Silver-level articleAristolochia

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A. californica
Against allopathy

Alternative medicine

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Unproven articles

Birthwort (or Birthworts, Pipevine, or Dutchman's Pipe vine) is a common name given to plants in the genus Aristolochia. It is notable for its use in traditional Chinese medicine (TCM) — despite causing cancer and kidney failure. Home run for evidence based medicine!

Given the long and well-documented history of medical usage (since 300 BCE) and the extreme toxicity of birthwort, it could be argued that this is one of the best cases against the "appeal to tradition", or the related "appeal to ancient wisdom" and "argument from authority" fallacies.

Contents

[edit] History

[edit] Ancient times

Birthwort has been used for thousands of years in various cultures around the world as a panacea for numerous diseases. Birthwort was especially thought to be beneficial for women giving childbirth; the name aristolochia means "noble birth". It was commonly used in ancient Greek, Roman and Byzantine pharmaceutical recipes for a variety of conditions, including kidney ailments, peritonsillar abscess, bladder stones, edemas, gout, snakebite and uterine complaints.[1]

Theophrastus,Wikipedia's W.svg a student of Aristotle, wrote the first botanic description and first report on the pharmaceutical properties of birthwort in c. 300 BCE:[1][2]

There are many uses of it for various purposes are enumerated; it is best for bruises on the head, good also for other wounds, against snake-bites, to produce sleep, for the womb as a pessary: for some purposes it is soaked with water and applied as a plaster, for others it is scraped into honey and olive-oil: against snake-bites it is drunk in sour wine and also sprinkled over the bite; to induce sleep it is given pounded up in black dry wine: in cases of prolapsus uteri it is used in water as a lotion. This plant then seems to have a surpassing variety of usefulness.

Other ancient writers who recommended birthwort for medical treatment included: Diocles of CarystusWikipedia's W.svg (c. 375 - 295 BCE), Philinus of CosWikipedia's W.svg (3rd century BCE), Heraclides of TarentumWikipedia's W.svg (c. 2nd - 3rd century BCE), Aulus Cornelius CelsusWikipedia's W.svg (c. 25 BCE - c. 50 CE), Scribonius LargusWikipedia's W.svg (c. 1 - c. 50 CE), Pedanius DioscoridesWikipedia's W.svg (c. 40 - 90 CE), and Pliny the Elder (23 - 79 CE).[1]

[edit] Medieval era

Saint Hildegard of BingenWikipedia's W.svg (1098-1179 CE), a medieval polymath, wrote several books, including the 9-volume Physica. Physica was written between 1151-1158 CE and includes a description of plants and their medical uses. A modern, English translation of the book includes this description of birthwort:[3]

Birthwort (byverwurtz) is hot, and a bit cold. Therefore, pulverize its root and leaves and add half as much feverfew powder and one-fourth as much cinnamon powder. Mix them together and eat it daily, either with bread or with warm wine, or in broth. You will have no great or lasting infirmity until the time you die. No one should shun powder prepared this way. If a healthy person eats this powder daily, he will not be lying sick in bed a long time. If he is sick and eats it, he will be well. In order to conserve this powder safely throughout the year, it should be placed in a new, earthenware vessel, enclosed in the earth. It will retain its powers.

Hildegard's Physica was the foundation of Hildegardian medicine, a now-minor field of quackery that is mostly practiced in Germany and Switzerland; it is not clear whether modern practitioners of Hildegardian medicine have prescribed birthwort.

[edit] Post-Medieval era

The Bencao GangmuWikipedia's W.svg (本草綱目) or Compendium of Materia Medica was first published in the 1578 by Li ShizhenWikipedia's W.svg (李時珍). Aristolochia appears in the Bencao Gangmu as "馬兜鈴" (birthwort).[4] Bernard Read's analysis of the Bencao Gangmu reported three species of Aristolochia (A. debilis, A. recurvilabra, and A. contorta),[5] but A. recurvilabra is now considered a synonym of A. debilis.[6]

G. A. Stuart reported that two species of Aristolochia were in use in 1911, A. kaempferi (馬兜鈴) and A. recurvilabra (A. debilis).[7] For A. kaempferi, Stuart stated:[7]

As the open, cellular structure of these fruits is considered by the Chinese to resemble the human lung, they are strongly recommended in all forms of pulmonary affections. They have very little taste or smell and are not poisonous [emphasis added]. Other diseases for which they are prescribed are hemorrhoids and ascites. One of the fruits burned over a lamp, and the charred remains taken with wine, is considered a sure cure for heartburn.

For A. debilis, Stuart stated:[7]

It is a highly valued remedy, being prescribed in combination with such drugs as ginseng and China root. It is used in digestive disorders and chronic fluxes, especially those of women and children. It is regarded as being especially useful in summer diarrhoea and in chronic diarrhoea and dysentery… But in addition, this is regarded to be especially efficacious in expelling the 蠱 (Ku) poison. So highly is it valued for this purpose by the inhabitants of Lingnan that they have given it the name of 三百兩銀藥 (San-pai-liang-yin-yao) "three-hundred-taels-of-silver-drug." It is also considered to be a good remedy for snake-bite.

The Bencao Gangmu has remained in use continuously since its publication, and was replaced in China by the 10-volume Zhong Hua Ben Cao (中华本草, Encyclopedia of Chinese Materia Medica) in 1999, which includes 23 species of Aristolochia, with little mention of toxicity.[8] The species A. manshuriensis, A. fangchi, A. debilis, and A. contorta are included in the official Pharmacopoeia of the People's Republic of China.[9]

In 1597, John GerardeWikipedia's W.svg wrote what became a very popular book, called The Herball, or Generall Historie of Plantes. The book cited three ancient authorities on the uses of birthwoorte: Pedanius Dioscorides, GalenWikipedia's W.svg (129 - c. 200/c. 216 CE) and Pliny the Elder.[10] The uses for "long birthwoorte" (A. longa) and "round birthwoorte" (A. rotunda) included:[10]

  • Dioscorides writeth, that a dram waight of long Birthwoort drunke with wine and also applied is good against serpents and deadly things: and that being drunk with myrrhe and pepper, it expelleth whatsoever is left in the matrix after the childe is delivered, the flowers also & dead children: and that being put up in a pessarie, it performeth the same.
  • Round Birthwoorte serveth for all these things, and also the rest of the other poisons: it is likewise available against the stuffing of the lungs, the hicket, the shakings or shiverings of agues, hardness of the milt or spleene, burstings, cramps and convolutions, paines of the sides, if it be drunk with water.
  • It plucketh out thornes, splinters, and shivers, and being mixed in plaisters, or pulteses, it draweth foorth scales or bones, removeth rottennesse and corruption, mundifieth and scoureth foule and filthie ulcers, and filleth them up with new flesh, if it be mixed with Ireos and honey.
  • Galen saith, that branched Birthwoort is of a more sweete and pleasant smell: it therefore is used in ointments; but it is weaker in operations than the former ones.
  • Birthwoort as Plinie writeth being drunk with water is a moste excellent remedie for crampes and convulsions, burses, and for such as have fallen from high places.
  • It is good for them that are short winded, and troubled with falling sickness.
  • The rounde Aristolochia doth beautifie, clense, and saften the teeth, if they be often frosted or rubbed with the powder thereof.

A. serpentaria is known to have been used medicinally by several Native American tribes (Koasati, Delaware, Osage, Choctaw, Náhuatl, Cherokee, Natchez, Alabama, Micmac, Mohegan, and Penobscot). Starting as early as the 1600s, European colonists, calling the plant "Virginia snakeroot", used it to treat snakebite.[11]

The 1931 book A Modern Herbal by Maud Grieve,Wikipedia's W.svg reported the following on Aristolochia (note that no mention whatsoever is made of any possible side effects):[12]

Said to be useful as an aromatic stimulant in rheumatism and gout and for removing obstructions, etc., after childbirth. Dose, 1/2 to 1 drachm of the powdered root.

---Other Species---
Aristolochia cymbifera from Brazil and Mexico is said to have medicinal properties similar to the official species. Butte affirms it is a depressant to the sensory nerve centres and is useful in neuralgia and pruritis; it was formerly considered alexiteric, antiparalytic, antiperiodic and aphrodisiac.

A. argentina root is used in that republic as a diuretic and diaphoretic, especially for rheumatism.

A. indica is used as an emmenagogue, antiarthritic, stomachic, purgative and vermifuge, and in the East Indies is used for similar purposes as the American and European species.

A. sempervirens is said to be used by the Arabians as a remedy against the poisonous effects of snake-bite.

A. foetida in Mexico is used as a stimulant to foul ulcers.

A. serpentaria used in bilious, typhoid and typhus fevers, smallpox, pneumonia, amenorrhoea and fevers of a septicaemic type. It is often given in combination with Peruvian Bark [i.e., Cinchona spp.], rendering it more active and preventing ill effects on the stomach. It is also used in North America, as are several other varieties of the species, as an alexiteric and for the bites of mad dogs.

Birthwort is still being used by some traditional medicine practitioners despite there being absolutely no evidence it actually works for anything. One indication of birthwort in TCM is for eczema.[13][14]

Back in 1881 the Dutch Association Against Quackery already warned against pills with birthwort as a form of quackery, and described them as "pills made of nothing", but added that they "contain nothing harmful". Well, they were half right…[15]

[edit] Discovery of toxicity

AA I and AA II

As a result of scientific research conducted in the 20th century, it was discovered that birthwort can cause cancer and kidney failure because it contains aristolochic acid (AA), which is, in the amounts present in birthwort, a poison.[16] Aristolochic acid is one of the most potent carcinogens in the Carcinogenic Potency Database.[14][17]

In Belgium between 1990 and 1992, a weight-loss spa using TCM herbs thought that they were giving their clients Stephania tetrandraWikipedia's W.svg and Magnolia officinalisWikipedia's W.svg to help with weight loss. In reality the herbal supplements contained birthwort (Aristolochia fangchi), and as a result, more than 100 out of its 1800 patients developed kidney failure. Several also developed urothelial and kidney cancers, and 39 had to undergo kidney transplants. Because TCM allows for the substitution of identically or similarly named plants, plants that are botanically unrelated may be substituted. In this case, the relatively safe Stephania tetrandra (漢防己, Han Fang Ji) was intended for the clients, but the lethal Aristolochia fangchi (廣防己, Guang Fang Ji) was given to the clients.[18][19]

By 2002, the International Agency for Research on Cancer (IARC) had concluded that herbal remedies containing Aristolochia are carcinogenic to humans. This conclusion was based upon sufficient evidence of carcinogenicity of AA in animals and sufficient evidence of carcinogenicity of herbal remedies containing Aristolochia in humans.[20] In 2012, IARC revised their evaluation to conclude there there was also sufficient evidence that AA itself is carcinogenic to humans. This conclusion was based on additional sufficient evidence showing that extracts of plants containing AA are carcinogenic to animals, as well as limited evidence that AA itself is carcinogenic to humans.[21]

As epidemiologist Geoffrey Kabat noted:[22]

What is essential to realize is that the effects of Aristolochia [birthwort] were identified only thanks to the large cluster of cases of kidney failure occurring in young women who had attended the same spa. It is much more likely that isolated cases will go unnoticed, as happened with ephedra, and it could take years to identify a common cause.

People failed to recognize the nephrotoxic effects of Aristolochia in spite of its use in many cultures worldwide over thousands of years. In an interview, Grollman explained why: “The reason, of course, is quite simple. It’s painless, and the damage happens much later, so you don’t put together the fact that you took this medicine and four years later, you have kidney failure. It’s been part of Ayurvedic, European, Chinese, and South American medicine for centuries. All of the great civilizations have used it. And not one reported its toxicity until the Belgians did 20 years ago. There are certain things that tradition can’t tell you.

A. clematitis seeds

European birthwort (A. clematitis), which was also used as a medicine, has been linked to Balkan endemic nephropathyWikipedia's W.svg (BEN), though this conclusion has taken decades to arrive at since BEN was first diagnosed in the 1920s.[23][24] The source of BEN is likely wheat that is contaminated by seeds of A. clematitis[18] and/or bioaccumulation in grain from soil and water where A. clematitis has grown.[25][26] BEN has been found in Bosnia and Herzegovina, Serbia, western Romania and western Bulgaria.[27] A 2016 study confirmed that AA-contaminated soil is a pathway to human exposure via bioaccumulation in food crops.[28]

The true number of cases of aristolochic acid nephropathy (AAN), which is usually fatal, is unknown and is probably underestimated.[29] "Approximately 5–10% of individuals exposed to AA develop renal insufficiency and/or cancer", and this suggests that there is a genetic component to AA nephropathy.[30]

It is suspected that all species of Aristolochia contain some form of aristolochic acid (AA), and 23 species are known to contain either AA I or AA II.[31]

[edit] Butterflies love it, birds hate it

Illustration from 1797 by John Abbot of the pipevine swallowtail (Battus philenor) and its host plant, Virginia snakeroot (A. serpentaria)

Many species of Aristolochia are food for the larvae (caterpillars) of species of swallowtail butterflies (family Papilionidae). It has been demonstrated that the aristolochic acid is sequestered in the caterpillars, and retained in the adult butterflies, making them unpalatable to most predators (mainly birds).[32][33]

Not all species of Aristolochia are palatable to all species of swallowtails. It has been found that introduced South American A. elegans in Queensland, Australia are lethal to the larvae of native swallowtails, the Richmond (Ornithoptera richmondia) and Cairns (O. euphorion) birdwing butterflies.[34][35] This suggests the swallowtails and Aristolochia have been engaged in evolutionary arms race.Wikipedia's W.svg

[edit] Continuing usage

In 2003, two years after the US FDA issued warnings about herbal remedies containing AA, it was reported that 19 herbal products were available over the internet with Aristolochia as a stated ingredient, and 95 additional products were suspected to contain AA.[36]

A 2009 ethnobotanical literature review found that 99 species of Aristolochia have been used ethnobotanically, but only 24 of these species have been studied phytochemically.[37][14]

The English-language portion of the Internet regarding birthwort consists mainly of documents that describe the presence of aristolochic acid in birthwort and the plant's use in traditional medicine, as well as scientific studies of the plant's composition and toxicity. In other languages, however, there are many herbalist sites that actively recommend birthwort as a panacea for virtually everything.[38][39] (One makes the claim that birthwort prevents cancer, and makes no mention of any potential carcinogenity.)[39] Needless to say, such claims of efficacy are never accompanied by any actual statistical evidence.

In 2016, it was estimated that ~100,000 people in the Balkans were at risk of BEN, and that ~25,000 people actually had BEN.[40]

A 2016 survey of plant food supplements found that 3 of 18 samples (17%) contained AA, and that a literature survey found that 206 of 573 samples (36%) contained AA.[41]

[edit] Algeria

A. longa is widely used in Algerian traditional medicine. It is used to treat cancer, skin infections, and diabetes.[42]

[edit] Bangladesh

Larva of southern birdwing butterfly (Troides minos) eating leaves of A. indica

As of 2013, A. indica was in use among herbalists in Bangladesh. Knowledge of toxicity among herbalists was limited and administered doses were often "very high".[43]

[edit] Brazil

A 2015 ethno-medicinal study of Paraná, Brazil in the vicinity of Parque Estadual da Cabeça do Cachorro found that A. triangularis was the second most frequently used herbal medicine.[44]

[edit] Bulgaria

A. clematitis

A. clematitis is used in Bulgarian herbal medicine for many indications. One Bulgarian site goes on and on about the very many diseases that can be cured by birthwort, and contains the reproachful sentence: "Though it has been successfully used in China for pulmonary diseases, pain, and fluid retention, birthwort is banned in Germany because of the toxic aristolochic acid it contains."[45] In other words, "This is such a wonderful panacea, but those awful allopathic regulators aren't letting us use it! The fiends!"

[edit] Chile

A. chilensis

A. chilensis is used in Chilean herbalism for various indications, including arthritis, hemorrhoids, gout, inflammation, weight loss, and overall health.[46][47] It is also used in teas.[46] According to researchers at Chile's Universidad de Santiago, consuming 1mg of the plant can cause harmful effects months after it was initially ingested.[47]

[edit] China

In Wenzhou, China, 102 patients were reported with end-stage nephropathy between the years 2004 and 2013. These patients had an astoundingly high incidence of cancer, 41%, which is typical in populations of patients with AAN.[48]

As of 2016, Chinese companies are still making A. debilis, A. manshuriensis, A. fangchi and A. bracteolata available for export for medicinal purposes.[49]

[edit] Colombia

A. anguicida was reported to be used in traditional medicine in the Atlantic Coast of Colombia. AA I was previously detected in A. anguicida.[50]

[edit] France

A. trilobata painted by Louis van Houtte in 1861

In 2016, it was reported that AA I and AA II were detected in a traditional medicine known as chiniy-trèf that is used in the French overseas region of Martinique. Chiniy-trèf is used for poisoning and hexes. It is prepared from caterpillars of the butterfly Battus polydamas, which feeds on the leaves of A. trilobata.[51]

[edit] India

A. indica

A. indica, known as isvari, is used in Ayurvedic medicine. According to Chandrakant Bhanushali, General Secretary of the Ayurvedic Drug Manufacturers Association, the doses typically used are much lower (100× less) than the toxic doses in Belgium.[52] This should not be particularly comforting since AA is sequestered by blood albumin, which also restricts excretion.[53] According to Bhanushali, A. indica is found in two medicines that are used internally: poogakhanda and gorochanadi vati, but use of these medicines is negligible.[52] Also not particularly comforting is that the main ingredient of poogakhanda (or pooga khanda) is another human carcinogen, betelnut (Areca catechu),[54] and gorochanadi contains the toxic heavy metal lead as an ingredient.[55]

Isvari was included in a list of Ayurvedic herbs without comment in a 2010 World Health Organization report on training Ayurvedic medicine practitioners.[56]

[edit] Iran

In Iran, Aristolochia species are known as zaravand or chopoghak (A. longa and A. olivieri), and are still used in herbal medicine as of 2015.[57][58][59]

[edit] Morocco

A. baetica

In Morocco, A. baetica and A. longa were reported to be in use among herbalists as of 2015, often substituted by the differently toxic and unrelated Bryonia dioica under the common name "bereztem".[60]

[edit] Papua New Guinea

A. indica is used for malaria, abortion, and uterine inflammation in parts of Papua New Guinea.[61]

[edit] Peru

It was reported in 2007 that A. ruiziana (known locally as bejuco de contra-aire) is used traditionally in the Amazonian part of Peru for "untangling a person who is confused or having trouble progressing in life."[62]

[edit] Romania

A. clematitis is recommended by many herbalists in Romania.[63] It is a component of various types of herbal products used in that country, such as tinctures, infusions, and creams.[63] It is used topically for a wide variety of diseases, including burns, varicose veins, eczema, psoriasis, acne, urticaria, hemorrhoids, skin cancer, genital herpes, and boils, among other things.[63][64] It is also claimed that, in low doses, birthwort taken internally is not carcinogenic, but is in fact an effective treatment for several forms of cancer and many other diseases.[63][65] There are many Romanian websites that promote the use of birthwort, complete with anecdotal evidence and all the usual alt-med trimmings. For instance, there are articles with names like "Birthwort: Romania's Most Powerful Medicinal Plant — The Miraculous Weed that can Cure Cancer", and "Birthwort: The plant that can cure cancer."[65] The latter makes the claim that birthwort "is one of the most powerful medicinal plants we have. It has so many possible applications that it would take entire tomes to describe them. It would not be amiss to say that the potency of birthwort's beneficial effects could be compared to that of an atomic bomb."[65]

One pro-birthwort article states, "Then [in the 1980s], there were attempts to semisynthesize a drug for internal use from the leaves, but it turned out that aristolochic acid, the main active immunostimulant secreted by birthwort, was very toxic for the liver, when separated from the other components of the plant. Then study of birthwort was abandoned, the plant remaining, as it had previously, in the realm of folk medicine."[65] This extremely misleading (and citation-free) passage implies that it is the "synthetic chemical" aristolochic acid that is toxic, and not the "natural, gentle plant", birthwort. Which is, of course, completely false, given that birthwort's toxicity was discovered as a result of medicinal use of the plant. One could just as well say that "Nicotine, separated from the other components of the tobacco plant, is a toxic chemical," with the implication being that it is fine to use tobacco itself.

[edit] Taiwan

It has been estimated that about a third of Taiwan's herbal medicine prescriptions contain AA, and birthwort is considered to be a significant cause of kidney failure and upper urinary tract cancer in Taiwan.[16] In Taiwan, 76% of clear cell renal cell carcinoma (ccRCC) cases had been exposed to AA based on examination of DNA adducts.[66] A case-control study found that cumulative consumption of 250 mg of AA increased the risk of ccRCC by odds ratio (OR)=1.25.[66]

[edit] United States

A limited (i.e., non-random) 2014 survey of 30 dietary supplements marked in the United States found 20% of samples contained AA I and 7% contained AA II.[67] Presumably the sample was of supplements that were suspected of containing AA.

One of the more popular herbal medicine books, The Herb Book by John Lust,[68] was reprinted in 2014, and has not been revised since its initial publication in 1974. Though there is a warning on usage of A. clematitis in the book, it is far from sufficient, particularly because the full danger was not known in 1974 and because instruction for usage is still given. The warning states:

CAUTION: Birthwort contains a substance that acts similar to the poisonous alkaloid colchicine.[note 1] Use with care, preferably under medical direction.
—John Lust[68]

If you manage to find a medical professional to supervise your consumption of A. clematitis, you're in more trouble than you think.

[edit] Zimbabwe

A. albida was reported to be used by traditional healers for treatment of malaria in Zimbabwe.[69]

[edit] External links

[edit] See also

[edit] Notes

  1. As an aside, colchicine (extracted from plants of the genus Colchicum, "autumn crocus") is also a renal (kidney) toxin, but its mechanism of action is different than that of aristolochic acid. Lust was a naturopath and not a toxicologist, so his understanding of toxicology was superficial.

[edit] References

  1. 1.0 1.1 1.2 Ancient Medicinal Use of Aristolochia: Birthwort's Tradition and Toxicity by John Scarborough, Pharmacy in History, Vol. 53, No. 1, 2011.
  2. Enquiry into Plants, Book 6 by Theophrastus, Arthur F. Hort (Translator). Harvard University Press (1916). ISBN 0674990889.
  3. Hildegard von Bingen's Physica: The Complete English Translation of Her Classic Work on Health and Healing, translated by Priscilla Throop (1998). Healing Arts Press. ISBN 0892816619.
  4. 本草綱目/草之七 Wikisource (Compendium of Materia Medica / Grass, Seven)
  5. Chinese Medicinal Plants from the Pen Tsʻao Kang Mu 本草綱目 A.D. 1596 by Bernard E. Read (1936). Peking Natural History Bulletin, 3rd ed.
  6. Aristolochia recurvilabra Hance
  7. 7.0 7.1 7.2 Chinese Materia Medica. 1. Vegetable Kingdom by G. A. Stuart (1911). Presbyterian Mission Press, revised from F. Porter Smith.
  8. Health Department and National Chinese Medicine Management Office (ed.). Zhong Hua Ben Cao, 3–460–509. Shanghai Science Technology Publication. 1999. ISBN 7532351068.
  9. Pharmacopoeia of the People's Republic of China (2005). Chemical Industry Press, 2 volumes: ISBN 7502520627 and ISBN 7502520635.
  10. 10.0 10.1 The Herball, or Generall Historie of Plantes] by John Gerarde (1597). John Gerard]
  11. Florida Ethnobotany by Daniel F. Austin (2004) CRC Press, pp. 109-110. ISBN 0849323320.
  12. Birthwort, A Modern Herbal.
  13. Aristolochic Acid: FDA Concerned About Botanical Products, Including Dietary Supplements, Containing Aristolochic Acid, FDA, May 31, 2000.
  14. 14.0 14.1 14.2 Research and Publications on Herbal Products Known or Suspected to Contain Aristolochic Acid, a Human Carcinogen
  15. Reconfortatief of gezondheids en zeer versterkende pillen (Maandblad 15 juli 1881, jaargang 1, nummer 7) (9 jan 2009 | Van de Webredactie | Laatste wijziging: 10 jun 2009) Kwakzalverij
  16. 16.0 16.1 Chung-Hsin Chena, et al. "Aristolochic acid-associated urothelial cancer in Taiwan." Proceedings of the National Academy of Sciences. 2012 April 9.
  17. Aristolochic acid, sodium salt: Cancer Test Summary
  18. 18.0 18.1 Aristolochic acid nephropathy: A worldwide problem by Debelle et al. Kidney International (2008) 74, 158–169; doi:10.1038/ki.2008.129.
  19. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi) by J. L. Nortier et al. N. Engl. J. Med. 2000 Jun 8;342(23):1686-92.
  20. Some Traditional Herbal Medicines, Some Mycotoxins, Naphthalene and Styrene. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume 82 (2002) World Health Organization, International Agency for Research on Cancer.
  21. Review of Human Carcinogens IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume 100A (2012) World Health Organization, International Agency for Research on Cancer.
  22. Natural Does Not Mean Safe
  23. Fifty years of Balkan endemic nephropathy: daunting questions, elusive answers by V. Batuman. Kidney International, Volume 69, Issue 4, 2 February 2006, Pages 644–646.
  24. Chinese herbs nephropathy and Balkan endemic nephropathy: toward a single entity, aristolochic acid nephropathy by Marc E. De Broe. Kidney International 81(6):513-5 · March 2012.
  25. Uptake and Accumulation of Nephrotoxic and Carcinogenic Aristolochic Acids in Food Crops Grown in Aristolochia clematitis-Contaminated Soil and Water by W. Li et al. J. Agric. Food Chem. 2016 Jan 13;64(1):107-12. doi: 10.1021/acs.jafc.5b05089. Epub 2015 Dec 22.
  26. Quantitation of Aristolochic Acids in Corn, Wheat Grain, and Soil Samples Collected in Serbia: Identifying a Novel Exposure Pathway in the Etiology of Balkan Endemic Nephropathy by W. Chan et al. J. Agric. Food Chem. 2016 Jul 27;64(29):5928-34. doi: 10.1021/acs.jafc.6b02203. Epub 2016 Jul 13.
  27. Organic compounds in water extracts of coal: Links to Balkan endemic nephropathy by S. V. M. Maharaj et al. Environmental Geochemistry and Health 03/2013; 36(1). DOI:10.1007/s10653-013-9515-1
  28. Uptake and Accumulation of Nephrotoxic and Carcinogenic Aristolochic Acids in Food Crops Grown in Aristolochia clematitis-Contaminated Soil and Water by W. Li et al. J. Agric. Food Chem. 2016 Jan 13;64(1):107-12. doi: 10.1021/acs.jafc.5b05089. Epub 2015 Dec 22.
  29. Aristolochic acid nephropathy: A worldwide problem
  30. Genetic loci that affect aristolochic acid-induced nephrotoxicity in the mouse by Thomas A. Rosenquist. Am. J. Physiol. Renal Physiol. 2011 Jun; 300(6): F1360–F1367.
  31. Local uses of Aristolochia species and content of nephrotoxic aristolochic acid 1 and 2-A global assessment based on bibliographic sources by M. Heinrich et al. J. Ethnopharmacol. 2009 Aug 17;125(1):108-44. doi: 10.1016/j.jep.2009.05.028. Epub 2009 Jun 6.
  32. Sequestration of aristolochic acids by the pipevine swallowtail, Battus philenor (L.): evidence and ecological implications
  33. The occurrence of aristolochic acids in neotropical troidine swallowtails (Lepidoptera: Papilionidae)
  34. Conserving the Richmond Birdwing Butterfly over two decades: Where to next? by Don Sands (2008). Ecological Management & Restoration vol. 9 no. 1. doi: 10.1111/j.1442-8903.2008.00382.x.
  35. Straatman R. (1962) Notes on certain Lepidoptera ovipositing on plants which are toxic to their larvae. Journal of the Lepidopterists Society 16, 99–103.
  36. Aristolochic Acid, an Herbal Carcinogen, Sold on the Web after FDA Alert by L. S. Gold & T. H. Slone (2003) New England Journal of Medicine 349:16
  37. Local uses of Aristolochia species and content of nephrotoxic aristolochic acid 1 and 2—a global assessment based on bibliographic sources by M. Heinrich et al. J. Ethnopharmacol. 2009 Aug 17;125(1):108-44. doi: 10.1016
  38. Plantasnet: Clematitide — Aristolochia clematitis Aristoloquia
  39. 39.0 39.1 Cepvi.com: Clematítide.
  40. Balkan endemic nephropathy: an update on its aetiology by M. Stiborová et al. Arch Toxicol. 2016 Aug 19 (Epub ahead of print).
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  42. Ethnobotanical study, antifungal activity, phytochemical screening and total phenolic content of Algerian Aristolochia longa by B. Benarba & B. Meddah J. Intercult. Ethnopharmacol. 2014 Oct-Dec;3(4):150-4. doi: 10.5455/jice.20140826030222.
  43. Is aristolochic acid nephropathy a widespread problem in developing countries? A case study of Aristolochia indica L. in Bangladesh using an ethnobotanical-phytochemical approach by J. Michl et al. J. Ethnopharmacol. 2013 Aug 26;149(1):235-44. doi: 10.1016/j.jep.2013.06.028. Epub 2013 Jun 24.
  44. Ethno-medicinal study of plants used for treatment of human ailments, with residents of the surrounding region of forest fragments of Paraná, Brazil by M. Bolson et al. J. Ethnopharmacol. 2015 Feb 23;161:1-10. doi: 10.1016
  45. Вълча ябълка by К.ЧерниковаИноватор
  46. 46.0 46.1 La maldición de las orejas de zorro, llega a su fin
  47. 47.0 47.1 La planta medicinal chilena “Oreja de zorro” provoca cáncer. Septiembre 24, 2013 Info-natura
  48. Analysis of potential risk factors for cancer incidence in patients with aristolochic acid nephropathy from Wenzhou, China by M. Sun et al. Ren. Fail. 2015 Mar;37(2):209-13. doi: 10.3109/0886022X.2014.990347. Epub 2014 Dec 26.
  49. File:Alibaba Aristolochia.pdf — Aristolochia for sale on Alibaba in 2016
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  51. Detection of aristolochic acids I and II in "Chiniy-trèf", a traditional medicinal preparation containing caterpillars feeding on Aristolochia trilobata L. in Martinique, French West Indies by X. Cachet et al. Toxicon. 2016 May;114:28-30. doi: 10.1016/j.toxicon.2016.02.013. Epub 2016 Feb 12.
  52. 52.0 52.1 Ayurveda is well versed with the toxic effects of Aristolochia indica by Chandrakant Bhanushali (Published on Wednesday, 05 June 2013 18:21) Express Pharma.
  53. Physiological and Molecular Characterization of Aristolochic Acid Transport by the Kidney by Kathleen G. Dickman et al. J. Pharmacol. Exp. Ther. 2011 Aug; 338(2): 588–597. doi: 10.1124/jpet.111.180984.
  54. Ayurvedic Medicine Information: Puga Khanda – Benefits, Dosage, Ingredients, Side Effects
  55. Ayurvedic Medicine Information: Gorochanadi Gulika – Benefits, Dosage, Ingredients And Side Effects
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  58. Useful plants and drugs of Iran and Iraq / by David Hooper. With notes by Henry Field Field Museum of Natural History Botanical Series Vol. 9, no. 3, 1937.
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  60. Substitution between Aristolochia and Bryonia genus in North-Eastern Morocco: toxicological implications by A. Yamani et al. J. Ethnopharmacol. 2015 May 26;166:250-60. doi: 10.1016/j.jep.2015.03.036. Epub 2015 Mar 19.
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  64. Ceaiuri care te pot îmbolnăvi Ziarul Ring
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