxication. Report of a fatal case. N Engl J Med 1979; 300: 238-40.
  18. Sadoff L, Fuchs K, Hollander J: Rapid death associated with laetrile ingestion. JAMA 1978; 239: 1532.
  19. Norddeutscher Rundfunk (NDR): Dangerous "miracle drug" against cancer: http://www.ndr.de/ratgeber/verbrauch/Vergiftungen-durch-bittere-Aprikosenkerne,aprikosenkerne100.html. Last checked: August 15, 2014.