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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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AYURVEDA……..Dronapushpi (দ্রোনপুষ্পি)


Dronapushpi is Sanskrit name of plant Leucas cephalotes. It is a medicinal herb that grows as a weed in India and many South East Asian countries. The folk use of this herb is for treating scorpion stings, snake bite, cough, fever etc. The whole plant has fever educing and insecticidal properties. The leaves are applied externally on snake bites and scorpion stings. To know more about this medicinal herb,

‘Leucas aspera ‘

‘Leucas aspera ‘. Common Leucas, known as Chhota halkusa in Hindi, Tumba in Malayalam, Tummachettu in Telugu, Ghal ghase in Bengali, Dronapushpi in Sanskrit and Thumbai in Tamil, is a medicinal plant.

 

SYNONYMS

 

  • Ksavapatra
  • Chatrini
  • Palepushpa
  • Guma
  • Nahula
  • Adhicchatra
  • Dvesyamesa
  • Gotamah
  • Putigandhika
  • Kumbhayoni
  • Kutumbaka
  • Drona
  • Swasanaka
  • Palindi
  • Chatrani
  • Chatraka
  • Koodinya
  • Vrakshasaraka
  • Dhirgapatra
  • Supuspa
  • Chitrapatrika

 

TYPES

 

According to Abhidhana ratnamala

  • Two varieties
  • Mahadrona
  • Dronapushpa

According to Raja narahari

  • Drona – Lucas aspera
  • Mahadrona – L. Cephalotus
  • Another species – L. indica

 

PART USED

  • Panchanga

 

FORMULATION

 

  • Plihari vati
  • Gorocanadi vati
  • Nimbadilepa
  • Sahacharadi taila

DOSAGE

 

  • Swarasa-5-10ml.
  • Churna-1-3gm

 

PROPERTIES

 

Rasa: katu, lavana, Madhura.

Guna: Guru, Ruksha, Theekshna

Veerya: Ushna.

Vipaka: Madhura

Doshsgnhtha: Kapha, vata, shamaka.

 

CHEMICAL COMPOSITION

  • Its Panchanga contains B-sisstesterol, flavinol, Glycoside.
  • Flowers  contain an essential oil, A bitter principle seeds a contain a fixed oil , caryophyllene, oxide, 26.56% Gama- Fenchene 12.02%, Alpha- cordional 2.13% , 1-hepten 3-01, 6.53%, menthol 6.30%, deca hydro naphthalene 5.15%, and trans –caryophyllene 4.05%.
  • Labdane, Noraladane, laballenic acid lauric acid, glutaric acid, Adipic acid , tridecanoic acid.

 

KARMA

  • Bhedana
  • Kaphagna
  • Amapacaka
  • Kamalahara
  • Shothoghna
  • Shvasagna
  • Krimigana
  • Swedajanana
  • Vata prashamana
  • Samsrana
  • Vishamajvarahara

 

PRAYOGA

  • Kaamala
  • Shotha
  • Shwasa
  • Vishamajvara
  • Kandu
  • Udara shoola
  • Pratisyaya
  • Jvara
  • Shira shoola

THERAPEUTIC USES

 

Vishamajvara– Fresh juice of dronapuspi and tulasi are useful.            [Sharangadhara Samhita madhyamakhanda]

 Kaamala: Anjana with the juice of dronapuspi useful. [Gadanigraha].                                            

Netrarogani: dronapuspi juice is mixed with rice water and used orally as well as topically.                                 [G.N]

Pittajavikara : Hima prepared by sariva, rasani, guduchi,  rakthachandana and dronapuspi.         [Siddhayogasangraha]

Paandu : Hima prepared by dronapuspi and padmaka, sariva drugs are useful.                 [Siddhayogasangraha]

 

PHARMACO THERAPEUTIC ACTION AND USES

 

Lecus cephalotes has been reported to exert hepatoprotective action in carbon tetra chloride induced hepatotoxicity in animals.

Juice of it has been reported to act as an antibilious in herbal therapy for jaundice

It has shown positive test in filariesis

The whole plant powder in the proportion of 70% in the herbal composition is patented to cure epileptic convulsions and cerebral function disorders.

It is also having the properties of antipyretic, stimulant , expectorant, aperients , diaphoretic, insecticidal, emmenagogue, and antioxidant, anti-inflammatory and anti diabetic.

They are useful in colic, dyspepsia arthralgia.

 

FOLKLORE USES

 

  • Plant decoction is used in the treatment of malarial fever .
  • The leaves juice is used topically in psoriasis, skin eruption , and scabies and internally for the treatment of urinary complaints.
  • The flowers are administered in the form of syrup or with honey for cough and cold.
  • The dried inflorescences are smoked and the smoke exhaled through the nose to treat nose bleeds.
  • Dried leaves along with tobacco (1:3) are smoked to treat bleeding as well as itching piles and fresh leaves eaten as a potent herb.

 

CULTIVATION

 

Cultivated fields as a weed , especially after a period of rain . It is collected for use as a leafy vegetable in rural areas . it is cultivated itself for its medicinal uses . And really available in market.

 

RESEARCH STUDIES

 

ANTIBACTERIAL

Leucas cephalotes a common ethanomedicinal plant’s used by folklore of tirupathi andrapradesh for fever and urinary tract infection.  Organic extracts hexane and methanolic extracts showed prominent antibacterial activity .

 

IN VITRO ANTHELMINTIC ACTIVITY

It is mild stimulant diaphoretic and used for fever

The overall study showed that dronapushpi decoction was beneficial to naveen (new) amavata.

The claim of folk ore amavata probably more beneficial if used with suitable vedanasthapana (analgesic)  drugs

Traditional medicinal uses

Dronapushpi is a weed that grows on wastelands. Medicinally, it has antimicrobial, insecticidal, fever reducing, larvicidal and inflammation reducing properties. It is useful in skin diseases. In malarial fever, the leaves juice is given. In some part of country, the decoction of whole plant is used for curing fever. The juice removes toxins from body. The leaves juice is applied externally for skin diseases and swelling. In cod and cough, the leaves juice is recommended.

Scorpion sting

In scorpion sting the plant is used internally as well externally. The leaves juice (few drops) is mixed with honey and taken orally.

Topically, the leaves juice is applied on place of sting.

Snake bite

The folk remedy is to put few drops of whole plant in nostrils.

Skin diseases, removing blood toxins

Skin diseases mainly occur due to toxins in blood. Dronapushpi plant has ability to flush the toxins from body.

In skin diseases, whole plant of Dronapushpi is used. The plant is dried. Five grams of dried powder is taken with three grams Neem/Margosa leaves in 2 glass water. This is boiled till volume reduce to one fourth. Then it filtered and taken two times a day.

Abnormally heavy bleeding at menstruation

The leaves of plant are taken a handful. These are washed and then ground to make fine paste. This paste is mixed with lemon juice and sesame oil/til oil (edible). The preparation is eaten empty stomach every morning for a week.

 

Asthma, cold, cough

The leaves juice of plant is taken in dose of 1-3 teaspoons.

Excessive thirst

The flowers (2 tablespoon) are boiled in water (150 ml) till volume reduces to half. This is filtered and taken thrice a day.

Cough, leucorrhoea

The leaves of plant are cooked and eaten with rice.

Skin diseases (itching, patchy skin, psoriasis, scabies etc.)

The paste of leaves is applied externally at the affected body areas.

Cough, congestion, blockage of nose, headache due to cough, Sinusitis, Migraine, Phlegm

The juice of leaves is put in nostrils as drops. For this purpose, the leaves juice is extracted and mixed with two times water. Then the diluted juice is put in nostrils (4 dops) for 3-4 days.

The flowers are heated in til/sesame oil and applied on head.

Fever (acute, chronic), Allergy

The decoction of plant (2-3 grams in boiled in two glass water till water reduces to one fourth) is used

This medicinal herb should be used in recommended doses only. It is hot in potency and heats up body. Avoid its use in excess. The leaves juice can be diluted for putting in nose of oral use.

DRONAPUSHPI

 

………..

SHIMOGA,  KARNATAKA, INDIA

Shimoga – Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Shimoga

Shimoga, officially renamed as Shivamogga, is a city and the district headquarters of Shimoga District in the central part of the state of Karnataka, India. The city …

Map of shimoga city.

 

Shimoga–Talaguppa railway

Kundadri, Shimoga

 

Shimoga Photos – Kudli Temple

 

 

Ornate baluster in Thripuranthakeshwara temple at Balligavi, Shimoga district.jpg

 

sigandur – Shimoga

////////

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Ayurveda………..Medicinal Benefits of Liquorice (Mulethi) (मुलेठी, 甘草, شیرین بیان)


liquorice-root

Licorice or Mulethi is a medicinal herb which is used in various Ayurvedic medicines. Its underground stems and roots are used for medicinal purpose. It has antioxidant, antimicrobial, anti-inflammatory and hepatoprotective properties.
Mulethi is useful in cough, sore throat, bronchitis, sexual weakness, skin problems, jaundice, hoarseness, vata dosha, ulcers etc. It has demulcent and expectorant properties.

read…………MY OLD ARTICLE

Liquorice, or licorice, (/ˈlɪk(ə)rɪʃ/ lik-(ə-)rish or /ˈlɪk(ə)rɪs/ lik-(ə-)ris)[2] is the root of Glycyrrhiza glabra from which a sweet flavour can be extracted. The liquorice plant is a legume native to southern Europe, India, and parts of Asia. It is not botanically related to anise, star anise, or fennel, which are sources of similar flavouring compounds. The word liquorice / licorice is derived (via the Old French licoresse) from the Greek γλυκύρριζα (glukurrhiza), meaning “sweet root”,[3] from γλυκύς (glukus), “sweet”[4] + ῥίζα (rhiza), “root”,[5][6] the name provided by Dioscorides.[7] It has been traditionally known and used as medicine in Ayurveda for rejuvenation.[8] It is called asadhimadhuram (அதிமதுரம்) in Tamil, irattimadhuram in Malayalam, yastimadhu (यस्टिमधु) in Sanskrit, mulethi (मुलेठी) in Hindi, andjethimadh (જેઠીમધ) in Gujarati language.[9]

Licorice (Glycyrrhiza glabra), locally known as mulethi, has been revered for centuries as a medicinal herb in Ayurveda. Besides possessing numerous medicinal properties, it is also a popular flavoring herb as it is 50 times sweeter than sugar, due to the presence of a compound called glycyrrhizin.

Through research, the anti-oxidant, anti-inflammatory, anti-microbial, analgesic (pain-relieving) and expectorant properties of this is sweet, moist herb have been established worldwide. It is also diuretic, rejuvenating and mildly laxative in nature. These properties have helped Licorice find a place in both Eastern and Western medicine for treating an array of ailments, ranging from cold and cough to arthritis, respiratory, digestive and liver problems.

The Sanskrit name for licorice is Yashtimadhu, which literally means “sweet root”. It is sweet, cool and heavy to digest. The Rasa (taste) of this herb is madhura (sweet), which makes it beneficial for vata and pitta doshas, while it’s Virya (action) is sheetal (cooling), which generally increases kapha when consumed in large doses over long term.

The medicinal property of mulethi is mainly because of the presence of powerful phytochemicals namely flavonoids, chalcones, saponins and xenoestrogens. Glycyrrhizin (salts of glycyrrhizic acid) is a popular saponin found in roots of mulethi that is responsible for the characteristic sweet taste (50 times more sweet than sugar) flavor. Liquiritin, licoflavonol, liquiritigenin, etc are the common chalcones that provide the distinct yellowish color to mulethi; while, the aroma of its root is mainly because of anethole. Here are the ten health benefits of mulethi:

Information

Latin name: Glycyrrhiza glabra
Sanskrit: Madhuyashti
Hindi: Mulhatti, Jethimadh, Mithilakdi
English: Sweetwood, Liquorice, Licorice
Bengali: Jashtimadhu
Gujrati: Jethi Madh
Marathi: Jeshtamadhu
Kannada: Jeshthamadhu
Malayalam: Itarttimadhuram, Erattimadhuram
Tamil: Atimadhuram
Telugu: Atimadhuramu

Anti-microbial activity – Roots of mulethi are very effective in protecting against virus, bacteria and fungi due to the presence of Glycyrrhizin that blocks the microbial growth. The root extract possesses the power to control malaria (as per preliminary research), influenza and also helps in the treatment of herpes resulting in virus suppression and severity of sores.

Anti-inflammatory activity – Liquorice has powerful anti-inflammatory and anti-allergic activity and can be used to treat chronic inflammation like rheumatic problems & arthritis, skin diseases and autoimmune diseases. It is also used for preventing any inflammatory conditions related to eye and also to treat conjunctivitis with the help of glycyrrhizin activity that counteracts negative effects caused by cortisol.

Improves immunity – Root extracts of mulethi aids in increasing the production of lymphocytes and macrophage thereby improving your defense mechanism & preventing microbial attack. It also helps in minimizing immune related allergic reactions and autoimmune complications.

Memory improvement – Roots of licorice exert supportive effect on the adrenal gland and thus indirectly aid in stimulating the brain. It not only decreases the effects of amnesia & improves learning but its antioxidant property (mulethi contains flavonoids) renders a shielding effect on the brain cells.

Anti-ulcer activity – The potent antioxidant and anti-inflamatory properties of licorice makes it the best natural medicinal aid to treat ulcers of stomach, intestine and mouth. The compound carbenoxolone synthesized from glycyrrhizin plays key role in healing mouth and gastric ulcers along with reducing gastric secretions and promoting development of intestinal mucus lining.

Liver protection – Licorice is one of the most common traditional remedy used to treat jaundice. Its antioxidant property is the key for preventing your liver from the action of free radicals and toxic materials. This herb is also reported to exhibit protection against diclofenac induced toxicity and also, in inhibiting damage of liver.

Digestive aid – Roots of licorice are also used to deal with stomach and digestion problems with the help of glycyrrhizin and its compound, carbenoxolone. It is one of the ancient home remedies for relieving constipation, acidity, heartburn, stomach discomfort, inflammation of digestive system and gastro esophageal acid reflux. As a mild laxative, it plays an effective role in bowel movements and also for treatment of allergic cough in addition to maintaining normal pH levels.

Hormonal regulation – The phytoestrogenic compounds present in mulethi roots exert valuable action against women hormonal imbalance problems, menopause symptoms like hot flashes & exhaustion, mood swings, etc. It is also found to help in cortisol production and relieving premenstrual issues like nausea and menstrual cramps. Licorice powder acts as the traditional medicine for nursing mothers to regulate body hormones and aid in milk secretion.

Heart healthy effects – Research studies have proved that licorice roots help in controlling cholesterol levels by increasing the body’s flow of bile and also reducing high blood cholesterol levels. The anti-oxidant property of licorice acts in increasing the blood capillary health, reducing inflammation, prevents blood vessel damage and block development of arterial plaque.

Other effects – Licorice roots work wonders in treatment of depression, diabetes and respiratory tract infection like sore throat (hoarseness of voice), cold and cough, etc in addition to rendering effective skin benefits, oral hygiene and weight loss. It is found to act as a cancer cure remedy, a potent aphrodisiac and a powerful analgesic agent.

Description

It is a herbaceous perennial, growing to 1 m in height, with pinnate leaves about 7–15 cm (3–6 in) long, with 9–17 leaflets. The flowers are 0.8–1.2 cm (1/3 to 1/2 in) long, purple to pale whitish blue, produced in a loose inflorescence. The fruit is an oblong pod, 2–3 cm (1 in) long, containing several seeds.[10] The roots are stoloniferous.[11]

Chemistry

The scent of liquorice root comes from a complex and variable combination of compounds, of which anethole is up to 3% of total volatiles. Much of the sweetness in liquorice comes from glycyrrhizin, which has a sweet taste, 30–50 times the sweetness of sugar. The sweetness is very different from sugar, being less instant, tart, and lasting longer.

The isoflavene glabrene and the isoflavane glabridin, found in the roots of liquorice, are phytoestrogens.[12][13]

Cultivation and uses

Liquorice, which grows best in well-drained soils in deep valleys with full sun, is harvested in the autumn two to three years after planting.[10] Countries producing liquorice include Iran, Afghanistan, the People’s Republic of China, Pakistan, Iraq, Azerbaijan, Uzbekistan, Turkmenistan, and Turkey.[14]

The world’s leading manufacturer of liquorice products is M&F Worldwide, which manufactures more than 70% of the worldwide liquorice flavours sold to end users.[15]

Safe dosage

Licorice is available in various forms – root, powder and extracts. Licorice root can be chewed directly while licorice tea (prepared by boiling licorice root in water) is also extremely beneficial as a home remedy.

Daily intake of 5-6 grams of licorice powder is considered safe while 250-500 mg of concentrated extracts can be taken thrice a day. Unsupervised use in high doses is not recommended for long term. People with hypertension or heart disease, pregnant women and breastfeeding mothers should avoid using licorice without prior consulation with an Ayurveda doctor.

plant

Medicine

The compound glycyrrhizin (or glycyrrhizic acid), found in liquorice, has been proposed as being useful for liver protection in tuberculosis therapy, but evidence does not support this use, which may in fact be harmful.[24] Glycyrrhizin has also demonstrated antiviral, antimicrobial, anti-inflammatory, hepatoprotective, and blood pressure-increasing effects in vitro and in vivo, as is supported by the finding that intravenous glycyrrhizin (as if it is given orally very little of the original drug makes it into circulation) slows the progression of viral and autoimmune hepatitis.[25][26] Liquorice has also demonstrated promising activity in one clinical trial, when applied topically, against atopic dermatitis.[27] Additionally, liquorice has also proven itself effective in treating hyperlipidaemia (a high amount of fats in the blood).[28] Liquorice has also demonstrated efficacy in treating inflammation-induced skin hyperpigmentation.[29][30] Liquorice may also be useful in preventing neurodegenerative disorders and dental caries.[31][32][33]

The antiulcer, laxative, antidiabetic, anti-inflammatory, immunomodulatory, antitumour and expectorant properties of liquorice have been investigated.[34]

Folk medicine

In traditional Chinese medicine, liquorice (मुलेठी, 甘草, شیرین بیان) is believed to “harmonize” the ingredients in a formula and to carry the formula to the 12 “regular meridians”.[35]

References

  1.  “Glycyrrhiza glabra information from NPGS/GRIN”. http://www.ars-grin.gov. Retrieved 6 March 2008.
  2.  licorice. Merriam-Webster’s Medical Dictionary, © 2007 Merriam-Webster, Inc.
  3.  γλυκύρριζα, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus
  4.  γλυκύς, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus
  5. Jump up^ ῥίζα, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus<
  6. Jump up^ liquorice, on Oxford Dictionaries
  7. Jump up^ google books Maud Grieve, Manya Marshall – A modern herbal: the medicinal, culinary, cosmetic and economic properties, cultivation and folk-lore of herbs, grasses, fungi, shrubs, & trees with all their modern scientific uses, Volume 2 Dover Publications, 1982 & Pharmacist’s Guide to Medicinal Herbs Arthur M. Presser Smart Publications, 1 Apr 2001 2012-05-19
  8. Jump up^ Balakrishna, Acharya (2006). Ayurveda: Its Principles & Philosophies. New Delhi, India: Divya prakashan. p. 206. ISBN 8189235567.
  9. Jump up^ “Top 10 health benefits of Mulethi or Liquorice”.
  10. ^ Jump up to:a b Huxley, A., ed. (1992). New RHS Dictionary of Gardening. ISBN 0-333-47494-5
  11. Jump up^ Brown, D., ed. (1995). “The RHS encyclopedia of herbs and their uses”. ISBN 1-4053-0059-0
  12. Jump up^ Somjen, D.; Katzburg, S.; Vaya, J.; Kaye, A. M.; Hendel, D.; Posner, G. H.; Tamir, S. (2004). “Estrogenic activity of glabridin and glabrene from licorice roots on human osteoblasts and prepubertal rat skeletal tissues”. The Journal of Steroid Biochemistry and Molecular Biology 91 (4–5): 241–246. doi:10.1016/j.jsbmb.2004.04.008. PMID 15336701.
  13. Jump up^ Tamir, S.; Eizenberg, M.; Somjen, D.; Izrael, S.; Vaya, J. (2001). “Estrogen-like activity of glabrene and other constituents isolated from licorice root”. The Journal of steroid biochemistry and molecular biology 78 (3): 291–298. doi:10.1016/S0960-0760(01)00093-0. PMID 11595510.
  14. ^ Jump up to:a b c M & F Worldwide Corp., Annual Report on Form 10-K for the Year Ended December 31, 2010.
  15. Jump up^ M & F Worldwide Corp., Annual Report on Form 10-K for the Year Ended December 31, 2001.
  16. Jump up^ Erik Assadourian, Cigarette Production Drops, Vital Signs 2005, at 70.
  17. Jump up^ M & F Worldwide Corp., Annual Report on Form 10-K for the Year Ended December 31, 2005.
  18. ^ Jump up to:a b c Marvin K. Cook, The Use of Licorice and Other Flavoring Material in Tobacco (Apr. 10, 1975).
  19. Jump up^ Boeken v. Phillip Morris Inc., 127 Cal. App. 4th 1640, 1673, 26 Cal. Rptr. 3d 638, 664 (2005).
  20. Jump up^ [1] the online Dutch food composition database]
  21. Jump up^ “Right good food from the Ridings”. AboutFood.com. 25 October 2007.
  22. Jump up^ “Where Liquorice Roots Go Deep”. Northern Echo. Retrieved 9 December 2008.
  23. Jump up^ http://science.howstuffworks.com/life/botany/licorice-info.htm
  24. Jump up^ Liu Q, Garner P, Wang Y, Huang B, Smith H (2008). “Drugs and herbs given to prevent hepatotoxicity of tuberculosis therapy: systematic review of ingredients and evaluation studies”.BMC Public Health (Systematic review) 8: 365. doi:10.1186/1471-2458-8-365. PMC 2576232. PMID 18939987.
  25. Jump up^ Chien, CF; Wu, YT; Tsai, TH (January 2011). “Biological analysis of herbal medicines used for the treatment of liver diseases.”. Biomedical Chromatography 25 (1-2): 21–38.doi:10.1002/bmc.1568. PMID 21204110.
  26. Jump up^ Yasui, S; Fujiwara, K; Tawada, A; Fukuda, Y; Nakano, M; Yokosuka, O (December 2011). “Efficacy of intravenous glycyrrhizin in the early stage of acute onset autoimmune hepatitis.”.Digestive Diseases and Sciences 56 (12): 3638–47. doi:10.1007/s10620-011-1789-5. PMID 21681505.
  27. Jump up^ Reuter, J; Merfort, I; Schempp, CM (2010). “Botanicals in dermatology: an evidence-based review.”. American Journal of Clinical Dermatology 11 (4): 247–67. doi:10.2165/11533220-000000000-00000. PMID 20509719.
  28. Jump up^ Hasani-Ranjbar, S; Nayebi, N; Moradi, L; Mehri, A; Larijani, B; Abdollahi, M (2010). “The efficacy and safety of herbal medicines used in the treatment of hyperlipidemia; a systematic review.”. Current pharmaceutical design 16 (26): 2935–47. doi:10.2174/138161210793176464. PMID 20858178.
  29. Jump up^ Callender, VD; St Surin-Lord, S; Davis, EC; Maclin, M (April 2011). “Postinflammatory hyperpigmentation: etiologic and therapeutic considerations.”. American Journal of Clinical Dermatology12 (2): 87–99. doi:10.2165/11536930-000000000-00000. PMID 21348540.
  30. Jump up^ Leyden, JJ; Shergill, B; Micali, G; Downie, J; Wallo, W (October 2011). “Natural options for the management of hyperpigmentation.”. Journal of the European Academy of Dermatology and Venereology 25 (10): 1140–5. doi:10.1111/j.1468-3083.2011.04130.x. PMID 21623927.
  31. Jump up^ Kannappan, R; Gupta, SC; Kim, JH; Reuter, S; Aggarwal, BB (October 2011). “Neuroprotection by spice-derived nutraceuticals: you are what you eat!” (PDF). Molecular Neurobiology 44(2): 142–59. doi:10.1007/s12035-011-8168-2. PMC 3183139. PMID 21360003.
  32. Jump up^ Gazzani, G; Daglia, M; Papetti, A (April 2012). “Food components with anticaries activity.”. Current Opinion in Biotechnology 23 (2): 153–9. doi:10.1016/j.copbio.2011.09.003.PMID 22030309.
  33. Jump up^ Messier, C; Epifano, F; Genovese, S; Grenier, D (January 2012). “Licorice and its potential beneficial effects in common oro-dental diseases.”. Oral Diseases 18 (1): 32–9.doi:10.1111/j.1601-0825.2011.01842.x. PMID 21851508.
  34. Jump up^ Shibata, S (October 2000). “A drug over the millennia: pharmacognosy, chemistry, and pharmacology of licorice.”. Yakugaku Zasshi 120 (10): 849–62. PMID 11082698.
  35. Jump up^ Bensky, Dan; et al. (2004). Chinese Herbal Medicine: Materia Medica, Third Edition. Eastland Press. ISBN 0-939616-42-4.
  36. Jump up^ Olukoga, A; Donaldson, D (June 2000). “Liquorice and its health implications.”. The Journal of the Royal Society for the Promotion of Health 120 (2): 83–9.doi:10.1177/146642400012000203. PMID 10944880.
  37. Jump up^ Armanini, D; Fiore, C; Mattarello, MJ; Bielenberg, J; Palermo, M (September 2002). “History of the endocrine effects of licorice.”. Experimental and Clinical Endocrinology & diabetes 110 (6): 257–61. doi:10.1055/s-2002-34587. PMID 12373628.
  38. Jump up^ Omar, Hesham R; Komarova,, Irina; El-Ghonemi,, Mohamed; Ahmed, Fathy; Rashad, Rania; Abdelmalak, Hany D; Yerramadha, Muralidhar Reddy; Ali, Yaseen; Camporesi, Enrico M. “How much is too much? in Licorice abuse: time to send a warning message from Therapeutic Advances in Endocrinology and Metabolism”. http://www.ncbi.nlm.nih.gov. SAGE Publications. Retrieved 13 January 2015.

38 Toxicology Center[2]

External links

Boswellia serrata, -The cure for osteoarthritis in ayurveda, Shallaki,


Boswellia serrata (Salai) in Kinnarsani WS, AP W2 IMG 5840.jpg

in Kinnerasani Wildlife Sanctuary,Andhra Pradesh, India.

Boswellia serrata, -The cure for osteoarthritis in ayurveda, Shallaki,

Shallaki-Boswellia serrata

In degenerative and inflammatory pathologies invoving joints, there is no other drug as useful as Guggulu. Many international companies today use shallaki for the manufacture of drugs, ayurvedic and allopathic alike.

Family : Berseraceae

Scientific name : Boswellia serrata

Nomenclature in other languages :

Sanskrit : Shallaki, Susrava, Gajabhakshya

Hindi : Salei

Gujarathi : Dhoopa

Bengali : Salei

Tamil : Olibana

English : Indian Olibanum

Distribution : Gujarat, Rajasthan, Bihar are most commonly the residence of this plant.

Botanical description : It’s a resinous tree that grows to a height of 12m. A tree of moderate height , its bark are grey in colour. Upon time the bark sheds off like scales of a snake. The younger branches and leaflets of this tree are very smooth. The leaves which are compound(pinnate) in nature are 20-37 cm long. The leaflets are 2-5cm long and 1-2.5cm wide. The leaflets are oval shaped. The leaves contains 8 pairs or more of the leaflets . The margins of leaflets are serrated. Flowers are many and the inflorescence is terminal raceme, with it seen in the axilla of the leaf and stem. The petals and sepals are hairy and five in number. The stamen are 10 in number, they are diercted inwards. The fruits are seen in 3-4 numbers and are seen as drupes along with cones. The flowering season in April-May.

C hemical constituents and action

The bark contains carbohydrates, glycosides, beta-sitosterol. The resin contains ditrepene alcohol. This is knownn by the name sitosterol. In addition to that 11-keto-b-boswellic acid also has been extracted from the resin.

Ayurvedic Pharmacoepia

Rasa : kashaya, tikta, madhura

Guna : laghu, rooksha

Veerya : sheeta

Vipaka : katu

Medicinal properties :

Alleiviates vata kapha disorders. Also cures chronic skin lesions of all kinds infective and inflammatory, ulcers, wounds, piles, diseases of mouth, diarhhoea, hepatic disorders etc.

Useful parts : Bark, Resin

Therapeutic uses :

-1gm of resin taken in tablet form daily three times cures rheumatic, neurologic complaints and rheumatic fever.

-for gangrenes in diabetes the resin of this palnt may be applied externally and it taken internally as pills regularly

-the resin of this plant when chewed cures bad odour of mouth and mouth ulcers.

Medical uses

In Ayurvedic medicine Indian frankincense (Boswellia serrata) has been used for hundreds of years for treating arthritis.

Extracts of Boswellia serrata have been clinically studied for osteoarthritis and joint function, particularly for osteoarthritis of the knee, with the research showing a slight improvement of both pain and function compared to a placebo. Positive effects of Boswellia in some chronic inflammatory diseases including rheumatoid arthritis, bronchial asthma, osteoarthritis, ulcerative colitis and Crohn’s disease have been reported. A Boswellia extract marketed under the name Wokvel has undergone human efficacy, comparative, pharmacokinetic studies. Some see Boswellia serrata as a promising alternative to NSAIDs, warranting further investigation in pharmacological studies and clinical trials.

Topical application

Boswellia serrata has been recently developed for topical use in a patent-pending formula in Sano Relief Gel. Boswellia serrata is used in the manufacture of the supposed anti-wrinkle agent “Boswelox”,which has been criticised as being ineffective.

Potential for anti-cancer activity

Boswellic acid, an extract from Boswellia serrata, has been studied for anti-neoplastic activity, especially in experimental primary and secondary brain tumors, indicating potential efficacy from in vitro and limited clinical research. Boswellic acid is also undergoing an early-stage clinical trial at the Cleveland Clinic.

Active constituents

Boswellic acid and other pentacyclic triterpene acids are present. Beta-boswellic acid is the major constituent.

Mechanism of action

Animal studies performed in India show ingestion of a defatted alcoholic extract of Boswellia decreased polymorphonuclear leukocyte infiltration and migration, decreased primary antibody synthesis and almost totally inhibited the classical complement pathway.

Properties

Shallaki has potent analgesic and anti-inflammatory effects that can reduce the pain and inflammation of joints.

Frankincense ‘can ease arthritis’ researches have suggested

Extracts from Boswellia serrata, a similar species to the variety famous for its role in the Christian nativity, were tested on dozens of patients.

Those who received it reported better movement and less pain and stiffness.

The herb has been used for thousands of years in Indian Ayurvedic medicine, reports the journal Arthritis Research and Therapy.
Osteoarthritis is the most common form of the condition, and normally affects the weight bearing joints such as hands, wrists, feet and spine.

Current treatments carry a great many adverse effects, and scientists have been hunting for an alternative.

The investigation into the properties of Boswellia serrata was led by Dr Siba Raychaudhuri at the University of California, Davis.

Eventually they tested an extract of the plant enriched with the chemical – AKBA – thought to be its active ingredient.

Some of the 70 patients with severe arthritis in their knees recruited into the trial were given a low-dose capsule, some a higher dose capsule, and the remainder were given a dummy pill with no active ingredients.

In as little as seven days, patients taking the frankincense drug reported improvements in their pain and stiffness levels compared with the placebo group, and these continued until the 90-day mark, when the study ended.

Alternative therapies

Tests of the fluid within affected joints also revealed falls in levels of enzymes linked to the condition.

Dr Raychaudhuri said: “We have shown that B. serrata enriched with AKBA can be an effective treatment for osteoarthritis of the knee.”

However, UK experts urged caution. Professor Philip Conaghan, from Leeds University, and a spokesman for the Arthritis Research Campaign, said: “Certainly osteoarthritis is in need of new safe analgesics, although many effective therapies that reduce pain such as muscle strengthening exercises, shock-absorbing footwear and weight loss have very few bad side-effects.

“This report on treating knee pain with a chemical derivative of B. serrata is interesting but the patient numbers are small, there were some problems with the reported trial design and we need more information on its medium to long-term safety.”

Boswellia serrata: an overall assessment of in vitro, preclinical, pharmacokinetic and clinical data.

Non-steroidal anti-inflammatory drug (NSAID) intake is associated with high prevalence of gastrointestinal or cardiovascular adverse effects. All efforts to develop NSAIDs that spare the gastrointestinal tract and the cardiovasculature are still far from achieving a breakthrough. In the last two decades, preparations of the gum resin of Boswellia serrata (a traditional ayurvedic medicine) and of other Boswellia species have experienced increasing popularity in Western countries. Animal studies and pilot clinical trials support the potential of B. serrata gum resin extract (BSE) for the treatment of a variety of inflammatory diseases like inflammatory bowel disease, rheumatoid arthritis, osteoarthritis and asthma. Moreover, in 2002 the European Medicines Agency classified BSE as an ‘orphan drug’ for the treatment of peritumoral brain oedema. Compared to NSAIDs, it is expected that the administration of BSE is associated with better tolerability, which needs to be confirmed in further clinical trials. Until recently, the pharmacological effects of BSE were mainly attributed to suppression of leukotriene formation via inhibition of 5-lipoxygenase (5-LO) by two boswellic acids, 11-keto-β-boswellic acid (KBA) and acetyl-11-keto-β-boswellic acid (AKBA). These two boswellic acids have also been chosen in the monograph of Indian frankincense in European Pharmacopoiea 6.0 as markers to ensure the quality of the air-dried gum resin exudate of B. serrata. Furthermore, several dietary supplements advertise the enriched content of KBA and AKBA. However, boswellic acids failed to inhibit leukotriene formation in human whole blood, and pharmacokinetic data revealed very low concentrations of AKBA and KBA in plasma, being far below the effective concentrations for bioactivity in vitro. Moreover, permeability studies suggest poor absorption of AKBA following oral administration. In view of these results, the previously assumed mode of action – that is, 5-LO inhibition – is questionable. On the other hand, 100-fold higher plasma concentrations have been determined for β-boswellic acid, which inhibits microsomal prostaglandin E synthase-1 and the serine protease cathepsin G. Thus, these two enzymes might be reasonable molecular targets related to the anti-inflammatory properties of BSE. In view of the results of clinical trials and the experimental data from in vitro studies of BSE, and the available pharmacokinetic and metabolic data on boswellic acids, this review presents different perspectives and gives a differentiated insight into the possible mechanisms of action of BSE in humans. It underlines BSE as a promising alternative to NSAIDs, which warrants investigation in further pharmacological studies and clinical trials.

Reference :

http://www.ncbi.nlm.nih.gov/pubmed/21553931

http://en.wikipedia.org/wiki/Boswellia_serrata

http://news.bbc.co.uk/2/hi/health/7535733.stm

尼达尼布 ニンテダニブ NINTEDANIB For Idiopathic pulmonary fibrosis


Nintedanib

NINTEDANIB, BBIF 1120, Intedanib

Boehringer Ingelheim Corp

As a potential treatment for a range of different solid tumour types
CAS 656247-17-5
CAS 1377321-64-6 (nintedanib bisethanesulfonate)
CAS [656247-18-6]  mono ethane sulfonate
3(Z)-[1-[4-[N-Methyl-N-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenylamino]-1-phenylmethylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester
MW 539.62, MF C31 H33 N5 O4

Launched 2014 USA….Idiopathic pulmonary fibrosis

 chinese, japanese  尼达尼布    ニンテダニブ

ChemSpider 2D Image | Nintedanib esylate | C33H39N5O7S

Ethanesulfonic acid – methyl (3Z)-3-{[(4-{methyl[(4-methyl-1-piperazinyl)acetyl]amino}phenyl)amino](phenyl)methylene}-2-oxo-6-indolinecarboxylate (1:1)

Nintedanib esylate

Cas 656247-18-6 [RN]

Methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate ethanesulfonate

Nintedanib esylate [USAN]

(3Z)-2,3-Dihydro-3-[[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-1H-indole-6-carboxylic acid methyl ester ethanesulfonate

1H-Indole-6-carboxylic acid, 2,3dihydro-3-[[[4-[methyl[(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-,methyl ester, (3Z)-, ethanesulfonate (1:1)

Nintedanib esylate, 656247-18-6, UNII-42F62RTZ4G, , NSC753000, NSC-753000, KB-62821
Molecular Formula: C33H39N5O7S   Molecular Weight: 649.75706

ニンテダニブエタンスルホン酸塩

Highly crystalline (mp = 305 °C) and exhibits a log P of 3.0 and good aqueous solubility (>20 mg/mL in water)…..J. Med. Chem., 2015, 58 (3), pp 1053–1063

str1
Nintedanib esilate is a bright yellow powder soluble in water. The solubility increases at lower pH and decrease at higher pH due to the non-protonated free base which has a low solubility in water.At room temperature, the active substance exists only in one single crystalline form . The active substance contains no chiral centres. The double bond at C
-3 of the indole moiety allows forE/Zisomerism, but the activesubstance is the Z

Trade Name:Ofev® / Vargatef®

MOA:Tyrosine kinase inhibitor

Indication:Idiopathic pulmonary fibrosis (IPF); Non small cell lung cancer (NSCLC)

In 2011, orphan drug designation was assigned in the U.S. and Japan for the treatment of idiopathic pulmonary fibrosis. In 2013, orphan drug designation was also assigned for the same indication in the E.U. In 2014, a Breakthrough Therapy Designation was assigned to the compound for the treatment of idiopathic pulmonary fibrosis.

Nintedanib (formerly BIBF 1120) is a small molecule tyrosine-kinase inhibitor, targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR) being developed by Boehringer Ingelheim as an anti-angiogenesis anti-cancer agent under the trade name Vargatef, and recently approved for treatment of idiopathic pulmonary fibrosis as Ofev.

The use of nintedanib or its salts, particularly its esylate salt is claimed for treating non-small cell lung cancer (NSCLC) in a patient who has received prior treatment with an anti-tumor therapy other than with nintedanib, wherein the patient to be treated is selected for treatment on the basis showing progression of the cancer within a period of 9 months or less after the initiation of said prior treatment. It is also claimed that the compound may be administered in combination with an anti-cancer drug, eg docetaxel. Nintedanib is known to be an antagonist of FGF-1, FGF-2, FGF-3, VEGF-1, VEGF-2, VEGF-3, PDGF-α and PDGF-β receptors.
Use of nintedanib for the treatment of non-small cell lung cancer in a patient who has received prior anti-tumour therapy other than with nintedanib. Boehringer Ingelheim has developed and launched Ofev, an oral capsule formulation of nintedanib, for the treatment of idiopathic pulmonary fibrosis (IPF), hepatic insufficiency and cancer, including metastatic NSCLC, ovarian, prostate and colorectal cancer. In October 2014, the US FDA approved the drug and an NDA was filed in Japan for IPF. Picks up from WO2014049099, claiming pharmaceutical combinations comprising nintedanib and sunitinib.
Nintedanib is an indolinone derivative angiogenesis inhibitor, originated at Boehringer Ingelheim. In 2014, the product candidate was approved and launched in the U.S. for the treatment of idiopathic pulmonary fibrosis, and a positive opinion was received by the EMA for the same indication. Also in 2014, Nintedanib was approved in the E.U. for the oral treatment of locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after first-line chemotherapy, in combination with docetaxel.The drug candidate is a small-molecule triple kinase inhibitor targeting the angiogenesis kinases (angiokinases) vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR). By allowing the vascularization necessary for the nourishment of tumors, these angiokinases have been implicated in tumor growth, proliferation and metastasis. In previous studies, intedanib potently and selectively inhibited human endothelial cell proliferation and induced apoptosis in human umbilical vein endothelial cells (HUVEC). It showed good oral bioavailability and tolerance, and significant antitumor activity was observed in a number of human tumor xenograft models.

Mechanism of action

Nintedanib is an indolinone-derived drug that inhibits the process of blood vessel formation (angiogenesis). Angiogenesis inhibitors stop the formation and reshaping of blood vessels in and around tumours, which reduces the tumour’s blood supply, starving tumour cells of oxygen and nutrients leading to cell death and tumour shrinkage. Unlike conventional anti-cancer chemotherapy which has a direct cell killing effect on cancer cells, angiogenesis inhibitors starve the tumour cells of oxygen and nutrients which results in tumour cell death. One of the advantages of this method of anti-cancer therapy is that it is more specific than conventional chemotherapy agents, therefore results in fewer and less severe side effects than conventional chemotherapy.

The process of new blood vessel formation (angiogenesis) is essential for the growth and spread of cancers. It is mediated by signaling molecules (growth factors) released from cancer cells in response to low oxygen levels. The growth factors cause the cells of the tumour’s blood vessel to divide and reorganize resulting in the sprouting of new vessels in and around the tumour, improving its blood supply.

Angiogenesis is a process that is essential for the growth and spread of all solid tumours, blocking it prevents the tumour from growing and may result in tumour shrinkage as well as a reduction in the spread of the cancer to other parts of the body. Nintedanib exerts its anti-cancer effect by binding to and blocking the activation of cell receptors involved in blood vessel formation and reshaping (i.e. VEGFR 1-3, FGFR 1-3 AND PDGFRα and β). Inhibition of these receptors in the cells that make up blood vessels (endothelial cells, smooth muscle cells and pericytes) by Nintedanib leads to programmed cell death, destruction of tumor blood vessels and a reduction in blood flow to the tumour. Reduced tumour blood flow inhibits tumor cell proliferation and migration hence slowing the growth and spread of the cancer.[1]

Adverse effects

Preclinical studies have shown that nintedanib binds in a highly selective manner to the ATP binding pocked of its three target receptor families, without binding to similarly shaped ATP domains in other proteins, which reduces the potential for undesirable side effects.[2]

The most common side effects observed with nintedanib were reversible elevation in liver enzymes (10-28% of patients) and gastrointestinal disturbance (up to 50%). Side effects observed with nintedanib were worse with the higher 250 mg dose, for this reason subsequent trials have used the equally clinically effective 200 mg dose.[1][2][3][4][5][6][7][8][9]

Nintedanib inhibits the growth and reshaping of blood vessels which is also an essential process in normal wound healing and tissue repair. Therefore a theoretical side effect of nintedanib is reduced wound healing however, unlike other anti-angiogenic agents, this side effect has not been observed in patients receiving nintedanib.

Studies

Preclinical studies have demonstrated that nintedanib selectively binds to and blocks the VEGF, FGF and PDGF receptors, inhibiting the growth of cells that constitute the walls of blood vessels (endothelial and smooth muscle cells and pericytes) in vitro. Nintedanib reduces the number and density of blood vessels in tumours in vivo, resulting in tumour shrinkage.[1][2] Nintedanib also inhibits the growth of cells that are resistant to existing chemotherapy agents in vitro, which suggests a potential role for the agent in patients with solid tumours that are unresponsive to or relapse following current first line therapy.[10]

Early clinical trials of nintedanib have been carried out in patients with non-small cell lung, colorectal, uterine, endometrial, ovarian and cervical cancer and multiple myeloma.[4][5][7][8][9] These studies reported that the drug is active in patients, safe to administer and is stable in the bloodstream. They identified that the maximum tolerated dose of nintedanib is 20 0 mg when taken once a day.

Clinical studies

In the first human trials, nintedanib halted the growth of tumours in up to 50% of patients with non-small cell lung cancer and 76% of patients with advanced colorectal cancer and other solid tumours.[4][8] A complete response was observed in 1/26 patients with non-small cell lung and 1/7 patients with ovarian cancer treated with nintedanib. A further 2 patients with ovarian cancer had partial responses to nintedanib.[8][9]

Two phase II trials have been carried out assessing the efficacy, dosing and side effects of nintedanib in non-small cell lung and ovarian cancer. These trials found that nintedanib delayed relapse in patients with ovarian cancer by two months[6] and that overall survival of patients with non-small cell lung who received nintedanib was similar to that observed with the FDA approved VEGFR inhibitor sorafenib. These trials also concluded that increasing the dose of the nintedanib has no effect on survival.[3]

SYNTHESIS

 

WO2009071523A1

NINTEDANIB JYOJO

 

 

MORE SYNTHESIS

Route 1

Reference:1. WO0127081A1.

2. US6762180B1.

3. J. Med. Chem. 2009, 52, 4466-4480.

Route 2

Reference:1. WO2009071523A1 / US8304541B2.

Route 3

Reference:1. CN104262232A.

Route 4

Reference:1. CN104844499A.

Current clinical trials

Nintedanib is being tested in several phase I to III clinical trials for cancer. Angiogenesis inhibitors such as nintedanib may be effective in a range of solid tumour types including; lung, ovarian, metastatic bowel, liver and brain cancer. Patients are also being recruited for three phase III clinical trials that will evaluate the potential benefit of nintedanib when added to existing 1st line treatments in patients with ovarian.[11] and 2nd line treatment in non-small cell lung cancer [12][13] The phase III trials of nintedanib in lung cancer have been named LUME-Lung 1 and LUME-Lung 2.

Current phase II trials are investigating the effect of nintedanib in patients with metastatic bowel cancer, liver cancer and the brain tumour: glioblastoma multiforme.[14]

Phase III trials are investigating the use of nintedanib in combination with the existing chemotherapy agents permexetred and docetaxel in patients with non-small cell lung cancer,[15] and in combination with carboplatin and paclitaxel as a first line treatment for patients with ovarian cancer.[16]

A phase III clinical trial was underway examining the safety and efficacy of nintedanib on patients with the non-cancerous lung condition idiopathic pulmonary fibrosis.[17] Nintedanib, under the brand name Ofev, was approved by the FDA for treatment of idiopathic pulmonary fibrosis on 15 Oct 2014. [18]

In terms of clinical development, additional phase III clinical trials are ongoing for the treatment of epithelial ovarian cancer, fallopian tube or primary peritoneal cancer, in combination with chemotherapy, and for the treatment of refractory metastatic colorectal cancer. Phase II clinical trials are also ongoing at the company for the treatment of glioblastoma multiforme, previously untreated patients with renal cell cancer, and for the treatment of patients with unresectable malignant pleural mesothelioma. The National Cancer Center of Korea (NCC) is evaluating the compound in phase II studies as second line treatment for small cell lung cancer (SCLC). The Centre Oscar Lambret is also conducting phase II clinical trials for the treatment of breast cancer in combination with docetaxel. Phase II trials are under way at EORTC as second line therapy for patients with either differentiated or medullary thyroid cancer progressing after first line therapy. The compound is also in early clinical development for the treatment of cancer of the peritoneal cavity, hepatocellular carcinoma, acute myeloid leukemia and ovarian cancer. Clinical trials have been completed for the treatment of prostate cancer and for the treatment of colorectal cancer. Boehringer Ingelheim is also conducting phase I/II clinical trials for the treatment of NSCLC and acute myeloid leukemia in addition to low-dose cytarabine. Phase I clinical studies are ongoing at the company for the treatment of epithelial ovary cancer and for the treatment of patients with mild and moderate hepatic impairment. The company had been evaluating the compound in early clinical trials for the treatment of prostate cancer in combination with docetaxel, but recent progress reports for this indication are not available at present.

In 2011, orphan drug designation was assigned in the U.S. and Japan for the treatment of idiopathic pulmonary fibrosis. In 2013, orphan drug designation was also assigned for the same indication in the E.U. In 2014, a Breakthrough Therapy Designation was assigned to the compound for the treatment of idiopathic pulmonary fibrosis.

PAPER

http://pubs.acs.org/doi/full/10.1021/jm501562a

Nintedanib: From Discovery to the Clinic

Department of Medicinal Chemistry; §Department of Drug Metabolism and Pharmacokinetics; Department of Non-Clinical Drug Safety; Department of Translational Medicine and Clinical Pharmacology; Department of Respiratory Diseases Research; and #Corporate Division Medicine, TA Oncology, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Riss, Germany
Clinical Development and Medical Affairs, Respiratory, Boehringer Ingelheim Inc., Ridgefield, Connecticut 06877, United States
Boehringer Ingelheim RCV GmbH & Co. KG, A-1121 Vienna, Austria
J. Med. Chem., 2015, 58 (3), pp 1053–1063
DOI: 10.1021/jm501562a
Abstract Image

Nintedanib (BIBF1120) is a potent, oral, small-molecule tyrosine kinase inhibitor, also known as a triple angiokinase inhibitor, inhibiting three major signaling pathways involved in angiogenesis. Nintedanib targets proangiogenic and pro-fibrotic pathways mediated by the VEGFR family, the fibroblast growth factor receptor (FGFR) family, the platelet-derived growth factor receptor (PDGFR) family, as well as Src and Flt-3 kinases. The compound was identified during a lead optimization program for small-molecule inhibitors of angiogenesis and has since undergone extensive clinical investigation for the treatment of various solid tumors, and in patients with the debilitating lung disease idiopathic pulmonary fibrosis (IPF). Recent clinical evidence from phase III studies has shown that nintedanib has significant efficacy in the treatment of NSCLC, ovarian cancer, and IPF. This review article provides a comprehensive summary of the preclinical and clinical research and development of nintedanib from the initial drug discovery process to the latest available clinical trial data.

  1. Roth, G. J.; Heckel, A.; Colbatzky, F.; Handschuh, S.; Kley, J.; Lehmann-Lintz, T.; Lotz, R.; Tontsch-Grunt,U.; Walter, R.; Hilberg, F.Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120) J. Med. Chem.2009, 52, 44664480
  2. 2.Roth, G. J.; Sieger, P.; Linz, G.; Rall, W.; Hilberg, F.; Bock, T. 3-Z-[1-(4-(N-((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone monoethanesulphonate and the use thereof as a pharmaceutical composition. WO2004/013099. 2004.

  3. 3.Merten, J.; Linz, G.; Schnaubelt, J.; Schmid, R.; Rall, W.; Renner, S.; Reichel, C.; Schiffers, R. Process for the manufacture of an indolinone derivative. WO2009/071523. 2009

PAPER

http://pubs.acs.org/doi/abs/10.1021/jm900431g

J. Med. Chem., 2009, 52 (14), pp 4466–4480
DOI: 10.1021/jm900431g
Abstract Image

Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a new treatment modality in oncology. Preclinical findings suggest that blockade of additional pro-angiogenic kinases, such as fibroblast and platelet-derived growth factor receptors (FGFR and PDGFR), may improve the efficacy of pharmacological cancer treatment. Indolinones substituted in position 6 were identified as selective inhibitors of VEGF-, PDGF-, and FGF-receptor kinases. In particular, 6-methoxycarbonyl-substituted indolinones showed a highly favorable selectivity profile. Optimization identified potent inhibitors of VEGF-related endothelial cell proliferation with additional efficacy on pericyctes and smooth muscle cells. In contrast, no direct inhibition of tumor cell proliferation was observed. Compounds 2 (BIBF 1000) and 3 (BIBF 1120) are orally available and display encouraging efficacy in in vivo tumor models while being well tolerated. The triple angiokinase inhibitor 3 is currently in phase III clinical trials for the treatment of nonsmall cell lung cancer.

PATENT

WO-2014180955

The present invention relates to a beneficial treatment of tumours in patients suffering from NSCLC, and to a clinical marker useful as predictive variable of the responsiveness of tumours in patients suffering from NSCLC. The present invention further relates to a method for selecting patients likely to respond to a given therapy, wherein said method optionally comprises the use of a specific clinical marker. The present invention further relates to a method for delaying disease progression and/or prolonging patient survival of NSCLC patients, wherein said method comprises the use of a specific clinical marker.

The monoethanesulphonate salt form of this compound presents properties which makes this salt form especially suitable for development as medicament. The chemical structure of 3-Z-[l-(4-(N-((4-methyl-piperazin-l-yl)-methylcarbonyl)-N-methyl-amino)-anilino)- 1 -phenyl-methylene] -6-methoxycarbonyl-2-indolinone-monoethanesulphonate (ΓΝΝ name nintedanib esylate) is depicted below as Formula Al .

Formula Al

This compound is thus for example suitable for the treatment of diseases in which angiogenesis or the proliferation of cells is involved. The use of this compound for the treatment of immunologic diseases or pathological conditions involving an

immunologic component is being described in WO 2004/017948, the use for the treatment of, amongst others, oncological diseases, alone or in combination, is being described in WO 2004/096224 and WO 2009/147218, and the use for the treatment of fibrotic diseases is being described in WO 2006/067165.

A method using biomarkers for monitoring the treatment of an individual with the compound 3-Z-[l-(4-(N-((4-methyl-piperazin-l-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-l -phenyl-methylene] -6-methoxycarbonyl-2-indolinone or a pharmaceutically acceptable salt thereof, wherein it is determined if a sample from said individual comprises a biomarker in an amount that is indicative for said treatment, is disclosed in WO 2010/103058.

PATENT

http://www.google.com/patents/US20110201812

The present invention relates to a process for the manufacture of a specific indolinone derivative and a pharmaceutically acceptable salt thereof, namely 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and its monoethanesulfonate, to new manufacturing steps and to new intermediates of this process.

The indolinone derivative 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and its monoethanesulfonate are known from the following patent applications: WO 01/027081, WO 04/013099, WO 04/017948, WO 04/096224 and WO 06/067165. These patent applications disclose the compound, a process for its manufacture, a specific salt form of this compound and the use of the compound or its salt in a pharmaceutical composition to treat oncological or non-oncological diseases via inhibition of the proliferation of target cells, alone or in combination with further therapeutic agents. The mechanism of action by which the proliferation of the target cells occurs is essentially a mechanism of inhibition of several tyrosine kinase receptors, and especially an inhibition of the vascular endothelial growth factor receptor (VEGFR).

Figure US20110201812A1-20110818-C00001

Figure US20110201812A1-20110818-C00003

Figure US20110201812A1-20110818-C00004

EXAMPLE 1Synthesis of the 6-methoxycarbonyl-2-oxindole in accordance with the process shown in synthesis scheme CSynthesis of benzoic acid, 4-chloro-3-nitro-, methylester

    • 20 kg of 4-chloro-3-nitro-benzoic acid (99.22 mol) is suspended in 76 L methanol. 5.9 kg thionylchloride (49.62 mol) is added within 15 minutes and refluxed for about 3 hours. After cooling to about 5° C., the product is isolated by centrifugation and drying at 45° C.
    • Yield: 19.0 kg (88.8% of theoretical amount)
    • Purity (HPLC): 99.8%

Synthesis of propanedioic acid, [4-(methoxycarbonyl)-2-nitrophenyl]-, dimethylester

    • 12.87 kg of malonic acid, dimethylester (97.41 mol) is added to a hot solution (75° C.) of 10.73 kg sodium-tert.amylate (97.41 mol) in 35 L 1-methyl-2-pyrrolidinone (NMP). A solution of 10 kg benzoic acid, 4-chloro-3-nitro-, methylester (46.38 mol) in 25 L 1-methyl-2-pyrrolidinone is added at 75° C. After stirring for 1.5 hours at about 75° C. and cooling to 20° C., the mixture is acidified with 100 L diluted hydrochloric acid to pH 1. After stirring for 1.5 hours at about 5° C., the product is isolated by centrifugation and drying at 40° C.
    • Yield: 13.78 kg (95.4% of theoretical amount)
    • Purity (HPLC): 99.9%
    • Alternatively, propanedioic acid, [4-(methoxycarbonyl)-2-nitrophenyl]-, dimethylester can be synthesized as follows:
    • 33.1 kg of malonic acid, dimethylester (250.6 mol) and 27.0 kg benzoic acid, 4-chloro-3-nitro-, methylester (125.3 mol) are subsequently added to a solution of 45.1 kg sodium-methylate (250.6 mol) in 172 kg 1-methyl-2-pyrrolidinone (NMP) at 20° C. After stirring for 1.5 hours at about 45° C. and cooling to 30° C., the mixture is acidified with 249 L diluted hydrochloric acid. At the same temperature, the mixture is seeded, then cooled to 0° C. and stirred for an additional hour. The resulting crystals are isolated by centrifugation, washed and dryed at 40° C.
    • Yield: 37.5 kg (86% of theoretical amount)
    • Purity (HPLC): 99.7%

Synthesis of 6-methoxycarbonyl-2-oxindole

A solution of 13 kg propanedioic acid, [4-(methoxycarbonyl)-2-nitrophenyl]-, dimethylester (41.77 mol) in 88 L acetic acid is hydrogenated at 45° C. and under 40-50 psi in the presence of 1.3 kg Pd/C 10%. After standstill of the hydrogenation, the reaction is heated up to 115° C. for 2 hours. The catalyst is filtered off and 180 L water is added at about 50° C. The product is isolated after cooling to 5° C., centrifugation and drying at 50° C.

    • Yield: 6.96 kg (87.2% of theoretical amount)
    • Purity (HPLC): 99.8%

EXAMPLE 2Synthesis of the “chlorimide” (methyl-1-(chloroacetyl)-2-oxoindoline-6-carboxylate)

Method 1

6-methoxycarbonyl-2-oxindole (400 g; 2.071 mol) is suspended in toluene (1200 ml) at room temperature. Chloroacetic anhydride (540 g; 3.095 mol) is added to this suspension. The mixture is heated to reflux for 3 h, then cooled to 80° C. and methyl cyclohexane (600 ml) is added within 30 min. The resulting suspension is further cooled down to room temperature within 60 min. The mother liquor is separated and the solid is washed with ice cold methanol (400 ml). The crystals are dried to afford 515.5 g (93.5%) of the “chlorimide” compound as a white solid. 1H-NMR (500 MHz, DMSO-d6) δ: 8.66 (s, 1H, 6-H); 7.86 (d, J=8.3 Hz, 1H, 8-H); 7.52 (d, J=8.3 Hz, 1H, 9-H); 4.98 (s, 2H, 15-H2); 3.95 (s, 3H, 18-H3); 3.88 (s, 2H, 3-H2). 13C-NMR (126 MHz, DMSO-d6) δ: 174.7 (C-2); 36.0 (C-3); 131.0 (C-4); 140.8 (C-5); 115.7 (C-6); 128.9 (C-7); 126.1 (C-8); 124.6 (C-9); 166.6 (C-10); 165.8 (C-13); 46.1 (C-15); 52.3 (C-18). MS: m/z 268 (M+H)+. Anal. calcd. for C12H10ClNO4: C, 53.85; H, 3.77; Cl, 13.25; N, 5.23. Found: C, 52.18; H, 3.64; Cl, 12.89; N, 5.00.

Method 2

6-Methoxycarbonyl-2-oxindole (10 g; 0.052 mol) is suspended in n-butyl acetate (25 ml) at room temperature. To this suspension a solution of chloroacetic anhydride (12.8 g; 0.037 mol) in n-butyl acetate (25 ml) is added within 3 min. The mixture is heated to reflux for 2 h, then cooled to 85° C. and methyl cyclohexane (20 ml) is added. The resulting suspension is further cooled down to room temperature and stirred for 2 h. The mother liquor is separated and the solid is washed with methanol (400 ml) at ambient temperature. The crystals are dried to afford 12.7 g (91.5%) of the “chlorimide” compound as a slightly yellow solid.

EXAMPLE 3Synthesis of the “chlorenol” (methyl-1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate)

Method 1

Methyl-1-(chloroacetyl)-2-oxoindoline-6-carboxylate (12.0 g; 0.045 mol) is suspended in toluene (60 ml) at ambient temperature. Acetic anhydride (16.2 g; 0.157 mol) is added to this suspension. The mixture is heated to not less than 104° C. and trimethyl orthobenzoate (20.0 g; 0.108 mol) is added within 60 min. During the addition period and subsequent stirring at the same temperature for 3 h, volatile parts of the reaction mixture are distilled off. The concentration of the reaction mixture is kept constant by replacement of the distilled part by toluene (40 ml). The mixture is cooled down to 5° C., stirred for 1 h and filtrated. The solid is subsequently washed with toluene (14 ml) and with a mixture of toluene (8 ml) and ethyl acetate (8 ml). After drying, 16.3 g (91.7%) of the “chlorenol” compound are isolated as slightly yellow crystals. 1H-NMR (500 MHz, DMSO-d6) δ: 8.73 (d, J=1.5 Hz, 1H, 6-H); 8.09 (d, J=8.0 Hz, 1H, 9-H); 7.90 (dd, J=8.1; 1.5 Hz, 1H, 8-H); 7.61-7.48 (m, 5H, 21-H, 22-H, 23-H, 24-H, 25-H); 4.85 (s, 2H, 18-H2); 3.89 (s, 3H, 27-H3); 3.78 (s, 3H, 15-H3). 13C-NMR (126 MHz, DMSO-d6) δ: 165.9 (C-2+C16); 103.9 (C-3); 127.4; 128.6; 130.0; 135.4 (C-4+C-5+C-7+C-20); 115.1 (C-6); 126.1 (C-8); 122.5 (C-9); 166.7 (C-10); 173.4 (C-13); 58.4 (C-15); 46.4 (C-18); 128.6 (C-21+C-22+C-24+C-25); 130.5 (C-23); 52.2 (C-27). MS: m/z 386 (M+H)+. Anal. calcd. for C20H16ClNO5: C, 62.27; H, 4.18; Cl, 9.19; N, 3.63. Found: C, 62.21; H, 4.03; Cl, 8.99; N, 3.52.

Method 2

Methyl-1-(chloroacetyl)-2-oxoindoline-6-carboxylate (12.0 g; 0.045 mol) is suspended in xylene (60 ml) at ambient temperature. Acetic anhydride (16.2 g; 0.157 mol) is added to this suspension. The mixture is heated to reflux, trimethyl orthobenzoate (20.0 g; 0.108 mol) is added within 40 min and heating is maintained for 4 h. The mixture is cooled down to 0° C. and the mother liquor is separated. The solid is subsequently washed with xylene (14 ml) and a mixture of xylene (8 ml) and ethyl acetate (8 ml). After drying 14.3 g (81.0%) of the “chlorenol” compound are isolated as yellow crystals.

Method 3

Methyl-1-(chloroacetyl)-2-oxoindoline-6-carboxylate (12.0 g; 0.045 mol) is suspended in toluene (60 ml) at ambient temperature. Acetic anhydride (16.2 g; 0.157 mol) is added to this suspension. The mixture is heated to reflux, trimethyl orthobenzoate (20.0 g; 0.108 mol) is added within 40 min and heating is maintained for 3 h. The mixture is cooled down to 0° C. and the mother liquor is separated. The solid is subsequently washed with toluene (14 ml) and a mixture of toluene (8 ml) and ethyl acetate (8 ml). After drying 15.3 g (87.3%) of the “chlorenol” compound are isolated as fawn crystals.

EXAMPLE 4Synthesis of the “enolindole” (methyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate)

Method 1

A solution of potassium hydroxide (0.41 g, 0.006 mol) in methanol (4 ml) is added at 63° C. to a suspension of methyl-1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (8.0 g; 0.020 mol) in methanol (32 ml). The mixture is then stirred for 30 min, cooled to 0° C. and stirring is maintained for 2 h. After filtration, the solid is washed with methanol (24 ml) and dried to afford 6.0 g (94.6%) of the “enolindole” compound as yellow crystals. 1H-NMR (500 MHz, CDCl3) δ: 8.08 (s, 1H, 1-H); 7.88 (d, J=7.8 Hz, 1H, 9-H); 7.75 (m, 1H, 8-H); 7.52-7.56 (m, 3H, 18-H, 19-H, 20-H); 7.40-7.45 (m, 3H, 6-H, 17-H, 21-H); 3.92 (s, 3H, 23-H3); 3.74 (s, 3H, 13-H3). 13C-NMR (126 MHz, CDCl3) δ: 168.8 (C-2); 107.4 (C-3); 130.8 (C-4); 138.2 (C-5); 109.4 (C-6); 128.2 and 128.3 (C-7, C-16); 123.5 (C-8); 123.1 (C-9); 170.1 (C-11); 57.6 (C-13); 167.2 (C-14); 128.7 and 128.9 (C-17, C-18, C-20, C-21); 130.5 (C-19); 52.1 (C-23). MS (m/z): 310 (M+H)+. Anal. calcd. for C18H15NO4: C, 69.89; H, 4.89; N, 4.53. Found: C, 69.34; H, 4.92; N, 4.56.

Method 2

A suspension of methyl-1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (7.0 g; 0.018 mol) in methanol (28 ml) is heated to reflux. Within 3 min, a solution of sodium methoxide in methanol (0.24 g, 30 (w/w), 0.001 mol) is added to this suspension. The mixture is then stirred for 30 min, cooled to 5° C. and stirring is maintained for 2 h. After filtration, the solid is washed with methanol (9 ml) and dried to afford 5.4 g (89.7%) of the “enolindole” compound as yellow crystals.

Method 3

A suspension of methyl-1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (8.0 g; 0.021 mol) in methanol (32 ml) is heated to reflux. A solution of sodium methoxide in methanol (0.74 g, 30% (w/w), 0.004 mol), further diluted with methanol (4 ml), is added dropwise to this suspension. The mixture is then stirred for 90 min, cooled to 0° C. and stirring is maintained for 2 h. After filtration, the solid is washed with methanol (24 ml) and dried to afford 5.9 g (91.2%) of the “enolindole” compound as yellow crystals.

EXAMPLE 5Synthesis of the “chloroacetyl” (N-(4-nitroanilino)-N-methyl-2-chloro-acetamide)

Method 1

A suspension of N-methyl-4-nitroaniline (140 g; 0.920 mol) in ethyl acetate (400 ml) is heated to 70° C. Within 90 min, chloro acetylchloride (114 g; 1.009 mol) is added to this suspension. The resulting solution is then refluxed for 1 h, cooled to 60° C. and methyl cyclohexane (245 ml) is added. The suspension is further cooled down to 0° C. and stirred for 1 h. The reaction mixture is filtrated, washed with methyl cyclohexane (285 ml) and the precipitate is dried to afford 210.4 g (92.7%) of the “chloroacetyl” compound as white crystals. 1H-NMR (500 MHz, DMSO-d6) δ: 8.29 (d, J=8.5 Hz, 2H, 1-H+3-H); 7.69 (d, J=8.5 Hz, 2H, 4-H+6-H); 4.35 (s, 2H, 9-H2); 3.33 (s, 3H, 12-H3). 13C-NMR (126 MHz, DMSO-d6) δ: 124.6 (C-1+C-3); 145.6 (C-2); 127.4 (C-4+C-6); 148.6 (C-5); 165.6 (C-8); 42.7 (C-9); 37.2 (C-12). MS (m/z): 229 (M+H)+. Anal. calcd. for C9H9ClN2O3: C, 47.28; H, 3.97; N, 12.25. Found: C, 47.26; H, 3.99; Cl, 15.73; N, 12.29.

Method 2

A suspension of N-methyl-4-nitroaniline (20.0 g; 0.131 mol) in ethyl acetate (20 ml) is heated to 60° C. Within 15 min, a solution of chloro acetic anhydride (26.0 g; 0.151 mol) in ethyl acetate (60 ml) is added to this suspension. The resulting solution is then refluxed for 1 h, cooled to 75° C. ° C. and methyl cyclohexane (80 ml) is added. After seeding at 60° C., the suspension is further cooled down to 0° C. and stirred for 1 h. The reaction mixture is filtrated, washed with methyl cyclohexane (40 ml) and the precipitate is dried to afford 25.9 g (83.3%) of the “chloroacetyl” compound as grey crystals.

EXAMPLE 6Synthesis of the “nitroaniline” (N-(4-nitrophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide) and of the “aniline” (N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide)

Method 1

A suspension of N-(4-nitroanilino)-N-methyl-2-chloro-acetamide (20.0 g; 0.087 mol) in toluene (110 ml) is heated to 40° C. Within 30 min, 1-methylpiperazine (21.9 g; 0.216 mol) is added dropwise. After purging of the dropping funnel with toluene (5 ml) the reaction mixture is stirred for 2 h at 55° C., cooled to ambient temperature and washed with water (15 ml). The organic layer is diluted with isopropanol (100 ml) and Pd/C (10%; 1.0 g) is added. After subsequent hydrogenation (H2, 4 bar) at 20° C. the catalyst is removed. Approximately ⅘ of the volume of the resulting solution is evaporated at 50° C. The remaining residue is dissolved in ethyl acetate (20 ml) and toluene (147 ml) heated to 80° C., then cooled to 55° C. and seeded. The reaction mixture is further cooled to 0° C. and stirred for 3 h at the same temperature. After filtration, the solid is washed with ice cold toluene (40 ml) and dried to afford 20.2 g (88.0%) of the “aniline” compound as white crystals. 1H-NMR (500 MHz, DMSO-d6) δ: 6.90 (d, J=8.5 Hz, 2H, 4-H+6-H); 6.65 (d, J=8.5 Hz, 2H, 1-H+3-H); 5.22 (2H, 19-H2); 3.04 (s, 3H, 9-H3); 2.79 (s, 2H, 11-H2); 2.32 (m, 4H, 13-H2+17-H2); 2.23 (m, 4H, 14-H2+16-H2); 2.10 (s, 3H, 18-H3). 13C-NMR (126 MHz, DMSO-d6) δ: 114.0 (C-1+C-3); 148.0 (C-2); 127.6 (C-4+C-6); 131.5 (C-5); 168.9 (C-8); 36.9 (C-9); 58.5 (C-11); 52.4 (C-13+C-17); 54.6 (C-14+C-16); 45.7 (C-18). MS (m/z): 263 (M+H)+. Anal. calcd. for C14H22N4O: C, 64.09; H, 8.45; N, 21.36. Found: C, 64.05; H, 8.43; N, 21.39.

Method 2

A suspension of N-(4-nitroanilino)-N-methyl-2-chloro-acetamide (14.5 g; 0.063 mol) in ethyl acetate (65 ml) is heated to 40° C. Within 30 min, 1-methylpiperazine (15.8 g; 0.156 mol) is added dropwise. After purging of the dropping funnel with ethyl acetate (7 ml) the reaction mixture is stirred at 50° C. for 90 min, cooled to ambient temperature and washed with water (7 ml). The organic layer is diluted with isopropanol (75 ml) and dried over sodium sulphate. After separation of the solid, Pd/C (10%; 2.0 g) is added and the solution is hydrogenated (H2, 5 bar) at ambient temperature without cooling. Subsequently the catalyst is removed by filtration and the solvent is evaporated at 60° C. The remaining residue is dissolved in ethyl acetate (250 ml) and recrystallized. After filtration and drying 10.4 g (60.4%) of the “aniline” compound are isolated as white crystals.

EXAMPLE 7Synthesis of the “anilino” (3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone)

Method 1

A suspension of methyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (10.0 g; 0.032 mol) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (8.6 g; 0.032 mol) in a mixture of methanol (72 ml) and N,N-dimethylformamide (18 ml) is heated to reflux. After 7 h of refluxing the suspension is cooled down to 0° C. and stirring is maintained for additional 2 h. The solid is filtered, washed with methanol (40 ml) and dried to afford 15.4 g (88.1%) of the “anilino” compound as yellow crystals. 1H-NMR (500 MHz, DMSO-d6) δ: 11.00 (s, 1H, 23-H); 12.23 (s, 19-H); 7.61 (t; J=7.1 Hz, 1H, 33-H); 7.57 (t, J=7.5 Hz, 2H, 32-H+34-H); 7.50 (d, J=7.7 Hz, 2H, 31-H+35-H); 7.43 (d, J=1.6 Hz, 1H, 29-H); 7.20 (dd, J=8.3; 1.6 Hz, 1H, 27-H); 7.13 (d, J=8.3 Hz, 2H, 14-H+18-H); 6.89 (d, 8.3 Hz, 2H, 15-H+17-H); 5.84 (d, J=8.3 Hz, 1H, 26-H); 3.77 (s, 3H, 40-H3); 3.06 (m, 3H, 12-H3); 2.70 (m, 2 H, 8-H2); 2.19 (m, 8H, 2-H2, 3-H2, 5-H2, 6-H2); 2.11 (s, 3H, 7-H3). 13C-NMR (126 MHz, DMSO-d6) δ: 54.5 (C-2+C-6); 52.2 (C-3+C-5); 45.6 (C-7); 59.1 (C-8); 168.5 (C-9); 36.6 (C-12); 140.1 (C-13); 127.6 (C-14+C-18); 123.8 (C-17+C-15); 137.0 (C-16); 158.3 (C-20); 97.5 (C-21); 170.1 (C-22); 136.2 (C-24); 128.9 (C-25); 117.2 (C-26); 121.4 (C-27); 124.0 (C-28); 109.4 (C-29); 131.9 (C-30); 128.4 (C-31+C-35); 129.4 (C-32+C-34); 130.4 (C-33); 166.3 (C-37); 51.7 (C-40). MS (m/z): 540 (M+H)+. Anal. calcd. for C31H33N5O4: C, 69.00; H, 6.16; N, 12.98. Found: C, 68.05; H, 6.21; N, 12.81.

Method 2

A suspension of methyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (20.0 g; 0.064 mol) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (17.1 g; 0.065 mol) in methanol (180 ml) is heated to reflux for 7.5 h. The resulting suspension is cooled down to 10° C. within 1 h and stirring is maintained for 1 h. After filtration, the solid is washed with ice cold methanol (80 ml) and dried to afford 31.0 g (89.0%) of the “anilino” compound as yellow crystals.

EXAMPLE 8Synthesis of the 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, monoethanesulfonate

A suspension of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone (30.0 g; 0.055 mol) in methanol (200 ml) and water (2.4 ml) is heated to 60° C. Aqueous ethanesulfonic acid (70% (w/w); 8.75 g; 0.056 mol) is added to the reaction mixture. The resulting solution is cooled to 50° C., seeded and then diluted with isopropanol (200 ml). The mixture is further cooled to 0° C. and stirred for 2 h at this temperature. The precipitate is isolated, washed with isopropanol (120 ml) and dried to furnish 35.1 g (97.3%) of the monoethanesulfonate salt of the compound as yellow crystals. 1H-NMR (400 MHz, DMSO-d6) δ: 12.26 (s, 11-H); 10.79 (s, 1H, 1-H); 9.44 (s, 1H, 24-H); 7.64 (m, 1H, 32-H); 7.59 (m, 2H, 31-H+33-H); 7.52 (m, 2H, 30-H+34-H); 7.45 (d, J=1.6 Hz, 1H, 7-H); 7.20 (dd, J=8.2; 1.6 Hz, 1H, 5-H); 7.16 (m, 2H, 14-H+16-H); 6.90 (m, 2H, 13-H+17-H); 5.85 (d, J=8.2 Hz, 1H, 4-H); 3.78 (s, 3H, 37-H3); 3.45-2.80 (broad m, 4H, 23-H2+25-H2); 3.08 (s, 3H, 28-H3); 2.88 (s, 2H, 20-H2); 2.85-2.30 (broad m, 4H, 22-H2+26-H2); 2.75 (s, 3H, 27-H3); 2.44 (q, J=7.4 Hz, 2H, 39-H2); 1.09 (t, J=7.4 Hz, 3H, 38-H3). 13C-NMR (126 MHz, DMSO-d6) δ: 9.8 (C-38); 36.6 (C-28); 42.3 (C-27); 45.1 (C-39); 51.7 (C-37); 48.9 (C-22+C-26); 52.6 (C-23+C-25); 57.5 (C-20); 97.7 (C-3); 109.5 (C-7); 117.3 (C-4); 121.4 (C-5); 123.8 (C-13+C-17); 124.1 (C-6); 127.7 (C-14+C-16); 128.4 (C-30+C-34); 128.8 (C-9); 129.5 (C-31+C-33); 130.5 (C-32); 132.0 (C-29); 168.5 (C-9); 136.3 (C-8); 137.3 (C-12); 139.5 (C-15); 158.1 (C-10); 166.3 (C-35); 168.0 (C-19); 170.1 (C-2). MS (m/z): 540 (M(base)+H)+. Anal. calcd. for C33H39N5O7S: C, 60.17; H, 6.12; N, 10.63; S, 4.87. Found: C, 60.40; H, 6.15; N, 10.70; S, 4.84.

CLIPS

Figure

After a classical malonic ester addition to arene 3, the resulting nitro benzene (4) is hydrogenated under acidic conditions, furnishing the 6-methoxycarbonyl-substituted oxindole 5 via decarboxylative cyclization. Condensation of 5 with trimethyl orthobenzoate in acetic anhydride leads to compound 6, one of the two key building blocks of the synthesis. The concomitant N-acetylation of the oxindole activates the scaffold for the condensation reaction.
The aniline side chain (9) can be prepared by a one-pot bromo-acetylation/amination of the para-nitro-phenylamine (7) using bromoacetyl bromide and N-methylpiperazine and a subsequent hydrogenation furnishing 9 as the second key building block. Condensation of both building blocks in an addition–elimination sequence and subsequent acetyl removal with piperidine furnishes 2 as free base (pKa = 7.9), which subsequently is converted into its monoethanesulfonate salt (1). Compound 1 is highly crystalline (mp = 305 °C) and exhibits a log P of 3.0 and good aqueous solubility (>20 mg/mL in water).

 

 

CLIPS

see

http://www.yaopha.com/2014/07/09/synthesis-of-vargatef-nintedanib-boehringer-ingelheim-idiopathic-pulmonary-fibrosis-drug/

NINTEDANIB SINA

CLICK ON PIC

Updates………..

“J.Med.Chem” 2009 Vol. 52, page 4466-4480 and the “Chinese Journal of Pharmaceuticals” 2012, Vol. 43, No. 9, page 726-729 reported a further intermediate A and B synthesis, and optimized from the reaction conditions, the reaction sequence, the feed ratio and catalyst selection, etc., so that the above-described synthetic routes can be simplified and reasonable.

 

 

 

PATENT

CN105461609A

NINTE PIC

MACHINE TRANSLATED FROM CHINESE

Synthesis of Trinidad Neeb (I),

A 500ml reaction flask was charged 30g of compound V, 22.5g compound of the VI, ethanol 300ml, sodium bicarbonate and 15g, the reaction was heated to reflux for 2 hours, the reaction mixture was added to 600ml of water, there are large amount of solid precipitated, was filtered, the cake washed with 100ml washed once with methanol, a yellow solid 41.9g refined Trinidad Neeb (I). Yield 92.7%.

4 bandit R (400MHz, dmso) δ11 · 97 (s, 1H), 8.38 (s, 1H), 7.97 (dd, J = 11.9, 5.0Hz, 2H), 7.67 (d, J = 8.1Hz, 1H), 7.16 (ddd, J = 26.9, 22.1, 7.0Hz, 5H), 6.85 (d, J = 8.6Hz, 2H), 6.63 (d, J = 8.7Hz, 2H), 3.90 (s, 3H), 2.99 (s, 3H), 2.69 (s, 2H), 2.51-2.24 (m, 8H), 2.20 (s, 3H) MS:. m / z540 (m + 1) + 2 Example: Preparation of compound IV 250ml reaction flask was added 28.7g of 2- oxindole-6-carboxylate, 130ml ethanol, stirred open, then added 30.3ml (31.8g) benzaldehyde, 2.97 mL piperidine was heated to 70 ° C-80 after ° C for 2 hours, allowed to cool to 20 ° C- 30 ° C, the precipitate was filtered, the filter cake was washed with absolute ethanol, 50 ° C 5 hours and dried in vacuo give a yellow solid 38.7g (IV of), yield: 92.4% Preparation of compound V square in 500ml reaction flask was added 30g compound IV, dichloromethane 360ml, cooled with ice water to 0-5 ° C, 71/92 bromine 3.lml (9.7g), drop finished warmed to 20- 30 ° C, 3 hours after the reaction, the reaction solution was washed once with 150ml dichloromethane layer was concentrated oil was done by adding 200ml ethanol crystallization, filtration, 60 ° C and dried under vacuum 36.lg white solid (V ), yield: 93 · 8%.

 After Trinidad Technip (I) are synthesized in the reaction flask was added 500ml of 30g compound V, 33.0g compound of the VI, ethanol 300ml, sodium bicarbonate, 15g, was heated to reflux for 2 hours, the reaction mixture was added to 600ml water, there are large amount of solid precipitated, was filtered, the filter cake washed once with 100ml methanol obtained 42.3g of yellow solid was purified by Technip Trinidad (I). Yield 93.6%.

 ΧΗNMR (400MHz, dmso) δ11.94 (s, 1Η), 8.36 (s, 1H), 7.96 (dd, J = 11.9, 5.0Hz, 2H), 7.67 (d, J = 8.1Hz, 1H) , 7.16 (ddd, J = 26.9, 22.1, 7.0Hz, 5H), 6.85 (d, J = 8.6Hz, 2H), 6.61 (d, J = 8.7Hz, 2H), 3.90 (s, 3H), 2.99 ( s, 3H), 2.65 (s, 2H), 2.50-2.30 (m, 8H), 2.20 (s, 3H) MS:. m / z540 (m + 1) + square

PATENT

WO2016037514

(I) 2.30g, yield 85.3%. Melting point 241 ~ 243 ℃, Mass spectrum (the EI): m / Z 540 (the M + the H), 1 the H NMR (of DMSO D . 6 ): 2.27 (S, 3H), 2.43 (m, 8H), 2.78 (S, 2H) , 3.15 (s, 3H), 3.82 (s, 3H), 5.97 (d, J = 8.3Hz, 1H), 6.77 (d, J = 8.7Hz, 1H), 6.96 (d, J = 8.6Hz, 2H) , 7.32-7.62 (m, 8H), 8.15 (s, 1H), 12.15 (s, 1H).

 

CLIPS

http://pubs.rsc.org/en/content/articlelanding/2015/ay/c5ay01207d#!divAbstract

Nintedanib
Nintedanib

Nintedanib
Systematic (IUPAC) name
Methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate
Clinical data
Trade names Vargatef, Ofev
AHFS/Drugs.com Consumer Drug Information
Pregnancy cat.
Legal status
Routes Oral and intravenous
Identifiers
CAS number 656247-17-5 
ATC code None
Chemical data
Formula C31H33N5O4 
Mol. mass 539.6248 g/mol

References

  1. Hilberg, F.; G. J. Roth, M. Krssak, S. Kautschitsch, W. Sommergruber, U. Tontsch-Grunt, P. Garin-Chesa, G. Bader, A. Zoephel, J. Quant, A. Heckel, W. J. Rettig (2008). “BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy”. Cancer Res 68 (12): 4774–82. doi:10.1158/0008-5472.CAN-07-6307. ISSN 1538-7445. PMID 18559524.
  2. Hilberg, F.; U. Tontsch-Grunt, F. Colbatzky, A. Heckel, R. Lotz, J.C.A. van Meel, G.J. Roth (2004). “BIBF1120 a novel, small molecule triple angiokinase inhibitor: profiling as a clinical candidate for cancer therapy”. European Journal of Cancer Supplements 2 (50).
  3. Reck, M.; R. Kaiser; C. Eschbach; M. Stefanic; J. Love; U. Gatzemeier; P. Stopfer; J. von Pawel (2011). “A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer”. Ann Oncol. ISSN 1569-8041.
  4. Okamoto, I.; H. Kaneda, T. Satoh, W. Okamoto, M. Miyazaki, R. Morinaga, S. Ueda, M. Terashima, A. Tsuya, A. Sarashina, K. Konishi, T. Arao, K. Nishio, R. Kaiser, K. Nakagawa (2010). “Phase I safety, pharmacokinetic, and biomarker study of BIBF 1120, an oral triple tyrosine kinase inhibitor in patients with advanced solid tumors”. Mol Cancer Ther 9 (10): 2825–33. doi:10.1158/1535-7163.MCT-10-0379. ISSN 1538-8514. PMID 20688946.
  5. Mross, K.; M. Stefanic, D. Gmehling, A. Frost, F. Baas, C. Unger, R. Strecker, J. Henning, B. Gaschler-Markefski, P. Stopfer, L. de Rossi, R. Kaiser (2010). “Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors”. Clin Cancer Res 16 (1): 311–9. doi:10.1158/1078-0432.CCR-09-0694. ISSN 1078-0432. PMID 20028771.
  6. Ledermann, J.A. (2009). “A randomised phase II placebo-controlled trial using maintenance therapy to evaluate the vascular targeting agent BIBF 1120 following treatment of relapsed ovarian cancer (OC)”. J Clin Oncol 27 (15s): (suppl; abstr 5501).
  7. Kropff, M.; J. Kienast; G. Bisping; W. E. Berdel; B. Gaschler-Markefski; P. Stopfer; M. Stefanic; G. Munzert (2009). “An open-label dose-escalation study of BIBF 1120 in patients with relapsed or refractory multiple myeloma”. Anticancer Res 29 (10): 4233–8. ISSN 1791-7530. PMID 19846979.
  8. Ellis, P. M.; R. Kaiser; Y. Zhao; P. Stopfer; S. Gyorffy; N. Hanna (2010). “Phase I open-label study of continuous treatment with BIBF 1120, a triple angiokinase inhibitor, and pemetrexed in pretreated non-small cell lung cancer patients”. Clin Cancer Res 16 (10): 2881–9. doi:10.1158/1078-0432.CCR-09-2944. ISSN 1078-0432. PMID 20460487.
  9. du Bois, A.; J. Huober; P. Stopfer; J. Pfisterer; P. Wimberger; S. Loibl; V. L. Reichardt; P. Harter (2010). “A phase I open-label dose-escalation study of oral BIBF 1120 combined with standard paclitaxel and carboplatin in patients with advanced gynecological malignancies”. Ann Oncol 21 (2): 370–5. doi:10.1093/annonc/mdp506. ISSN 1569-8041. PMID 19889612.
  10. Xiang, Q. F.; F. Wang; X. D. Su; Y. J. Liang; L. S. Zheng; Y. J. Mi; W. Q. Chen; L. W. Fu (2011). “Effect of BIBF 1120 on reversal of ABCB1-mediated multidrug resistance”. Cell Oncol (Dordr) 34 (1): 33–44. doi:10.1007/s13402-010-0003-7. ISSN 2211-3436.
  11. “Boehringer Ingelheim – AGO-OVAR 12 / LUME-Ovar 1 Trial Information”. 2011.
  12. “Boehringer Ingelheim – LUME-Lung 2 Trial Information”. 2011.
  13. “Boehringer Ingelheim – LUME-Lung 1 Trial Information”. 2011.
  14. http://clinicaltrials.gov/ct2/results?term=++%09+BIBF+1120&phase=1
  15. http://clinicaltrials.gov/ct2/show/NCT00805194 Phase III LUME-Lung 1: BIBF 1120 Plus Docetaxel as Compared to Placebo Plus Docetaxel in 2nd Line Non Small Cell Lung Cancer
  16. http://clinicaltrials.gov/ct2/show/NCT01015118 Phase III BIBF 1120 or Placebo in Combination With Paclitaxel and Carboplatin in First Line Treatment of Ovarian Cancer
  17. http://clinicaltrials.gov/ct2/show/NCT01335477 Safety and Efficacy of BIBF 1120 at High Dose in Idiopathic Pulmonary Fibrosis Patients II
  18. “FDA approves Ofev to treat idiopathic pulmonary fibrosis”. 2014.
  19. F. Hilberg et al. Cancer Res. 2008, 68, 4774

    2. M. Reck et al. Ann. Oncol. 2011, 22, 1374

    3. M. Reck et al. J. Clin. Oncol. 2013 (suppl.), Abst LBA8011

    4. N. H. Hanna et al. J. Clin. Oncol. 2013, 2013 (suppl.), Abst 8034

    5. J.A. Ledermann et al. J. Clin Oncol. 2011, 29, 3798

    6. Glioblastoma: A. Muhac et al. J. Neurooncol. 2013, 111, 205

    7. O. Bouche et al. Anticancer Res. 2011, 31, 2271

    8. T. Eisen et al. J. Clin. Oncol. 2013 (suppl.), Abst. 4506

    MORE…………….

    Reference:

    [6]. Japan PMDA.

    [7]. Drug@FDA, NDA205832 Pharmacology Review(s).

    [8]. Med. Chem. 2015, 58, 1053-1063.

    [9]. Drug@EMA, EMEA/H/C/002569 Vargatef: EPAR-Assessment Report.

    [10]. Drug Des. Devel. Ther. 2015, 9, 6407-6419.

    [11]. Cancer Res. 2008, 68, 4774-4782.

    [12]. J. Med. Chem. 2009, 52, 4466-4480.

    [13]. J. Pharmacol. Exp. Ther. 2014, 349, 209-220.

    [14]. Clin. Cancer. Res. 2015, 21, 4856-4867.

    Merten, J.; et. al. Process for the manufacture of an indolinone derivative. US20110201812A1
    2. Roth, G. J.; et. al. 3-z-[1-(4-(n-((4-methyl-piperazin-1-yl)-methylcarbonyl)-n-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and the use thereof as a pharmaceutical composition. WO2004013099A1
    3. Roth, G. J.; et. al. Design, Synthesis, and Evaluation of Indolinones as Triple Angiokinase Inhibitors and the Discovery of a Highly Specific 6-Methoxycarbonyl-Substituted Indolinone (BIBF 1120). J Med Chem, 2009, 52(14), 4466-4480.

  20. ニンテダニブエタンスルホン酸塩
    Nintedanib Ethanesulfonate

    C31H33N5O4.C2H6O3S : 649.76
    [656247-18-6]
    US7119093 * Jul 21, 2003 Oct 10, 2006 Boehringer Ingelheim Pharma Gmbh & Co. Kg 3-Z-[1-(4-(N-((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and the use thereof as a pharmaceutical composition

     

    ///////////////

EPILEPSY AND SEIZURES ; 100% CURABLE BY AYURVEDA AND AYUSH TREATMENT


Aesculus … Hippocastani semen/cortex Aesculus hippocastanum L. Horse-Chestnut Seed/Bark


Aesculus hippocastanum flori.jpg

Aesculus

Illustration Aesculus hippocastanum0 clean.jpg
Aesculus hippocastanum

 

The genus Aesculus (/ˈɛskjʊləs/[1] or /ˈskjʊləs/) comprises 13–19 species of trees and shrubs native to the temperate Northern Hemisphere, with 6 species native to North America and 7–13 species native to Eurasia; there are also several hybridsAesculus exhibits a classical arcto-Tertiary distribution.[a] The genus has traditionally been treated in the ditypic family Hippocastanaceae along with Billia,[3] but recent phylogenetic analysis of morphological[4] and molecular data[5] has caused this family, along with the Aceraceae (Maples andDipteronia), to be included in the soapberry family (Sapindaceae).

Linnaeus named the genus Aesculus after the Roman name for an edible acorn. Common names for these trees include “buckeye” and “horse chestnut”. Some are also called white chestnut or red chestnut (as in some of the Bach flower remedies). In Britain, they are sometimes called conker trees because of their link with the game of conkers, played with the seeds, also called conkers. Aesculus seeds were traditionally eaten, after leaching, by the Jōmon people of Japan over about four millennia, until 300 AD.[6]

 

Aesculus glabra Ohio buckeye

Flower of Aesculus x carnea, the red Horse Chestnut

 

Description

Aesculus species have stout shoots with resinous, often sticky, buds; opposite, palmately divided leaves, often very large—to 65 cm (26 in) across in the Japanese horse chestnut Aesculus turbinata. The seeds of the Aesculus are traditionally used in a game called conkers in Europe. Species are deciduous or evergreen. Flowers are showy, insect- or bird-pollinated, with four or five petals fused into a lobedcorolla tube, arranged in a panicle inflorescence. Flowering starts after 80–110 growing degree days. The fruit matures to a capsule, 2–5 cm (2532–1 3132 in) diameter, usually globose, containing one to three seeds (often erroneously called a nut) per capsule. Capsules containing more than one seed result in flatness on one side of the seeds. The point of attachment of the seed in the capsule (hilum) shows as a large circular whitish scar. The capsule epidermis has “spines” (botanically: prickles) in some species, while other capsules are warty or smooth. At maturity, the capsule splits into three sections to release the seeds.[7][8][9]

The species of Aesculus include:

Cultivation

The most familiar member of the genus worldwide is the common horse chestnut Aesculus hippocastanum. The yellow buckeye Aesculus flava (syn. A. octandra) is also a valuable ornamental tree with yellow flowers, but is less widely planted. Among the smaller species, the bottlebrush buckeye Aesculus parviflora also makes a very interesting and unusual flowering shrub. Several other members of the genus are used as ornamentals, and several horticultural hybrids have also been developed, most notably the red horse chestnut Aesculus × carnea, a hybrid between A. hippocastanum and A. pavia.

Use in alternative medicine

Aesculus has been listed as one of the 38 substances used to prepare Bach flower remedies,[10] a kind of alternative medicine promoted for its effect on health. However according to Cancer Research UK, “there is no scientific evidence to prove that flower remedies can control, cure or prevent any type of disease, including cancer”.[11]

References

  1. Jump up^ This designation has as a part of it a term, ‘Tertiary‘, that is now discouraged as a formal geochronological unit by the International Commission on Stratigraphy.[2]
  1. Jump up^ Sunset Western Garden Book, 1995:606–607
  2. Jump up^ Ogg, James G.; Gradstein, F. M; Gradstein, Felix M. (2004). A geologic time scale 2004. Cambridge, UK: Cambridge University Press.ISBN 0-521-78142-6.
  3. Jump up^ Hardin, JW. 1957. A revision of the American Hippocastanaceae I. Brittonia 9:145-171.
  4. Jump up^ Judd, WS, RW Sanders, MJ Donoghue. 1994. Angiosperm family pairs. Harvard Papers in Botany. 1:1-51.
  5. Jump up^ Harrington, Mark G.; Edwards, Karen J.; Johnson, Sheila A.; Chase, Mark W.; Gadek, Paul A. (Apr–Jun 2005). “Phylogenetic inference in Sapindaceae sensu lato using plastid matK and rbcL DNA sequences”. Systematic Botany 30 (2): 366–382. doi:10.1600/0363644054223549JSTOR 25064067.
  6. Jump up^ Harlan, Jack R. (1995). The Living Fields: Our Agricultural Heritage (1. publ. ed.). Cambridge [u.a.]: Cambridge Univ. Press. p. 15. ISBN 0-521-40112-7.Harlan cites Akazawa, T & Aikens, CM, Prehistoric Hunter-Gathers in Japan (1986), Univ. Tokyo Press; and cites Aikens, CM & Higachi, T, Prehistory of Japan (1982), NY Academic Press.
  7. Jump up^ Hardin, JW. 1957. A revision of the American Hippocastanaceae I. Brittonia 9:145-171
  8. Jump up^ Hardin, JW. 1957. A revision of the American Hippocastanaceae II. Brittonia 9:173-195
  9. Jump up^ Hardin, JW. 1960. A revision of the American Hippocastanaceae V, Species of the Old World. Brittonia 12:26-38
  10. Jump up^ D. S. Vohra (1 June 2004). Bach Flower Remedies: A Comprehensive Study. B. Jain Publishers. p. 3. ISBN 978-81-7021-271-3. Retrieved 2 September 2013.
  11. Jump up^ “Flower remedies”Cancer Research UK. Retrieved September 2013.

External links

 

 

 

Aesculus hippocastanum is a large deciduous tree, commonly known as horse-chestnut or conker tree.

Gallery

  • Horse-chestnut planted as a feature tree in a park

  • Leaves and trunk

  • Foliage and flowers

  • Close-up of flowers

  • Trunk

  • Germination on lawn

Distribution

Aesculus hippocastanum is native to a small area in the Pindus Mountains mixed forests and Balkan mixed forests of South East Europe.[1]It is widely cultivated in streets and parks throughout the temperate world.

Growth

A. hippocastanum grows to 36 metres (118 ft) tall, with a domed crown of stout branches; on old trees the outer branches often pendulous with curled-up tips. The leaves are opposite and palmately compound, with 5–7 leaflets; each leaflet is 13–30 cm long, making the whole leaf up to 60 cm across, with a 7–20 cm petiole. The leaf scars left on twigs after the leaves have fallen have a distinctive horseshoe shape, complete with seven “nails”. The flowers are usually white with a small red spot; they are produced in spring in erect panicles 10–30 cm tall with about 20–50 flowers on each panicle. Usually only 1–5 fruit develop on each panicle; the shell is a green, spiky capsule containing one (rarely two or three) nut-like seeds called conkers or horse-chestnuts. Each conker is 2–4 cm diameter, glossy nut-brown with a whitish scar at the base.[2]

Etymology

The common name “horse-chestnut” (often unhyphenated) is reported as having originated from the erroneous belief that the tree was a kind of chestnut (though in fact only distantly related), together with the observation that eating the fruit cured horses of chest complaints[3] despite this plant being poisonous to horses.

Uses

Cultivation for its spectacular spring flowers is successful in a wide range of temperate climatic conditions provided summers are not too hot, with trees being grown as far north asEdmonton, AlbertaCanada,[4] the Faroe Islands,[5] ReykjavíkIceland and HarstadNorway.

In Britain and Ireland, the nuts are used for the popular children’s game conkers. During the First World War, there was a campaign to ask for everyone (including children) to collect horse-chestnuts and donate them to the government. The conkers were used as a source of starch for the fermentation via the Clostridium acetobutylicum method devised by Chaim Weizmann to produce acetone. Any starch plant would have done, but they chose to ask for conkers to avoid causing starvation by using food. Weizmann’s process could use any source of starch, but it was never particularly efficient and the factory only produced acetone for three months. The aim was to produce acetone for use as solvent which aided in the production of cordite, which was then used in military armaments.

A selection of fresh conkers from a horse-chestnut

The nuts, especially those that are young and fresh, are slightly poisonous, containing alkaloid saponins and glucosides. Although not dangerous to touch, they cause sickness when eaten; consumed by horses, they can cause tremors and lack of coordination.[6] Somemammals, notably deer, are able to break down the toxins and eat them safely.[citation needed]

Though the seeds are said to repel spiders there is little evidence to support these claims. The presence of saponin may repel insects but it is not clear whether this is effective on spiders.[7]

Horse-chestnuts have been threatened by the leaf-mining moth Cameraria ohridella, whose larvae feed on horse chestnut leaves. The moth was described from Macedonia where the species was discovered in 1984 but took 18 years to reach Britain.[8]

The flower is the symbol of the city of Kiev, capital of Ukraine.[9] Although the horse-chestnut is sometimes known as the buckeye, this name is generally reserved for the New World members of the Aesculus genus.

Medical uses

The seed extract standardized to around 20 percent aescin (escin) is used for its venotonic effect, vascular protection, anti-inflammatory and free radical scavenging properties.[10][11] Primary indication is chronic venous insufficiency.[11][12] A recent Cochrane Review found the evidence suggests that Horse Chestnut Seed Extract is an efficacious and safe short-term treatment for chronic venous insufficiency.[13]

Aescin reduces fluid leaks to surrounding tissue by reducing both the number and size of membrane pores in the veins.

Safety in medical use

Two preparations are considered; whole horsechestnut extract (whole HCE) and purified β-aescin. Historically, whole HCE has been used both for oral and IV routes (as of year 2001). The rate of adverse effects are low, in a large German study, 0.6%, consisting mainly of gastrointestinal symptoms. Dizziness, headache and itching have been reported. One serious safety issue is rare cases of acute anaphylactic reactions, presumably in a context of whole HCE. Purified β-aescin would be expected to have a better safety profile.

Another is the risk of acute renal failure, “when patients, who had undergone cardiac surgery were given high doses of horse chestnut extract i.v. for postoperative oedema. The phenomenon was dose dependent as no alteration in renal function was recorded with 340 μg kg−1, mild renal function impairment developed with 360 μg kg−1 and acute renal failure with 510 μg kg−1″.[14] This almost certainly took place in a context of whole HCE.

Three clinical trials were since performed to assess the effects of aescin on renal function. A total of 83 subjects were studied; 18 healthy volunteers given 10 or 20 mg iv. for 6 days, 40 in-patients with normal renal function given 10 mg iv. two times per day (except two children given 0.2 mg/kg), 12 patients with cerebral oedema and normal renal function given a massive iv. dose on the day of surgery (49.2 ± 19.3 mg) and 15.4 ± 9.4 mg daily for the following 10 days and 13 patients with impaired renal function due to glomerulonephritis or pyelonephritis, who were given 20–25 mg iv. daily for 6 days. “In all studies renal function was monitored daily resorting to the usual tests of renal function: BUN, serum creatinine, creatinine clearance, urinalysis. In a selected number of cases paraaminohippurate and labelled EDTA clearance were also measured. No signs of development of renal impairment in the patients with normal renal function or of worsening of renal function in the patients with renal impairment were recorded.” It is concluded that aescin has excellent tolerability in a clinical setting.[15]

Raw Horse Chestnut seed, leaf, bark and flower are toxic due to the presence of esculin and should not be ingested. Horse chestnut seed is classified by the FDA as an unsafe herb.[11] The glycoside and saponin constituents are considered toxic.[11]

Aesculus hippocastanum is used in Bach flower remedies. When the buds are used it is referred to as “chestnut bud” and when the flowers are used it is referred to as “white chestnut”.

Other chemicals

Quercetin 3,4′-diglucoside, a flavonol glycoside can also be found in horse chestnut seeds.[16] Leucocyanidinleucodelphinidin and procyanidin A2 can also be found in horse chestnut.

Anne Frank Tree

A famous specimen of the horse-chestnut was the Anne Frank Tree in the centre of Amsterdam, which she mentioned in her diary and which survived until August 2010, when a heavy wind blew it over.[17][18] Eleven young specimens, sprouted from seeds from this tree, were transported to the United States. After a long quarantine in Indianapolis, each tree was shipped off to a new home at a notable museum or institution in the United States, such as the 9/11 Memorial Park, Central H.S. in Little Rock, and two Holocaust Centers. One of them was planted outdoors in March 2013 in front of the Children’s Museum of Indianapolis, where they were originally quarantined. [1]

Bonsai

The horse-chestnut is a favourite subject for bonsai.[19]

Diseases

 

 

 

 

 

 

Name Language First published Last updated
Final Community herbal monograph on Aesculus hippocastanum L., cortex (English only) 27/06/2012  
Opinion of theHMPC on a Community herbal monograph on Aesculus hippocastanum L., cortex (English only) 27/06/2012  
Final assessment report on Aesculus hippocastanum L., cortex (English only) 27/06/2012  
Final list of references supporting the assessment of Aesculus hippocastanum L., cortex (English only) 27/06/2012  
Overview of comments received onCommunity herbal monograph on Aesculus hippocastanum L., cortex
Draft Community herbal monograph on Aesculus hippocastanum L., cortex (English only) 26/10/2011  
Draft assessment report on Aesculus hippocastanum L., cortex (English only) 26/10/2011  
Draft list of references supporting the assessment of Aesculus hippocastanum L., cortex (English only) 26/10/2011  
Procedure for calls for scientific data for use in HMPCassessment work
Latin name of the genus Aesculus
Latin name of herbal substance Hippocastani cortex
Botanical name of plant Aesculus hippocastanum L.
English common name of herbal substance Horse-chestnut bark
Status F: Assessment finalised
Date added to the inventory 06/05/2010
Date added to priority list 06/05/2010
Outcome of European assessment Community herbal monograph
Draft community herbal monograph on Aesculus hippocastanum L., semen (English only) 04/09/2008  
Draft list of references for assessment of: Hippocastani semen Aesculus hippocastanum L., semen (horse chestnut seed)
Latin name of the genus Aesculus
Latin name of herbal substance Hippocastani semen
Botanical name of plant Aesculus hippocastanum L.
English common name of herbal substance Horse-Chestnut Seed
Status F: Assessment finalised
Date added to the inventory 07/09/2006
Date added to priority list 07/09/2006
Outcome of European assessment Community herbal monograph
Name Language First published Last updated
Final community herbal monograph on Aesculus hippocastanum L., semen (English only) 16/07/2009  
Opinion of the Committee on Herbal Medicinal products on a community herbal monograph on Aesculus Hippocastanum L., semen (English only) 16/07/2009  
Final list of references for assessment of: Hippocastani semen Aesculus hippocastanum L., semen (horse chestnut seed) (English only) 16/07/2009  
Assessment report on Aesculus hippocastanum L., semen (English only) 16/07/2009  
Overview of comments received on community herbal monograph on Aesculus hippocastanum L., semen (EMEA/HMPC/225319/2008) (E
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Japanese knotweed extract (Polygonum cuspidatum) Resveratrol 98%


Shanghai Natural Bio-engineering Co., Ltd

 

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Shanghai Natural Bio-engineering Profile

Shanghai Natural Bio-engineering Co., Ltd, export branch of Hunan Keyuan Bio-products co., Ltd, established in 2003, is a professional large-scale high-tech manufacturer of raw materials for nutraceuticals, nutritional supplements, and pharmaceuticals. Plant extracts, Active Pharmaceutical Ingredient (API) & intermediates are our focused areas.Key products include resveratrol, curcumin,artemisinin,artemether,artesunate,dihydroartemisinin,Lumefantrine,etc

 

 

Japanese knotweed extract (Polygonum cuspidatum) Resveratrol 98%

Japanese knotweed extract (Polygonum cuspidatum) Resveratrol 98%

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Stanford Lee

Sales Manager at Shanghai Natural Bio-engineering Co., Ltd

 

synonyms Japanese knotweed extract, Polygonum cuspidatum, red wine extract, trans-3,5,4′-trihydroxystilbene, trans-Resveratrol, cis-resveratrol
CAS number 501-36-0
Latin Name Polygonum cuspidatum
Botanical source 1.Japanese knotweed plant Polygonum cuspidatum
2. red wine
3. red grape extracts
Molecular Formula C14H12O3
Molecular weight 228.24
Appearance white powder with slight yellow
Solubility in water 0.03 g/L
Dosage 500mg
Key benefits Anti-aging, Anti-Cancer, cardiovascular support, regulate estrogen level, weight loss
Applied industry Sports nutrition, nutraceuticals, cosmetics

What is resveratrol?

When talk about resveratrol, we have to mention red wine since resveratrol is first popularly known in red wine. In fact, resveratrol was actually first isolated in 1940 from white hellebore roots by the Japanese scientist Michio Takaoka. Red wine, in moderation, has long been thought of as heart healthy. However, the most popular source of resveratrol is from Japanese knotweed extract (Latin name:Polygonum cuspidatum)

Resveratrol (3,5,4′-trihydroxystilbene) is a polyphenolic phytoalexin. It is a stilbenoid, a derivate of stilbene, and is produced in plants with the help of the enzyme stilbene synthase.

Resveratrol exists as two geometric isomers: “cis-” (“Z”) and “trans-” (“E”). The ”trans-” form can undergo isomerisation to the “cis-” form when exposed to ultraviolet irradiation. Trans-resveratrol in the powder form was found to be stable under “accelerated stability” conditions of 75% humidity and 40 degrees C in the presence of air. Resveratrol content also stayed stable in the skins of grapes and pomace taken after fermentation and stored for a long period.

Sources of resveratrol

The resveratrol in red wine comes from the skin of grapes used to make wine. Because red wine is fermented with grape skins longer than is white wine, red wine contains more resveratrol. Simply eating grapes, or drinking grape juice, has been suggested as one way to get resveratrol without drinking alcohol. Red and purple grape juices may have some of the same heart-healthy benefits of red wine.

Other foods that contain some resveratrol include peanuts, blueberries and cranberries. It’s not yet known how beneficial eating grapes or other foods might be compared with drinking red wine when it comes to promoting heart health. The amount of resveratrol in food and red wine can vary widely.

Benefits of taking reveratrol supplements

Numerous studies have been conducted regarding various purported resveratrol benefits. Studies have primarily been conducted on laboratory animals, and while human search is very promising, is still in its earliest stages. Current research into resveratrol benefits points to resveratrol having amazing anti-aging properties, hence dubbed “The Fountain of Youth.” Many other key benefits such as cardiovascular effects, anti-cancer, estrogen regulating effects are mentioned here.

1.Resveratrol and its anti-aging benefits

The study by Harvard Medical School researchers shows that resveratrol stimulates production of SIRT1, a serum that blocks diseases by speeding up the cell’s energy production centers known as mitochondria.

Resveratrol affects the activity of enzymes called sirtuins. Sirtuins control several biological pathways and are known to be involved in the aging process. Resveratrol is only one of many natural and synthetic sirtuin-activating compounds (STACs) now known. Certain metabolic diseases, including type 2 diabetes and heart disease, tend to strike as we age. In animal studies, severely restricting calories can help prevent some of these diseases. Over a decade ago, researchers found that resveratrol can mimic calorie restriction in some ways and extend the lifespans of yeast, worms, flies and fish.

2.Resveratrol and cardiovascular benefits

Resveratrol is famous for its Cardioprotective effects.According to Wikipedia, moderate drinking of red wine has long been known to reduce the risk of heart disease. This is best known as “the French paradox”.

Studies suggest resveratrol in red wine may play an important role in this phenomenon. It achieves the effects by the following functions: (1) inhibition of vascular cell adhesion molecule expression;(2) inhibition of vascular smooth muscle cell proliferation;(3) stimulation of endolethelial nitric oxide synthase (eNOS) activity;(4) inhibition of platelet aggregation;and (5) inhibition of LDL peroxidation.

The cardioprotective effects of resveratrol also are theorized to be a form of preconditioning—the best method of cardioprotection, rather than direct therapy.Study into the cardioprotective effects of resveratrol is based on the research of Dipak K. Das, however, who has been found guilty of scientific fraud and many of his publications related to resveratrol have been retracted. A 2011 study concludes, “Our data demonstrate that both melatonin and resveratrol, as found in red wine, protect the heart in an experimental model of myocardial infarction via theSAFE pathway.”

Resveratrol, a polyphenol in red wine, induces nitric oxide (NO) synthase, the enzyme responsible for the biosynthesis of NO, in cultured pulmonary artery endothelial cells, suggesting that Resveratrol could afford cardioprotection by affecting the expression of nitric oxide synthase.

3.Reveratrol and anti-cancer benefits

Experts already claim it can help you beat cancer – from brain tumours to breast, colon, prostate cancers and many more. Resveratrol is being studied to see how it affects the initiation, promotion, and progression of cancer. With regard to tumor initiation, it has been shown to act as an antioxidant by inhibiting free radical formation and as an anti-mutagen in rat models. Studies related to progression have found that resveratrol induced human promyelocytic leukemia cell differentiation, inhibited enzymes that promote tumor growth, and exerted antitumor effects in neuroblastomas. Noting that in animal studies, resveratrol was effective against tumors of the skin, breast, gastrointestinal tract, lung, and prostate gland. Memorial Sloan-Kettering, the American pillar of cancer treatment, conducted research on theinflammatory effects on cells leading to cancer. It is widely known that an enzyme, COX-2, lies behind the stimulation of localised hormones (eicosanoids) causing inflammation, the precursor to cancer. In the research Resveratrol completely turned off the COX-2 driver. MD Anderson´s studies have shown this same anti-inflammatory benefit too. Plus, after conversion in the liver to a sulphated form the compound can attack several of the steps in the cancer process even killing cancer cells.

4. The Benefits of Resveratrol Weight Loss

Resveratrol is actually a very popular nutrient that has been shown on Dr. Oz, Oprah, Barbara Walters, and a number of other national television shows. It is quickly becoming one of the country’s best natural supplements.

How does Resveratrol help you lose weight? Resveratrol on its own will not be effective at helping you to lose weight, but you have to use it in conjunction with exercise and a proper diet if you really want to obtain the maximum benefits from the supplement.

However, the vitamin, when in concentrated form, has been proven to help speed up the metabolism. This speeding up of the metabolism causes the body to metabolize and process to food consumed faster, which causes the calories in the food to be used more effectively. When the body metabolizes food faster, there is less risk of excess calories being stored in the body in the form of fat.

However, in order to ensure that Resveratrol actually works, you need to take sufficient amounts of the vitamin. The supplement is effective because it is a concentrated form of the helpful vitamin, and taking the supplement is the best way to ensure that Resveratrol works effectively in helping you shed those excess pounds.

Another way Resveratrol helps you to lose weight is through reducing the amounts of estrogen that your body produces. Estrogen increases body fat and decreases muscle mass, so reducing the amounts of estrogen produced by your body will help you lose weight and build muscle. Taking Resveratrol can be a good way to ensure that your body doesn’t produce the amounts of estrogen that will keep it from building muscle.

Side Effects of taking resveratrol supplements

Because there have been very few studies conducted on resveratrol in humans, doctors still can’t confirm what adverse effects these supplements might have on people over the long term. So far, studies have not discovered any severe side effects, even when resveratrol is taken in large doses. However, resveratrol supplements might interact with blood thinners such as warfarin (Coumadin), and nonsteroidal anti-inflammatory medications such as aspirin and ibuprofen, increasing the risk for bleeding.

Like other supplements, resveratrol isn’t regulated by the FDA, so it’s difficult for consumers to know exactly what they’re getting when they buy a bottle, or whether the product is actually effective.

Dosage of resveratrol supplements

There also isn’t any specific dosage recommendation, and dosages can vary from supplement to supplement. The dosages in most resveratrol supplements are typically far lower than the amounts that have been shown beneficial in research studies. Most supplements contain 250 to 500 milligrams of resveratrol. To get the equivalent dose used in some animal studies, people would have to consume 2 grams of resveratrol (2,000 milligrams) or more a day.

Fallopia japonica, commonly known as Japanese knotweed, is a large, herbaceous perennial plant of the family Polygonaceae, native toEastern Asia in Japan, China and Korea. In North America and Europe the species is very successful and has been classified as aninvasive species in several countries. Japanese knotweed has hollow stems with distinct raised nodes that give it the appearance ofbamboo, though it is not closely related. While stems may reach a maximum height of 3–4 m each growing season, it is typical to see much smaller plants in places where they sprout through cracks in the pavement or are repeatedly cut down. The leaves are broad oval with a truncated base, 7–14 cm long and 5–12 cm broad,[1] with an entire margin. The flowers are small, cream or white, produced in erectracemes 6–15 cm long in late summer and early autumn.

Closely related species include giant knotweed (Fallopia sachalinensis, syn. Polygonum sachalinense) and Russian vine (Fallopia baldschuanica, syn. Polygonum aubertii, Polygonum baldschuanicum).

Other English names for Japanese knotweed include fleeceflower, Himalayan fleece vine, monkeyweed, monkey fungus, Hancock’s curse, elephant ears, pea shooters, donkey rhubarb (although it is not a rhubarb), sally rhubarb, Japanese bamboo, American bamboo, and Mexican bamboo (though it is not a bamboo). In Chinese medicine, it is known as Huzhang (Chinese: 虎杖; pinyin: Hǔzhàng), which translates to “tiger stick.” There are also regional names, and it is sometimes confused with sorrel. In Japanese, the name is itadori (虎杖, イタドリ?).[2]

Old stems remain in place as new growth appears

A hedgerow made up of roses and Japanese knotweed in Caersws, Wales in 2010

Erect inflorescence

Invasive species

It is listed by the World Conservation Union as one of the world’s worst invasive species.[3]

The invasive root system and strong growth can damage concrete foundations, buildings, flood defences, roads, paving, retaining walls and architectural sites. It can also reduce the capacity of channels in flood defences to carry water.[4]

It is a frequent colonizer of temperate riparian ecosystems, roadsides and waste places. It forms thick, dense colonies that completely crowd out any other herbaceous species and is now considered one of the worst invasive exotics in parts of the eastern United States. The success of the species has been partially attributed to its tolerance of a very wide range of soil types, pH and salinity. Its rhizomes can survive temperatures of −35 °C (−31 °F) and can extend 7 metres (23 ft) horizontally and 3 metres (9.8 ft) deep, making removal by excavation extremely difficult.

The plant is also resilient to cutting, vigorously resprouting from the roots. The most effective method of control is by herbicideapplication close to the flowering stage in late summer or autumn. In some cases it is possible to eradicate Japanese knotweed in one growing season using only herbicides. Trials in the Queen Charlotte Islands (Haida Gwaii) of British Columbia using sea water sprayed on the foliage have demonstrated promising results, which may prove to be a viable option for eradication where concerns over herbicide application are too great.[citation needed]

Two biological pest control agents that show promise in the control of the plant are the psyllid Aphalara itadori[5] and a leaf spotfungus from genus Mycosphaerella.[6]

New Zealand

It is classed as an unwanted organism in New Zealand and is established in some parts of the country.[7]

United Kingdom

In the UK, Japanese Knotweed is established in the wild in many parts of the country and creates problems due to the impact on biodiversity, flooding management and damage to property. It is an offence under section 14(2) of the Wildlife and Countryside Act 1981 to “plant or otherwise cause to grow in the wild” any plant listed in Schedule nine, Part II to the Act, which includes Japanese knotweed. It is also classed as “controlled waste” in Britain under part 2 of the Environmental Protection Act 1990. This requires disposal at licensed landfill sites. The species is expensive to remove; Defra‘s Review of Non-native Species Policy states that a national eradication programme would be prohibitively expensive at £1.56 billion.[8]

The decision was taken on 9 March 2010 in the UK to release into the wild a Japanese psyllid insect, Aphalara itadori.[9] Its diet is highly specific to Japanese knotweed and shows good potential for its control.[10][11]

In Scotland, the Wildlife and Natural Environment (Scotland) Act 2011 came into force in July 2012 that superseded the Wildlife and Countryside Act 1981. This act states that is an offence to spread intentionally or unintentionally Japanese knotweed (or other non-native invasive species).

North America

The weed can be found in 39 of the 50 United States[12] and in six provinces in Canada. It is listed as an invasive weed in Maine,Ohio, Vermont, Virginia, West Virginia, New York, Alaska, Pennsylvania, Michigan, Oregon and Washington state.[13]

Uses

A variegated variety of Japanese Knotweed, used as a landscape plant

Japanese knotweed flowers are valued by some beekeepers as an important source of nectar for honeybees, at a time of year when little else is flowering. Japanese knotweed yields a monofloral honey, usually called bamboo honey by northeastern U.S. beekeepers, like a mild-flavored version of buckwheat honey (a related plant also in the Polygonaceae).

The young stems are edible as a spring vegetable, with a flavor similar to extremely sour rhubarb. In some locations, semi-cultivating Japanese knotweed for food has been used as a means of controlling knotweed populations that invade sensitive wetland areas and drive out the native vegetation.[14] It is eaten in Japan as sansai or wild foraged vegetable.

Similarly to rhubarb, knotweed contains oxalic acid, which when eaten may aggravate conditions such as rheumatism, arthritis, gout, kidney stones or hyperacidity.[15]

Both Japanese knotweed and giant knotweed are important concentrated sources of resveratrol and its glucoside piceid,[16] replacing grape byproducts. Many large supplement sources of resveratrol now use Japanese knotweed and use its scientific name in the supplement labels. The plant is useful because of its year-round growth and robustness in different climates.[17]

This antique locomotive at Beekbergen,Netherlands is overgrown by knotweed. A few years before, it was free of knotweed

Control

Japanese knotweed has a large underground network of roots (rhizomes). To eradicate the plant the roots need to be killed. All above-ground portions of the plant need to be controlled repeatedly for several years in order to weaken and kill the entire patch. Picking the right herbicide is essential, as it must travel through the plant and into the root system below. Glyphosate is the best active ingredient in herbicide for use on Japanese knotweed as it is ’systemic’; it penetrates through the whole plant and travels to the roots.

Digging up the rhizomes is a common solution where the land is to be developed, as this is quicker than the use of herbicides, but safe disposal of the plant material without spreading it is difficult; knotweed is classed as controlled waste in the UK, and disposal is regulated by law.Digging up the roots is also very labor-intensive and not always efficient. The roots can go to up to 10 feet (3 meters) deep, and leaving only a few inches of root behind will result in the plant quickly growing back.

Covering the affected patch of ground with a non-translucent material can be an effective follow-up strategy. However, the trimmed stems of the plant can be razor sharp and are able to pierce through most materials. Covering with non-flexible materials such as concrete slabs has to be done meticulously and without leaving even the smallest splits. The slightest opening can be enough for the plant to grow back.

More ecologically-friendly means are being tested as an alternative to chemical treatments. Soil steam sterilization [18] involves injecting steam into contaminated soil in order to kill subterranean plant parts. Research has also been carried out on Mycosphaerella leafspot fungus, which devastates knotweed in its native Japan. This research has been relatively slow due to the complex life cycle of the fungus.[19]

Research has been carried out by not-for-profit inter-governmental organisation CABI in the UK. Following earlier studies imported Japanese knotweed psyllid insects (Aphalara itadori), whose only food source is Japanese knotweed, were released at a number of sites in Britain in a study running from 1 April 2010 to 31 March 2014. In 2012, results suggested that establishment and population growth were likely, after the insects overwintered successfully.[20][21]

Detail of the stalk

Controversy

In the United Kingdom, Japanese Knotweed has received a lot of attention in the press as a result of very restrictive lending policies by banks and other mortgage companies. Several lenders have refused mortgage applications on the basis of the plant being discovered in the garden or neighbouring garden.[22] The Royal Institution of Chartered Surveyors published a report in 2012 in response to lenders refusing to lend “despite [knotweed] being treatable and rarely causing severe damage to the property.” [23]

There is a real lack of information and understanding of what Japanese Knotweed is and the actual damage it can cause. Without actual advice and guidance, surveyors have been unsure of how to assess the risk of Japanese Knotweed, which can result in inconsistent reporting of the plant in mortgage valuations. RICS hopes that this advice will provide the industry with the tools it needs to measure the risk effectively, and provide banks with the information they require to identify who and how much to lend to at a time when it is essential to keep the housing market moving.

—Philip Santo, RICS Residential Professional Group[23]

In response to this guidance, several lenders have relaxed their criteria in relation to discovery of the plant. As recently as 2012, the policy at the Woolwich (part of Barclays plc) was “if Japanese Knotweed is found on or near the property then a case will be declined due to the invasive nature of the plant.”[24][25] Their criteria have since been relaxed to a category-based system depending on whether the plant is discovered on a neighbouring property (categories 1 and 2) or the property itself (categories 3 and 4) incorporating proximity to the property curtilage and the main buildings. Even in a worst-case scenario (category 4), where the plant is “within 7 metres of the main building, habitable spaces, conservatory and/or garage and any permanent outbuilding, either within the curtilage of the property or on neighbouring land; and/or is causing serious damage to permanent outbuildings, associated structures, drains, paths, boundary walls and fences” Woolwich lending criteria now specify that this property may be acceptable if “remedial treatment by a Property Care Association (PCA) registered firm has been satisfactorily completed. Treatment must be covered by a minimum 10-year insurance-backed guarantee, which is property specific and transferable to subsequent owners and any mortgagee in possession.” [26] Santander have relaxed their attitude in a similar fashion (citation needed).

Property Care Association chief executive Steve Hodgson, whose trade body has set up a task force to deal with the issue, said: “japanese knotweed is not “house cancer” and could be dealt with in the same way qualified contractors dealt with faulty wiring or damp.”[27]

Japan

The plant is known as itadori (イタドリ, 虎杖?). The kanji expression is from the Chinese meaning “tiger staff”, but as to the Japanese appellation, one straightforward interpretation is that it comes from “remove pain” (alluding to its painkilling use),[28][29] though there are other etymological explanations offered.

It grows widely throughout Japan and is foraged as a wild edible vegetable (sansai), though not in sufficient quantities to be included in statistics.[30] They are called by such regional names as: tonkiba (Yamagata),[30] itazuiko (Nagano, Mie),[30] itazura (Gifu, Toyama, Nara, Wakayama, Kagawa),[30] gonpachi (Shizuoka, Nara, Mie, Wakayama),[30]sashi (Akita, Yamagata),[30] jajappo (Shimane, Tottori, Okayama),[30] sukanpo (many areas).

Young leaves and shoots, which look like asparagus, are used. They are extremely sour; the fibrous outer skin must be peeled, soaked in water for half a day raw or after parboiling, before being cooked.

Places in Shikoku such as central parts of Kagawa Prefecture [31] pickle the peeled young shoots by weighting them down in salt mixed with 10% nigari (magnesium chloride).Kochi also rub these cleaned shoots with coarse salt-nigari blend. It is said (though no authority is cited) that the magnesium of the nigari binds with the oxalic acid thus mitigating its hazard.[32]

A novel use for a related species known as oh-itadori (Polygonum sachalinense) in Hokkaido is feeding it to larvae of sea urchins in aquaculture.[33]

See also

References

  1. Jump up^ RHS. “RHS on Japanese Knotweed”. RHS. Retrieved 6 June 2014.
  2. Jump up^ “itadori”. Denshi Jisho — Online Japanese dictionary. Retrieved 9 March 2010.
  3. Jump up^ Synergy International Limited <http://www.synergy.co.nz> (2004-01-30). “IUCN Global Invasive Species Database”. Issg.org. Retrieved 2014-06-30.
  4. Jump up^ “Article on the costs of Japanese Knotweed”. Gardenroots.co.uk. Retrieved 2014-06-30.
  5. Jump up^ Matthew Chatfield (2010-03-14). “”Tell me, sweet little lice” Naturenet article on psyllid control of knotweed”. Naturenet.net. Retrieved 2014-06-30.
  6. Jump up^ Morelle, R. Alien invaders hit the UK. BBC News October 13, 2008.
  7. Jump up^ “Asiatic knotweed”. Biosecurity New Zealand. 14 January 2010. Retrieved 29 December 2012.
  8. Jump up^ “Review of non-native species policy”. Defra. Retrieved 14 July 2013.
  9. Jump up^ Morelle, Rebecca (2010-03-09). “BBC News”. BBC News. Retrieved 2014-06-30.
  10. Jump up^ Richard H. Shaw, Sarah Bryner and Rob Tanner. “The life history and host range of the Japanese knotweed psyllid, Aphalara itadori Shinji: Potentially the first classical biological weed control agent for the European Union”. UK Biological Control. Volume 49, Issue 2, May 2009, Pages 105-113.
  11. Jump up^ “CABI Natural control of Japanese knotweed”. Cabi.org. Retrieved 2014-06-30.
  12. Jump up^ PUSDA
  13. Jump up^ National Invasive Species Information Center. “USDA weed profile for Japanese knotweed”. Invasivespeciesinfo.gov. Retrieved 2014-06-30.
  14. Jump up^ “Pilot project of Bionic Knotweed Control in Wiesbaden, Germany”. Newtritionink.de. Retrieved 2014-06-30.
  15. Jump up^ “Japanese Knotweed”. Edible Plants. Retrieved 2014-06-30.
  16. Jump up^ Wang, H.; Liu, L.; Guo, Y. -X.; Dong, Y. -S.; Zhang, D. -J.; Xiu, Z. -L. (2007). “Biotransformation of piceid in Polygonum cuspidatum to resveratrol by Aspergillus oryzae”. Applied Microbiology and Biotechnology 75 (4): 763–768. doi:10.1007/s00253-007-0874-3. PMID 17333175. edit
  17. Jump up^ Pest Diagnostic Unit, University of Guelph[dead link]
  18. Jump up^ Soil-Steaming-Report, 03. Okt. 2009
  19. Jump up^ “Notes on Biological control and Japanese knotweed”. Gardenroots.co.uk. Retrieved 2014-06-30.
  20. Jump up^ “Testing the psyllid: first field studies for biological control of knotweed United Kingdom”. CABI. Retrieved 2014-06-30.
  21. Jump up^ “On CABI Web site, Japanese Knotweed Alliance: Japanese knotweed is one of the most high profile and damaging invasive weeds in Europe and North America”. Cabi.org. Retrieved 2014-06-30.
  22. Jump up^ Leah Milner Last updated at 11:30AM, July 8, 2013 (2013-07-08). “Japanese knotweed uproots home sales”. The Times. Retrieved 2014-06-30.
  23. ^ Jump up to:a b 05 Jul 2013 (2013-07-05). “RICS targets the root of Japanese Knotweed risk to property”. Rics.org. Retrieved 2014-06-30.
  24. Jump up^ “Woolwich Lending Criteria – Property Types”.
  25. Jump up^ “Japanese knotweed, the scourge that could sink your house sale”. The Guardian. 2014-09-08.
  26. Jump up^ “Residential Lending Criteria”. Woolwich. July 2014.
  27. Jump up^ “Brokers demand action on Japanese knotweed”. Mortgagesolutions.co.uk. 2013-08-14. Retrieved 2014-06-30.
  28. Jump up^ 日本國語大辞典 (Nihon kokugo daijiten) dictionary (1976)
  29. Jump up^ Daigenkai (大言海) dictionary, citing Wakunsai(『和訓菜』)
  30. ^ Jump up to:a b c d e f g MAFF 2004 山菜関係資料(Sansai-related material) (webpage pdf). Excerpted from “山菜文化産業懇話会報告書”
  31. Jump up^ “イタドリ”. 讃岐の食(Sanuki eating). 2001. Retrieved Apr 2012.
  32. Jump up^ Given in Japanese wiki article ja:イタドリ, traced to contribution 2006.2.17 (Fri) 16:23 by ウミユスリカ
  33. Jump up^ “北海道食材ものがたり21 ウニ”. 道新TODAY. Sept-1999 1999. Retrieved Apr 2012.

External links

Sage Kills 51% of Melanoma Cells in Vitro and Reduces Risk in Humans


Sage Kills 51% of Melanoma Cells in Vitro and Reduces Risk in Humans: The herb sage is rich in the powerful anti-cancer compound thujone, which in this study was shown to kill 51% of human melanoma cells in vitro. But does sage reduce melanoma risk in humans? Yes, according to a study out of the Italy, where this herb is often consumed as part of the traditional diet: people eating sage at least once weekly had 32% less risk of melanoma. Apart from thujone, this super-herb contains several other compounds with proven health benefits, including cineole, carnosol, caffeic acid and chlorogenic acid. Sage has been used in traditional medicine for centuries to treat a variety of conditions, and it’s many health benefits are now being confirmed by some remarkable new clinical trials. One trial showed that 333 mg of sage extract daily significantly improved memory performance in older adults while in another clinical trial, 60 drops daily of liquid extract significantly enhanced cognitive performance in patients with Alzheimer’s. Sage is also such a powerful natural antibacterial that one clinical trial (out of Switzerland) showed that a spray of sage + echinacea performed as well as chlorhexidine + lidocaine in treating sore throats! Sage can be consumed as supplements, prepared as a tea, or used generously as a herb in a variety of dishes.<br /><br />
#Sage #Herbs #Melanoma #Antibiotic #Alzheimer’s<br /><br />
http://www.ncbi.nlm.nih.gov/pubmed/21647317

Sage Kills 51% of Melanoma Cells in Vitro and Reduces Risk in Humans: The herb sage is rich in the powerful anti-cancer compound thujone, which in this study was shown to kill 51% of human melanoma cells in vitro.

But does sage reduce melanoma risk in humans? Yes, according to a study out of the Italy, where this herb is often consumed as part of the traditional diet: people eating sage at least once weekly had 32% less risk of melanoma. Apart from thujone, this super-herb contains several other compounds with proven health benefits, including cineole, carnosol, caffeic acid and chlorogenic acid.

Sage has been used in traditional medicine for centuries to treat a variety of conditions, and it’s many health benefits are now being confirmed by some remarkable new clinical trials. One trial showed that 333 mg of sage extract daily significantly improved memory performance in older adults while in another clinical trial, 60 drops daily of liquid extract significantly enhanced cognitive performance in patients with Alzheimer’s.

Sage is also such a powerful natural antibacterial that one clinical trial (out of Switzerland) showed that a spray of sage + echinacea performed as well as chlorhexidine + lidocaine in treating sore throats! Sage can be consumed as supplements, prepared as a tea, or used generously as a herb in a variety of dishes.
http://www.ncbi.nlm.nih.gov/pubmed/21647317

 

 

 

Sage

Sage – Nature Wonder Herb

(Salvia officinalis) is cultivated as a spice and medicinal herb. This plant is known from parts of Europe, especially the Balkans, where is used for obtaining essential oils.
The Latin name of the whole genus Salvia comes from the Latin word “salvare“, which means “rescue saving curing ” because the Romans 2000 years ago appreciated and used sage for healing.

sage

The effectiveness of the leaves is due primarily to the presence of etheric oil (1.5 – 2.5 percent), which has antimicrobial and anti-inflammatory action.

It has been proven that etheric oil destroys bacteria Eshericia colli, Schigela sonei, Salmonela, and has a slightly weaker activity against bacteria of a group of staphylococci and streptococci.

It is effective in destroying certain types of fungi as: cadida albicas, cadida krusei, cadidapseudotropicalis, torulopsis glabrata and cyptococcus eoformas.

sage-oil
Etheric sage oil is colorless or yellow-green liquid with an aromatic and bitter taste.
Because of this effect, sage is a useful herb for treating inflammation and infections of the mucous membranes in the mouth, gums and throat. For these diseases gargle from sage tea is recommended.
sage-Put 2 tablespoons of crushed dried sage leaves in 2 cups of boiling water water. Cover it and let it stay like that for 20 or 30 minutes, then drain it.

For treatment to be successful, you must do gargle regularly , every 3 hours .

Sage softens the mucous secretions from the inflamed mucosa of the respiratory organs. Because of that you can drink sage tea against bronchitis.

-The tea is prepared with 1 tablespoon dried leaves and 2 cups of boiling water. Drink it three times a day.

You should avoid long term drinking tea because etheric oil from sage contains toxic substance thujone.

Dry leaves are used as a spice because it improves the taste and scent of food, and helps the digestion too.
Tea can be used for improving the functions of bile and liver, because bitter substances and etheric oil increase the secretion of digestive juices in the body.
Sage tea has a diuretic effect, which is poorly expressed and due to the presence of flavonoids . It can help with chronic disease of urinary tract .

sage

From a long time ago is known that sage tea is very effective cure for sweating. This power of sage it’s explained by its effect on the nervous center which regulates the glands that secrete sweat.

Commonly is recommended against perspiration of neuromuscular origin or the heat waves that occur during menopause.
Applied on the skin , tea tightens skin and calms inflammation. Especially good for oily skin with open pores and irritated skin.

sage

Sage is a remarkable tool for whitening teeth, strengthening gums and aid in periodontitis. A small spoon of sage leaves is mixed with 1 drop of peppermint etheric oil and abit of baking soda. With this mixture rub the teeth and gums twice a week.

Golden Root (Rhodiola rosea)…….a queen of adaptogenic herbs


Rhodiola rosea a2.jpg

 Golden Root (Rhodiola rosea) – Also called Arctic Root or Roseroot, golden root is considered a queen of adaptogenic herbs. As one blogger puts it, “[Golden root] allows us to regulate our immune, physiological and neurological responses to stress, allowing us to survive not only rough environmental/weather challenges, but also to adapt and adjust our often neurotic mental habits and crazy social/political climates as well.

”The Russians use it to improve physical stamina and adapt to environmental stress. In Siberia, people still say, “Those who drink Rhodiola tea will live more than 100 years old.” The extract possesses positive mood enhancing and anti-stress properties with no detectable levels of toxicity. Golden root works by enhancing the body’s ability to make serotonin, dopamine, and other neurotransmitters that aid in happiness and stress-reduction.

 

Rhodiola rosea (commonly golden root, rose root, roseroot, Aaron’s rod, arctic root, king’s crown, lignum rhodium, orpin rose) is a perennial flowering plant in the family Crassulaceae. It grows in cold regions of the world, including much of the Arctic, the mountains ofCentral Asia, scattered in eastern North America from Baffin Island to the mountains of North Carolina, and mountainous parts of Europe, such as the Alps, Pyrenees, and Carpathian Mountains, Scandinavia, Iceland, Great Britain and Ireland. It grows on sea cliffs and on mountains[2] at altitudes up to 2280 meters.[where?][citation needed] Several shoots grow from the same thick root. Shoots may reach 5 to 35 cm in height. R. rosea is dioecious – having separate female and male plants.

History

The first time that R. rosea is described was from Dioscorides in De Materia Medica.

Uses

Plant

Some studies have found support for it having antidepressant effects.[3][4] It is not approved by the U.S. Food and Drug Administration (FDA) to cure, treat, or prevent any disease. In fact, the FDA has forcibly removed some products containing R. rosea from the market due to disputed claims that it treats cancer, anxiety, influenza, the common cold, bacterial infections, and migraines.[5]

R. rosea may be effective for improving mood and alleviating depression. Pilot studies on human subjects[6][7][8] showed it improves physical and mental performance, and may reduce fatigue.

In Russia and Scandinavia, R. rosea has been used for centuries to cope with the cold Siberianclimate and stressful life.[citation needed][9][10] Such effects were provided with evidence in laboratory models of stress using the nematode C. elegans,[11] and in rats in which Rhodiola effectively prevented stress-induced changes in appetite, physical activity, weight gain and the estrus cycle.[12]

The plant has been used in traditional Chinese medicine, where it is called hóng jǐng tiān (). The medicine can be used to prevent altitude sickness.[citation needed]

The aerial portion is consumed as food in some parts of the world, sometimes added to salads.[13]

Phytochemicals and potential health effects

Withering flower

Scientists have identified about 140 chemical compounds in the subterranean portions of R. rosea.[14] Rhodiola roots contain phenols,rosavin, rosin, rosarin, organic acids, terpenoids, phenolcarbonic acids and their derivatives, flavonoids, anthraquinones, and alkaloids.

The chemical composition of the essential oil from R. rosea root growing in different countries varies. For example, rosavin, rosarin and rosin at their highest concentration according to many tests can be found only in R. rosea of Russian origin; the main component of the essential oil from Rhodiola growing in Bulgaria are geraniol and myrtenol; in China the main components are geraniol and 1-octanol; and in India the main component is phenylethilic alcohol. Cinnamic alcohol was discovered only in the sample from Bulgaria.[15]

R. rosea contains a variety of compounds that may contribute to its effects,[16] including the class of rosavins that includes rosavin, rosarin, and rosin. Several studies have suggested that the most active components are likely to be rhodioloside and tyrosol,[17] with other components being inactive when administered alone, but showing synergistic effects when a fixed combination of rhodioloside, rosavin, rosarin and rosin was used.[18] Authentication, as well as potency, of R. rosea crude material and standardized extracts thereof are carried out with validated high-performance liquid chromatography analyses to verify the content of the marker constituents salidroside, rosarin, rosavin, rosin and rosiridin.[19]

Although rosavin, rosarin, rosin and salidroside (and sometimes p-tyrosol, rhodioniside, rhodiolin and rosiridin) are among suspected active ingredients of R. rosea, these compounds are mostly polyphenols. There is no evidence that these chemicals have any physiological effect in humans that could prevent or reduce risk of disease.[20]

Although these phytochemicals are typically mentioned as specific to Rhodiola extracts, there are many other constituent phenolic antioxidants, including proanthocyanidins,quercetin, gallic acid, chlorogenic acid and kaempferol.[21][22]

Dried R. rosea root

Animal tests have suggested a variety of beneficial effects for R. rosea extracts,[23] and there is some scientific evidence for its efficacy as a treatment for depression and fatigue [6][7][24][25] in humans.

Scientific evidence

R. rosea extract exerts an antifatigue effect that increases mental performance, particularly the ability to concentrate in healthy subjects[6][7][24] and burnout patients with fatigue syndrome.[25] Rhodiola significantly reduced symptoms of fatigue and improved attention after four weeks of repeated administration.[25] A 2007 clinical trial from Armenia showed significant effect for a Rhodiola extract in doses of 340–680 mg per day in male and female patients from 18 to 70 years old with mild to moderate depression. No side effects were demonstrated at these doses.[3] One study found inhibition of MAO-A and MAO-B.[26] Studies on whether Rhodiola improves physical performance have been inconclusive, with some studies showing some benefit,[27] while others show no significant difference.[28]

Two systematic reviews on R. rosea extracts concluded that the research evidence is contradictory, and definite conclusions over its efficacy to relieve mental and physical fatigue are hampered by the lack of rigorously-designed, well-controlled randomized control trials [29]

In clinical medical trials on people R. rosea extract has a positive effect on sensitive and fading skin improving overall skin condition.[30][full citation needed]

R. rosea promotes the release of norepinephrine from rat pineal corpus cavernosum smooth muscle cell and artery endothelium cell, which was correlated with its effect of resisting senility.[31] R. rosea extract has been found to increase the life span of fruit fly (Drosophila) by 24% independently of dietary restriction.[32]

R. rosea may enhance the detoxification of many toxic heavy metals.[33]

References

  1. Jump up^ “Rhodiola rosea – Plants For A Future database report”. http://www.pfaf.org. Retrieved 2008-02-23.
  2. Jump up^ Stace, C.A. (2010). New flora of the British isles (Third ed.). Cambridge, U.K.: Cambridge University Press. p. 138. ISBN 9780521707725.
  3. ^ Jump up to:a b Darbinyan V, Aslanyan G, Amroyan E, Gabrielyan E, Malmström C, Panossian A (2007). “Clinical trial of Rhodiola rosea L. extract in the treatment of mild to moderate depression”. Nord J Psychiatry 61 (5): 343–8. doi:10.1080/08039480701643290.PMID 17990195.
  4. Jump up^ Dwyer AV, Whitten DL, Hawrelak JA (March 2011). “Herbal medicines, other than St. John’s Wort, in the treatment of depression: a systematic review” (PDF). Altern Med Rev 16 (1): 40–9. PMID 21438645.
  5. Jump up^ See for example, Letter, dated April 21, 2005, Food and Drug Administration
  6. ^ Jump up to:a b c Shevtsov VA, Zholus BI, Shervarly VI, et al. (Mar 2003). “A randomized trial of two different doses of Rhodiola rosea extract versus placebo and control of capacity for mental work”. Phytomedicine 10 (2–3): 95–105. doi:10.1078/094471103321659780.PMID 12725561.
  7. ^ Jump up to:a b c Darbinyan V, Kteyan A, Panossian A, Gabrielian E, Wikman G, Wagner H (Oct 2000). “Rhodiola rosea in stress induced fatigue—a double blind cross-over study of a standardized extract with a repeated low-dose regimen on the mental performance of healthy physicians during night duty”. Phytomedicine 7 (5): 365–71. doi:10.1016/S0944-7113(00)80055-0. PMID 11081987.
  8. Jump up^ Ha Z, Zhu Y, Zhang X, et al. (Sep 2002). “[The effect of rhodiola and acetazolamide on the sleep architecture and blood oxygen saturation in men living at high altitude]”.Zhonghua Jie He He Hu Xi Za Zhi (in Chinese) 25 (9): 527–30. PMID 12423559.
  9. Jump up^ Azizov, AP; Seĭfulla, RD (May–Jun 1998). “[The effect of elton, leveton, fitoton and adapton on the work capacity of experimental animals].”. Eksperimental’naia i klinicheskaia farmakologiia 61 (3): 61–3. PMID 9690082.
  10. Jump up^ Darbinyan, V; Kteyan, A; Panossian, A; Gabrielian, E; Wikman, G; Wagner, H (Oct 2000). “Rhodiola rosea in stress induced fatigue–a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty.”. Phytomedicine : international journal of phytotherapy and phytopharmacology 7 (5): 365–71. doi:10.1016/S0944-7113(00)80055-0. PMID 11081987.
  11. Jump up^ Wiegant FA, Surinova S, Ytsma E, Langelaar-Makkinje M, Wikman G, Post JA (Jun 2008). “Plant adaptogens increase lifespan and stress resistance in C. elegans”.Biogerontology 10 (1): 27–42. doi:10.1007/s10522-008-9151-9. PMID 18536978.
  12. Jump up^ Mattioli L, Funari C, Perfumi M (May 2008). “Effects of Rhodiola rosea L. extract on behavioural and physiological alterations induced by chronic mild stress in female rats”.Journal of Psychopharmacology (Oxford) 23 (2): 130–42.doi:10.1177/0269881108089872. PMID 18515456.
  13. Jump up^ Saratikov A.S. (1974). Golden Root (Rhodiola Rosea) (2nd ed.). Publishing House of Tomsk University. p. 158.
  14. Jump up^ Panossian, A., Wikman, G. (2010). “Rosenroot (Roseroot): Traditional Use, Chemical Composition, Pharmacology, and Clinical Efficacy”. Phytomedicine 17 (5-6): 481–493.doi:10.1016/j.phymed.2010.02.002.
  15. Jump up^ Evstavieva L., Todorova M., Antonova D., Staneva J. (2010). “Chemical composition of the essential oils of Rhodiola rosea L. of three different origins”. Pharmacogn Mag. 6 (24): 256–258.
  16. Jump up^ Kucinskaite A, Briedis V, Savickas A (2004). “[Experimental analysis of therapeutic properties of Rhodiola rosea L. and its possible application in medicine]”. Medicina (Kaunas) (in Lithuanian) 40 (7): 614–9. PMID 15252224.
  17. Jump up^ Mao Y, Li Y, Yao N (Nov 2007). “Simultaneous determination of salidroside and tyrosol in extracts of Rhodiola L. by microwave assisted extraction and high-performance liquid chromatography”. J Pharm Biomed Anal 45 (3): 510–5. doi:10.1016/j.jpba.2007.05.031.PMID 17628386.
  18. Jump up^ Panossian A, Nikoyan N, Ohanyan N, et al. (Jan 2008). “Comparative study of Rhodiola preparations on behavioral despair of rats”. Phytomedicine 15 (1–2): 84–91.doi:10.1016/j.phymed.2007.10.003. PMID 18054474.
  19. Jump up^ Ganzera M, Yayla Y, Khan IA (April 2001). “Analysis of the marker compounds of Rhodiola rosea L. (golden root) by reversed phase high performance liquid chromatography”. Chem. Pharm. Bull. 49 (4): 465–7. doi:10.1248/cpb.49.465.PMID 11310675.
  20. Jump up^ Boudet AM (2007). “Evolution and current status of research in phenolic compounds”.Phytochemistry 68 (22–24): 2722–35. doi:10.1016/j.phytochem.2007.06.012.PMID 17643453.
  21. Jump up^ Yousef GG, Grace MH, Cheng DM, Belolipov IV, Raskin I, Lila MA (Nov 2006). “Comparative phytochemical characterization of three Rhodiola species”. Phytochemistry67 (21): 2380–91. doi:10.1016/j.phytochem.2006.07.026. PMID 16956631.
  22. Jump up^ Liu Q, Liu ZL, Tian X (Feb 2008). “[Phenolic components from Rhodiola dumulosa]”.Zhongguo Zhong Yao Za Zhi (in Chinese) 33 (4): 411–3. PMID 18533499.
  23. Jump up^ Perfumi M, Mattioli L (Jan 2007). “Adaptogenic and central nervous system effects of single doses of 3% rosavin and 1% salidroside Rhodiola rosea L. extract in mice”.Phytother Res 21 (1): 37–43. doi:10.1002/ptr.2013. PMID 17072830.
  24. ^ Jump up to:a b Spasov. A.A., Mandrikov, V.B., Mitonova, I.A., 2000b. The effect of Dhodaxonon psycho-physiologic and physical adaptation of students to the academic load. Experimental and Clinical Pharmacology 63 (1), 76-78.
  25. ^ Jump up to:a b c Olsson E.M.G., von Schéele B., Panossian A.G. (2009). “A randomized double-blind placebo controlled parallel group study of an extract of Rhodiola rosea roots as treatment for patients with stress related fatigue”. Planta medica 75 (2): 105–112.doi:10.1055/s-0028-1088346. PMID 19016404.
  26. Jump up^ van Diermen, D.; Marston, A.; Bravo, J.; Reist, M.; Carrupt, PA.; Hostettmann, K. (Mar 2009). “Monoamine oxidase inhibition by Rhodiola rosea L. roots.”. J Ethnopharmacol122 (2): 397–401. doi:10.1016/j.jep.2009.01.007. PMID 19168123.
  27. Jump up^ De Bock K, Eijnde BO, Ramaekers M, Hespel P (Jun 2004). “Acute Rhodiola rosea intake can improve endurance exercise performance”. Int J Sport Nutr Exerc Metab 14(3): 298–307. PMID 15256690.
  28. Jump up^ Walker TB, Altobelli SA, Caprihan A, Robergs RA (Aug 2007). “Failure of Rhodiola rosea to alter skeletal muscle phosphate kinetics in trained men”. Metab Clin Exp. 56(8): 1111–7. doi:10.1016/j.metabol.2007.04.004. PMID 17618958.
  29. Jump up^ Ishaque, Sana; Shamseer, Larrisa; Bukutu, Cecilia; Vohra, Sunita. “Rhodiola rosea for physical and mental fatigue: a systematic review”. BMC Complementary and Alternative Medicine 12 (1): 70. doi:10.1186/1472-6882-12-70. PMID 3541197.
  30. Jump up^ Diemant et al., 2008
  31. Jump up^ Effect of Rodiola on level of NO and NOS in cultured rats penile corpus cavernosum smooth muscle cell and artery endothelium cell Kong X., Shi F., Chen Y., Lu H., Yao M., Hu M. Chinese Journal of Andrology 2007 21:10 (6-11)
  32. Jump up^ Schriner, Samuel E.; Lee, Kevin; Truong, Stephanie; Salvadora, Kathyrn T.; Maler, Steven; Nam, Alexander; Lee, Thomas; Jafari, Mahtab; Englert, Christoph (21 May 2013). “Extension of Drosophila Lifespan by Rhodiola rosea through a Mechanism Independent from Dietary Restriction”. PLoS ONE 8 (5): e63886. doi:10.1371/journal.pone.0063886.
  33. Jump up^ Boon-Niermeijer, E.K.; van den Berg, A.; Wikman, G.; Wiegant, F.A.C. “Phyto-adaptogens protect against environmental stress-induced death of embryos from the freshwater snail Lymnaea stagnalis”. Phytomedicine 7 (5): 389–399. doi:10.1016/S0944-7113(00)80060-4.

External links

Gotu Kola (Centella asiatica), this herb is known for calming depressive episodes, strengthening cognitive function, and helping one deal with both mental and physical stress


Starr 020803-0094 Centella asiatica.jpg

Gotu Kola (Centella asiatica) – An antiseptic, antispasmodic, peripheral vasodilator, and nerving and relaxant, this herb is known for calming depressive episodes, strengthening cognitive function, and helping one deal with both mental and physical stress.

Centella asiatica, commonly known as centella and gotu kola, is a small, herbaceous, annual plant of the family Mackinlayaceae or subfamily Mackinlayoideae of family Apiaceae, and is native to wetlands in Asia.[2][3] It is used as a medicinal herb in Ayurvedic medicine,traditional African medicine, and traditional Chinese medicine. It is also known as the Asiatic pennywort or Indian pennywort in English, among various other names in other languages.

Description

Centella grows in tropical swampy areas.[4] The stems are slender, creeping stolons, green to reddish-green in color, connecting plants to each other. It has long-stalked, green, reniform leaves with rounded apices which have smooth texture with palmately netted veins. The leaves are borne on pericladial petioles, around 2 cm. The rootstock consists of rhizomes, growing vertically down. They are creamish in color and covered with root hairs.[5]

The flowers are white or pinkish to red in color, born in small, rounded bunches (umbels) near the surface of the soil. Each flower is partly enclosed in two green bracts. The hermaphrodite flowers are minute in size (less than 3 mm), with 5-6 corolla lobes per flower. Each flower bears five stamens and two styles. The fruit are densely reticulate, distinguishing it from species of Hydrocotyle which have smooth, ribbed or warty fruit.[3] The crop matures in three months, and the whole plant, including the roots, is harvested manually.

Habitat

Centella grows along ditches and in low, wet areas. In Indian and Southeast Asian centella, the plant frequently suffers from high levels of bacterial contamination, possibly from having been harvested from sewage ditches. Because the plant is aquatic, it is especially sensitive to pollutants in the water, which are easily incorporated into the plant.

Culinary use

Flowers and leaves centella asiatica

Bai bua bok served as a refreshing drink in Thailand

Centella is used as a leafy green in Sri Lankan cuisine, where it is called gotu kola. In Sinhalese, gotu is translated as “conical shape” andkola as “leaf”. It is most often prepared as malluma (මැල්ලුම), a traditional accompaniment to rice and curry, and goes especially well with vegetarian dishes, such as dhal, and jackfruit or pumpkin curry. It is considered quite nutritious. In addition to finely chopped gotu kola,malluma almost always contains grated coconut, and may also contain finely chopped green chilis, chili powder, turmeric powder and lime(or lemon) juice. A variation of the nutritious porridge known as kola kenda is also made with gotu kola by the Sinhalese people of Sri Lanka. Kola Kenda is made with very well-boiled red rice (with extra liquid), coconut milk and gotu kola, which is pureed. The porridge is accompanied with jaggery for sweetness. Centella leaves are also used in sweet “pennywort” drinks.

In Indonesia, the leaves are used for sambai oi peuga-ga, an Aceh type of salad, and is also mixed into asinan in Bogor.

In Vietnam and Thailand, this leaf is used for preparing a drink or can be eaten in raw form in salads or cold rolls. In Bangkok, vendors in the famous Chatuchak Weekend Market sell it alongside coconut, roselle, chrysanthemum, orange and other health drinks.

In Malay cuisine the leaves of this plant are used for ulam, a type of Malay salad.[6]

It is one of the constituents of the Indian summer drink thandaayyee.

In Bangladeshi cuisine mashed centella is eaten with rice and is popular for its medicinal properties.

 

 

Medicinal effects

According to the American Cancer Society, although centella is promoted for its health benefits, “available scientific evidence does not support claims of its effectiveness for treating cancer or any other disease in humans”.[7] However some research has shown a possible health benefit in the form of reduction of the progression of subclinical arterial lesions in low-risk asymptomatic subjects.[8]

Other names

In South Asia, other common names of centella include సరస్వతి ఆకు (sarswathi aku) in Telugu; കുടവൻ (kudavan), മുത്തിൾ (muththil), or കുടങ്ങൽ (kudangal) in Malayalam; থানকুনি (thankuni) in Bengali; ගොටුකොල (gotu kola) in Sinhala; मधुकपर्णी (mandukaparni) inSanskrit; ब्राम्ही / ब्राह्मी (brahmi) in Marathi: ಒಂದೆಲಗ (ondelaga) in Kannada; வல்லாரை (vallaarai) in Tamil; brahmi booti in Hindi; perookin Manipuri; মানিমুনি (manimuni) in Assamese; timare in Tulu; tangkuanteh in Paite; ब्रह्मबुटि (brahmabuti) or घोड टाप्रे (ghod-tapre) in Nepali; and खोलचा घायँ (kholcha ghyan) in Newari (Nepal Bhasa).

In India, particularly, it is popularly known by a variety of names: bemgsag, brahma manduki, brahmanduki, brahmi, ondelaga or ekpanni (south India, west India), sarswathi aku(Andhra Pradesh), gotu kola, khulakhudi, mandukparni, mandookaparni, or thankuni (Bengal), depending on region. Bacopa monnieri is the more widely known Brahmi; both have some common therapeutic properties in Vedic texts and are used for improving memory. C. asiatica is called brahmi particularly in north India,[9][10] although that may be a case of mistaken identity introduced during the 16th century, when brahmi was confused with mandukaparni, a name for C. asiatica.[11] [12] Probably the earliest study ofmandookaparni as medya rasayana (improving the mental ability) was carried out at the Dr. A. Lakshmipathy Research Centre (now under CCRAS).[13]

In Southeast Asia, it is known as ស្លឹកត្រចៀកក្រាញ់ (sleuk tracheakkranh) in Khmer; မြင်းခွာပင် (mying khwar ) in Burmese; ใบบัวบก (bai bua bok) in Thai; rau má (“mother vegetable”) in Vietnamese; pegagan or antanan in Indonesian; takip-kohol (literally “snail lid“)[14] or yahong yahong (“little bowl”) in Filipino; and pegagan or pegaga in Malay.

In East Asia, it is known as 雷公根 (lei gong gen; literally “thunder god’s root”) or 崩大碗 (“chipped big bowl”) in Chinese; and 병풀 (byeong-pul, literally “bottle/jar plant”) in Korean.

Folklore

Gotu kola is a minor feature in the longevity tradition of the T’ai chi ch’uan master Li Ching-Yuen. He purportedly lived to be 197 or 256, due in part to his usage of traditionalChinese herbs, including gotu kola.

See also

References

  1. Jump up^ “Pharmacological Review on Centella asiatica: A Potential Herbal Cure-all.”. Indian J Pharm Sci: 546–56. September 2010.
  2. Jump up^ United States Department of Agriculture. “Plant Profile for Centella asiatica”. Retrieved 15 July 2012 (Use Native Status Link on Page).
  3. ^ Jump up to:a b Floridata. Centella asiatica. Retrieved 15 July 2012.
  4. Jump up^ Meschino Health. “Comprehensive Guide to Gotu Kola (Centella asiatica)”. Retrieved 15 July 2012.
  5. Jump up^ “Leaf Extract Treatment During the Growth Spurt Period Enhances Hippocampal CA3 Neuronal Dendritic Arborization in Rats”. Evid Based Complement Alternat Med: 349–57. September 2006.
  6. Jump up^ “Nasi ulam”. Retrieved 2009-05-07.
  7. Jump up^ “Gotu Kola”. American Cancer Society. 28 November 2011. Retrieved August 2013.
  8. Jump up^ “Pycnogenol® and Centella Asiatica for asymptomatic atherosclerosis progression”.International Angiology. 33(1): 20–26. February 2014.
  9. Jump up^ Daniel, M. (2005). Medicinal plants: chemistry and properties. Science Publishers. p. 225. ISBN 978-1-57808-395-4.
  10. Jump up^ “In north India, however, brāhmī is commonly identified as Centella asiatica (Linn.) Urban, which in Malayalam is known as muttil. It seems that this identification of brāhmīas C. asiatica has been in use for long in northern India, as Hēmādri’s ‘Commentary on Aṣṭāṅgahṛdayaṃ (Āyuṛvēdarasāyanaṃ) treats maṇḍūkapaṛṇī (C. asiatica) as a synonym of brahmi.” Warrier, P K; V P K Nambiar, C Ramankutty, V.P.K. & Ramankutty, R Vasudevan Nair (1996). Indian Medicinal Plants: A Compendium of 500 Species, Volume 1. Orient Blackswan. p. 238. ISBN 978-81-250-0301-4.
  11. Jump up^ Khare, C. P. (2003). Indian Herbal Remedies: Rational Western Therapy, Ayurvedic, and Other Traditional Usage, Botany. Springer. p. 89. ISBN 978-3-540-01026-5.
  12. Jump up^ “Mandukaparni (Centella asiatica)”. National R & D Centre for Rasayana. Retrieved 15 August 2013.
  13. Jump up^ Appa Rao MVR, Srinivas K, Koteshwar Rao T. “The effect of Mandookaparni (Centella asiatica) on the general mental ability (medhya) of mentally retarded children”. J. Res Indian Med. 1973;8:9–16.
  14. Jump up^ “Takip-kohol / Centella asiatica / Pennyworth: Philippine Medicinal Herbs / Philippine Alternative Medicine”. Stuartxchange.org. Retrieved 2014-03-22.

External links

 

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