Kutakee (Picrorhiza kurroa)

Kutakee (Picrorhiza kurroa)


Introduction 
In the Ayurvedic system of medicine Kutakee, (Picrorhiza kurroa) was in vogue for the treatment of jaundice, asthma and heart ailments. It was also used for similar indications in China. 
Although apocynin was isolated from Kutakee (Picrorhiza kurroa) in 1971, Simons et al. isolated it to a pharmacologically useful level in 1990. Thereafter its ability to selectively block the formation of free radicals, reactive oxygen species, and peroxides in the body became well known to the medical fraternity. It was then, in true sense, Kutakee (Picrorhiza kurroa) was ‘proved’ to be ‘anti-inflammatory’ herb. Apocynin has since then been extensively studied for its capabilities and applications as a disease fighting agent. 
Based on the clinical data and ethnobotanical studies (the scientific study of the relationships between people and plants) Ashok B. Vaidya, D. S. Antarkar, Satyavati, M. Sirsat and Jayant Doshi eulogized (extolled) Kutakee (Kutakee (Picrorhiza kurroa)) as one among top ten plants for ‘liver care’. In fact Kutakee (Picrorhiza kurroa) does a lot more than just to offer hepatoprotection. [1] 
The modern research and eons of traditional usage suggest Kutakee (Picrorhiza kurroa) may be a valuable plant in treating a variety of human disorders. 
Mother Nature is wiser than the wisest of Nobel laureates. Will she not foster her children stumbling in ill health, rid them of ailments and help them attain and maintain good health? She will! Indeed she does!! She furnishes the wealth of healthcare plants for the wellbeing of mankind. Although the plant, Kutakee (Picrorhiza kurroa)is self regenerating; in our country, relentless and unregulated over-harvesting has threatened it to near extinction from the wild. Alas! Its domestic use is not regulated by any legal provision except in Uttar Pradesh, India. 
In China Kutakee (Picrorhiza kurroa) is included in the ‘China Plant Red Data Book of Rare and Endangered Plants’. It is listed as a "Category III species" under the Law of Medicinal Resources Protection. Article 15 states: ‘The medicinal parts of wild medicinal species under class 2 and 3 shall be exported in limited quantity, except stipulated by other State Regulations.’ [2], [3]
Because of the medicinal values of the plant attempts are made to prevent its extinction and develop methods of propagation. Its reproductive cycle has been studied for successful domestication. [4] 
I would say Kutakee (Picrorhiza kurroa) is a topnotch hepatoprotective herb!!


Other Names 
Botanical: Picrorhiza kurroa (also spelled Picrorhiza kurroaPicrorhiza kurroa Royle (Kutakee (Picrorhiza kurroa) Benth.), more properly known as P. lindleyana (Wall. Wettst)
Sanskrit: Kutakee, Katukaa, Katurohinee, Tikt, Tiktarohee, Sutiktaka, Kauka, Rohi
Assamese: Katki, Kutki
Chinese: Hu huang lian
English: Hellebore
Gujarati: Kadu, Katu
Hindi: Kutakee
Kannada: Katuka rohini       
Malayalam: Kaduk rohini, Katuka rohini
Marathi: Kutakee    
Oriya: Katuki
Pujjabi: Karru, Kaur
Tamil: Katuka rohini, Katuku rohini, Kadugurohini
Telugu: Karukarohini
Urdu: Kutki       [5], [6] 
AKA Indian gentian, Kuruwa, Kali-Kutakee or Black Kutakee. 

Taxonomic Classification 
Kingdom:  Plantae
(unranked):  Angiosperms
(unranked):  Eudicots
(unranked):  Asterids                                                       
Order:        Scrophulariaceae, Lamiales 
Division:     Magnoliophyta
Class:         Magnoliopsida
Family:      Scrophulariaceae, Plantaginaceae [7]
In Nighantu, two types are described:
(1) Katuka rohini (Picrorhiza kurroa)
(2) Ashoka rohini (Eucalyptus paniculata) 
Because of its medicinal properties, in Drawya-Guna-Wigyaana, Katuka rohini (Picrorhiza kurroa) is accepted as a medicinal plant. [8] 
Picrorrhiza kurorra belongs to Scrophulariaceae family which is a large family with 200 genera and 3000 species. [9] 
Picrorhiza kurroa Royale ex Bentham is the complete botanical name of Kutakee. It has two synonyms; (1) Picrorhiza lindleyana (Wall.) Steud. and (2) Veronica lindleyana Wall. 
In Greek “picros” means bitter and “rhiza” means root. (Picrorhiza= a bitter root). [10]
Geographical Distribution
Kutakee (Kutakee (Picrorhiza kurroa)) is a hairy perennial herb indigenous to the North-Western Himalayan region from Kashmir to Garhwal and Bhutan. It is also found in Sikkim, Nepal, West China, South-East Tibet and North Burma. In Himalayan region it is found at 3,000 to 5,000 meters of elevation, growing in rocky crevices, in moist and sandy soil. It grows in abundance in wild from alpine regions on rock and organic soils. [11], [12]
Plant Morphology
Macroscopic Morphology
The Plant

Kutakee (Picrorhiza kurroais a small, hairy, perennial, woody herb
occurring in cylindrical pieces which are 2 to 5 cm long and 4 to 8 mm                  thick. They sometimes terminate in the Stem or scaly leaf-bud.

Root thin, cylindrical, 5 to 10 cm long, 0.05 to 0.1 cm in diameter,
straight or slightly curved with a few longitudinal wrinkles and dotted
scars, mostly attached with rhizomes, dusty gray in color,

short, inner surface black with whitish xylem; odor pleasant, taste bitter.

Flowering stems: Scapes (a long, leafless stem rising directly from a bulb
or rhizome) ascending, stout,longer than leaves white or bluish. 
Rhizome is 2.5 to 8 cm long, thick, woody, subcylindrical, straight or
slightly curved, grayish-brown in color, surface rough due to longitudinal
wrinkles or furrows, circular scars of roots and bud scales and sometimes
roots attached, tip ends in a growing bud surrounded by tufted crown of    
leaves.  
Leaves are 4 to 10 cm long; at the base, flat; oval and sharply serrated
narrowed to a winged stalk and have a sharp apex. 
Flowers are white or pale purple or purplish blue, bisexual and borne on almost
leafless erect stems. They  are 8 mm, 5 lobed 
to the middle and with much longer stamens.
They bloom in June through August.   

Spikes (Inflorecence): 5-10cm long, cylindrical, 















Microscopic Structure
Rhizome- Shows 20-25 layers of cork consisting of elongated cells covered with suberine, a highly hydrophobic and a somewhat ‘rubbery’ material; primary cortex single layered with one or two small vascular bundles or absent in some cases; vascular bundles surrounded by a single layer of endodermis of thick walled cells; secondary phloem composed of phloem parenchyma and a few scattered fibers; cambium, a cylinder of unspecialized cells, 2-4 layered; secondary xylem consists of vessels and xylem  parenchyma; vessels vary in size and shape; xylem parenchyma thin walled and polygonal in shape; center occupied by a small pith consisting of thin walled round or oval cells; starch grains, measuring 25-104 microns in diameter abundantly found in all cells. 

Root- Young root shows single layered epidermis, epidermal cells elongate forming unicellular hairs; hypodermis single layered; cortex 8-14 layered, consisting of oval or polygonal thick-walled cells; stele, the central part of the root, enclosed by a single layered pericycle. 

Mature root shows 4-15 layers of cork, 1-2 layers of cork cambium; secondary phloem poorly developed, secondary xylem consists of vessels, tracheids (Tracheids are elongated cells that serve in the transport of water and minerals), parenchyma and fibers; vessels having varying size and shape, some cylindrical with tapering ends, some drum shaped with perforation on end walls or lateral walls; tracheids cylindrical with pointed ends; fibers a-septate, thick walled, lignified with tapering blunt chisel-like ends. 

Powder- Dusty gray; shows groups of fragments of cork cells, thick-walled, parenchyma, pitted vessels and fibers, round or oval starch grains measuring 25-104 microns in diameter. [18]

Parts Used

Root, bark, leaf, dried rhizome freed from attached rootlets and whole plant.

Phytochemistry

Kutakee (Picrorhiza kurroa) contains picroside I, II and III (6-feruloyl catalpol), kutkoside, monoterpene alkaloid, androsin, and apocynin; kutkin, a bitter glycosidal principle. Also isolated are D-mannitol, vanillic acidpicrorhizin, arvenin, kurrin, kuthinol, kutkiol, kutkoside, cucurbitacin, drosin, picein iridoid glycosides, minecoside  and nine cucurbitacins and some steroids kutkisterol. [19], [20], [21] 
Apocynin AKA acetovanillone, structurally related to vanillin is a solid natural organic compound with the faint odor of vanilla. It is soluble in hot water, alcohol, benzene, chloroform, and ether. It has melting point of 115 °C. 
From the roots of Kutakee (Picrorhiza kurroa), Q Jia et al isolated pikuroside, a novel iridoid having no anti-inflammatory activity. [22] 
From the seeds of Kutakee (Picrorhiza kurroa), Yanjun Zhang, David L DeWitt, Sorimuthu Murugesan, Muraleedharan G Nair isolated some novel tannins which inhibit cyclooxygenase and lipid-peroxidation. [23], [24]

Identity, Purity and Strength 

Foreign matter: Not more than 2 percent
Total ash: Not more than 7 percent
Acid-insoluble ash: Not more than 1 percent
Alcohol-soluble extractive: Not less than 10 percent
Water-soluble extractive: Not less than 20 percent

TLC pattern     

TLC of alcoholic extract of the drug on silica gel ‘G’ plate using Chloroform: Methanol (95:5) shows under UV light (366 nm) three fluorescent zones at Rf. 0.05 (blue); and 0.35 (green). 
On exposure to Iodine vapour nine spots appear at Rf. 0.10, 0.17, 0.21, 0.30, 0.37, 0.41, 0.62, 0.72 and 0.84 (all yellow)  
On spraying with 5% methonolic sulphuric acid reagent and heating the plate for about ten minutes at 105C seven spots appear at Rf. 0.05, 0.10, 0.17, 0.21, 0.30, 0.41 and 0.84 (all brownish gay) [25] 

Cytological Identity 

Recently chromosome number and reproductive behavior of Kutakee (Kutakee (Picrorhiza kurroa)) are reported. Meiosis is normal in the species with 2n=34 chromosomes. [26]

Genetic Study

By using DNA (RAPD), SCAR, ISSR, AFLP, SSR techniques accurate genetic identification of Kutakee (Picrorhiza kurroa) has been established [27]    

There are no specific guidelines regarding safety tests, permissible microbial limits in a given pharmaceutical preparation of Kutakee (Picrorhiza kurroa). However internationally accepted guidelines are as follows----

Safety Tests 

Heavy Metals:
Arsenic:          Not more than 5.0 mg/kg
Mercury:        Not more than 0.5mg/kg
Lead:              Not more than 10.0 mg/kg
Chromium:    Not more than 0.3 mg/kg 

Microbial Limits:

Total bacterial count:                                  Not more than 105cfu/g
Total yeast and mould count:                     Not more than 104cfu/g
Bile tolerant gram negative bacteria:          Not more than 104cfu/g 

Specific Pathogens: 

Salmonella spp:                          Absent in 25 g
Escherichia coli:                         Absent in 1g   
Staphylococcus aureus:             Absent in 1g          
Pseudomonas aeruginosa:        Absent in 1g

Properties and Pharmacology 

Ayurvedic Properties

Ganas (Classical Categories)
Charaka Ganas: Bhedaneeya (Laxative), Lekhaneeya (Weight reducer, Anti obesity), Stanyashodhan (Purifier of the breast milk), Tiktaskanda 
Sushruta+Ganas: Patolaadi, Pippalyaadi, Mustaadi 
Waagbhata: Patolaadi, Mustaadi, Pippalaadi [28] 

Energetics:

Rasa (Taste): Tikta (Bitter) .
Weerya/ Virya (Energy State): Sheeta (Cooling)
Wipaaka (End result, Post digestive effect): Katu (Acrid, Pungent,Piquant )
Prabhaawa (Special Effects, Prominent Effects): None
Gunas (Qualities): Laghu (Light), Rooksha (Dry)
Effects on Doshas: Pitta, Kapha; Kapha-Pitta-Shodhana
Actions on Dhatus (Tissues): Rasa (Lymph), Rakta (Blood), Meda (Fat)
Actions on Srotas (Systems): Praanawaha (Respiratory System), Annawaha (GI System), Pureeshawaha (Colorectal region), Rasawaha (Lymphatic System), Raktawaha (Hemopoetic System), Swedawaha (Sweat glands), Medowaha (Adipose System), Mootrawaha (Urinary System)

Ayurvedic Actions

Bhedana/Rechan – Laxative, increases bile.
Deepana - Appetizer
Hridya –Heart tonic, Beneficial to the heart, not often used for this
Jwaraghna - Anti-pyretic
Kaasahara –Antitussive
Krimighna –Anthelmintic
Kushthaghna - Antileprotic
Pramehaghna - Anti-diabetic
Shwaasahara –Rrelieves breathlessness (asthma) [29] 
Arshajit- Relieves fissure and piles
Daahajit- Relieves burning due to allergy, inflammation, (?burns)
Hridya- Beneficial to heart
Kapha, Pitta, Jwarahara- Relieves expectoration, antipyretic
Kushth-hara- Gives relief from leprosy 
When given in small doses, bitter taste of Kutakee stimulates the taste buds, increases appetite and stimulates liver. But in large doses (3 to 6 Grams) it is purgative 
Kutakee depresses heart resulting in bradycardia. Kutakee is diuretic. [30], [31]

Modern View 

The rhizome of Kutakee (Picrorhiza kurroa) is bitter tonic, antiperiodic (preventing regular recurrence of diseases such as in malaria), febrifuge, anti-oxidant, anti-inflammatory, immunomodulatory, stomachic, cholagogue, emetic and cathartic, emmenagogue, abortifacient and cardiotonic in large doses. It nourishes, strengthens and restores the body and the functions of the liver.  (Trophorestorative and adaptogen)

Kutkin: 

Kutkin, a bitter glycosidal principle is shown to be a mixed crystal of two C-9 iridoid glycosides-picroside I and kutakosid (kutkoside). In fact Kutkin is a mixture of Picrosides I and II
Molecular formula: Kutkin: C23H28O13 
Structural formula:





Molecular formula: Picroside I: C24H28O11    
Structural formula: Picroside I:
Molecular formula: Picroside II: C23H28O13
Structural formula: Picroside II:


www.sigmaaldrich.com/catalog/product/sigma/g0174

Molecular formula: Picroside III
Structural formula: Picroside III



http://www.sigmaaldrich.com/catalog/product/sigma/smb00154?lang=en&region=IN

Picrosides are involved in various vital bioactivities of cells. Picrosides play an important role in hepatoprotection. [34]
Picrosides I and II may become selective pharmacological tools for studying the MAP kinase (Mitogen-Activated Protein Kinase) -dependent signaling pathway in growth of neuritis (inflammation of the peripheral nerves) induced by many kinds of neuritogenic substances including bFGF (Basic Fifroblast Growth Factor) a pro-inflammatory molecule. [35]

Mechanism of action of Kutkin

1. Kutkin alters the structure of the membrane of the hepatocytes and prevents the penetration of toxins into the hepatocytes.
2. It stimulates the action of nucleolar polymerase A. This results in ribosomal protein synthesis which stimulates the regeneration of the liver cells and formation of new hepatocytes.
3. It modulates liver enzyme levels.
4. It shows anti-inflammatory action
5. It decreases lipid peroxidation and free radical production
6. It not only protects the liver from many hepatotoxic chemicals but also repairs and cures the liver damage. [36], [37]

Silymarin is a well known hepatoprotective agent. The mechanism of action of kutkin is similar to that of silymarin. However the studies have shown that kutkin is more potent than silymarin as far as hepatoprotective activity is concerned. [38]

Picroliv:


Picroliv is a standardized fraction from root and rhizome of Kutakee (Picrorhiza kurroa). In modern medicine it is commonly seen that a single chemical molecule exerts medicinal action. In case of Kutakee (Picrorhiza kurroa) instead of a single isolated molecule a group of components exerts the desired therapeutic effect. This is seen with “Picroliv”. “Picroliv” is obtained from 3-4 years old roots and rhizomes of Kutakee (Picrorhiza kurroa). It is an iridoid glycoside mixture containing 60% picroside I and kutkoside in the ratio of 1:1.5. It exhibits hepatoprotective activity. It shows choleretic and anticholestatic effects in rats, guinea pigs and cats treated with paracetamol and ethinyl estradiol. It shows antiviral and immune-stimulant activities without any untoward systemic effects. Its efficacy as a hepatoprotective agent is comparable to silymarin in rodent models of galactosamine, paracetamol and CCl4 induced hepatic damage. [39]

Oral administration of picroliv showed stimulation of nucleic acid and protein synthesis in the liver of rats. Results are comparable with silymarin. [40] 

Kutakee (Picrorhiza kurroa) acts as DNA topoisomerase inhibitor of Leishmania donovani and protects the liver from damage due to Leishmania donovani. [41], [42] 

Picroliv is useful in the treatment of vitiligo. This activity of picroliv is said to be due to its combined anti-inflammatory and hepatoprotective actions. [43] 


Study in BALB/c mice showed that administration of picroliv at 100 mg/kg bodyweight inhibited the development of sarcoma by 47% and at 200 mg/kg bodyweight by 53% on day 200 after administration of 20-MC (20-methylcholanthrene). DMBA (dimethylbenzanthracin) initiates dermal carcinogenesis and croton oil promotes it. Topical application of picroliv 1mg/ mouse half an hour prior to application of croton oil reduced the number of animals that developed papillomas to 48% and 5mg/mouse to 60%. There was also delay development of skin tumor in the group treated with picroliv. Oral administration of picroliv also prevented or delayed the development of tumors. [44]

Kutkoside:

Molecular formula: C23H28O13
Structural formula:



http://www.chemicalbook.com/ChemicalProductproperty_En/CB5755321.htm

Pharmacology of kutkoside is same as that of picroliv.

Androsin:

Molecular formula: C15H20O8
Structural formula:


https://pubchem.ncbi.nlm.nih.gov/compound/Androsin#section=Top

Androsin is antihistaminic and is used in pulmonary disorders. [47]

Apocynin

Molecular formula: C9H10O3
Structural formula:




https://en.wikipedia.org/wiki/Apocynin


Apocynin, also known as acetovanillone is a natural organic compound structurally related to vanillin. It has been isolated from a variety of plant sources and is being studied for its variety of pharmacological properties.
Apocynin is a solid with a melting point of 1150 C and the faint odor of vanilla. It is soluble in hot water, alcohol, benzene, chloroform and ether.   

Apocynin was first described by Oswald Schmiedeberg, a German pharmacologist in 1883. It was isolated from Kutakee (Picrorhiza kurroa) in 1971. In 1990, Simons et al isolated apocynin to a pharmacologically useful level. Apcynin has since then been extensively studied and used for its anti-inflammatory, anti-oxidant activities and for jaundice.   
The other phytochemicals present in Kutakee (Picrorhiza kurroa); D-mannitol, Kutkiol, kutkisterol and a ketone are identical with apocynin [49]

Mechanism of action:

Nicotinamide adenine dinucleotide phosphatate-oxidase (NADPH oxidase) is a membrane bound enzyme complex. NADPH oxidase reduces Oto superoxide (O2-) which can be used by the immune system to kill bacteria and fungi. Apocynin is a reversible inhibitor of NADPH oxidase activity and thus is effective in preventing the production of superoxide in human neutrophils. It does not however obstruct their phagocytic or other defense roles. Apocynin can be widely used as an inhibitor of NADPH oxidase without interfering in aspects of the immune system. [50]

The mechanism of NADPH oxidation by apocynin is not fully understood. However according to molecular biologists, apocynin is a prodrug that is converted by peroxidase-mediated oxidation to a dimer, which is more efficient than apocynin itself.
(Note: A dimer is a chemical entity consisting of two structurally similar monomers joined by bonds that can be either strong or weak.)  [51], [52] 

The in vitro anti-inflammatory effects of apocynin include the following:
1. The reduction of neutrophil oxidative burst
2. Neutrophil-mediated oxidative damage
3. The reduction of polymorphonuclear granulocyte chemotaxis
4. The inhibition of peroxynitrite
5. It prevents COX-2 expression
In experimental studies on rats, Daly et al showed that 20 hours after intra peritoneal administration of 120 mg/kg apocynin to rats, 80% was recovered unchanged in the urine of the animal. Side effects of apocynin are not known. After oral administration very low toxicity was observed in mice. This makes apocynin a “wonder molecule”! [53] 
Apocynin is useful in the treatment of various systemic disorders. As the aim of current work is to focus attention on the treatment of jaundice and liver disorders, its uses in other systemic disorders are discussed elsewhere.

Cucurbitacin:

Cucurbitacin is a triterpenoid substance. There are many varieties of cucrubitacins. Some of them are sterols, glucosides and may be of many more chemical groups. Of these, cucurbitacin-B (CuB), cucurbitacin-E (CuE) and cucurbitacin-Q (CuQ) show very potent anticancer activity. They are highly cytotoxic and possess very potent antitumor effects. The mechanism of cytotoxicity is nebulous and has not been elucidated to date. Probably it is multifactorial.
(A) Cucurbitacin E directly disrupts the cell membrane of prostate carcinoma cells. 
(B) Signal-transducer-and activator of transcription (STAT) is a family of seven proteins. STATs are cytoplasmic transcription factors. They are unique in their ability both to transduce (convert) extracellular signals and regulate transcription directly. In normal cells they regulate diverse physiological functions such as immune response, inflammation, proliferation, differentiation, development, cell survival, and apoptosis.

There are many STATs. Of these STAT3 is important, because when activated it is primarily involved in cell growth. Continued activation of STAT3 brings about mutations in the cell which culminates into carcinogenesis. Why STAT3 is activated continuously is not understood. Cucurbitacins suppress the activation of STAT3. Of these cucurbitacin Q is a selective STAT3- activation inhibitor showing potent antitumor activity.

(C) Cucurbitacin glucosides (B and E) exhibit pleiotropic effects on breast cancer cells. They arrest cell growth and induce apoptosis.  [54]

(D) The cytoskeleton is the skeleton or scaffolding of the cell. It is made up of proteins. Actin is the component of the cytoskeletal system which allows cell movements and cellular processes. Cucurbitacins disrupt the actin-cytoskeleton (collapse of actin), alter cell morphology and inhibit cell proliferation and gene expression of cancer cells resulting in their death. [55]
Cucurbitacins show the synergistic effect with known chemotherapeutic agents; such as doxorubicin, cisplatin and gemcitabine. Either singly or in combination cucurbitacins are now used in many centers of the world for the treatment of laryngeal carcinoma, Ca lung, Ca colon, squamous cell carcinoma etc.

Research workers induced arthritis and bone damage in Lewis rats. They then treated these rats with cucurbitacin R (Dose: 1mg/kg daily). The rats showed clinical improvement. The radiological signs of arthritis regressed. There was suppression of Tumor Necrosis Factor alpha in T lymphocytes and macrophages. Histologically there was reversal of arthritic changes and bone damage. [56]

Cucurbitacin-B protects the liver from acute liver injury induced by CCl4. (Yang Shi-jie et al Jilin University, Changchun 130021, China).

Cucurbitacin B protects the liver from oxidative stress and fibrosis induced by Schistosoma japonicum infection. (Xu Biao et al Wuhan 430035).

A detailed discussion on cucurbitacins is a subject for monograph. This is not intended here. Their pleiotropic actions will be taken advantage of tomorrow to treat many maladies. Hark and mark my words: Either in purified form or in herbal form as in Kutakee cucurbitacins might be anticancer agents of tomorrow! They might be used as monotherapy or in combination with other anticancer drugs mentioned above.

Kutakee (Picrorhiza kurroa) also contains monocyclic phenolic compounds like vanillic acid and apocynin; phenolic glycosides like picein and androsin, carbohydrates like D-mannitol, aromatic acids like cinnamic acid, vanillic acid and ferulic acid.  
The author regrets to find satisfactory information on drosin, picrorhizin, kurrin, kuthinol, kutkiol and kutkisterol. [57] 

Some testimonials from modern research:

General Pharmacology

The pharmacokinetic studies on rats showed a significant difference in oral bioavailability of picrosides from different preparations. The researchers claim that the analytical method developed by them and the pharmacokinetic parameters obtained would be helpful for the study of these compounds and quality control. [58]
Picrosides, the active phytochemicals of Kutakee (Picrorhiza kurroa) extract show very poor intestinal absorption; because they are sparingly soluble in water. To improve their bioavailability the researchers developed a nanoformulation of the plant extract by nanoprecipitation method.  [59]

In a bioavailability study, after oral administration to rats at a dose of 50mg/kg bodyweight, apocynin was rapidly absorbed. Peak plasma level was achieved in 5 minutes. Moreover the plasma levels were observed up to 48hours. The bioavailability of apocynin was found to be 8.3percent. In rats plasma protein binding was found to be 83.41-86.07 % and in human, plasma protein binding was 71.39-73.35 %. Apocynin was found to stable in gastric juice at pH 1.2, in intestine at pH 6.8. Apocynin did not convert to its diametric form diapocynin. [60]
Cellular adaptation to hypoxia involves regulation of specific genes such as VEGF (Vascular Endothelial Growth Factor), EPO (Erythropoetin) and HIF-1 (Hypoxia Inducible Factor-1).  The study of effect of picroliv on hypoxia-reoxigenation-injuries suggests that picroliv may offer a good protection againsn these injuries. The underlying mechanism may involve a novel signal transduction pathway.  [61]

Actions on the Skin

Leukoderma (vitiligo) causes depigmentation of the skin. According to Anderson and Voorhees vitiligo is a cell-mediated immunological disturbance and may be reversible. Kutakee (Picrorhiza kurroa) may potentiate photochemotherapy in vitiligo [62]

Picroliv is a standardized iridoid glycoside fraction isolated from the root and rhizome of Kutakee (Picrorhiza kurroa). It is a very potent anti-allergic and anti-anaphylactic agent. At a dose of 25mg/kg body weight picroliv inhibited cutaneous anaphylaxis in 82% of mice and in 50-85% of rats. Picroliv protected mast cells from degranulation in 60-80% cases. This action is dependent on concentration of the chemical. An experimental, in vitro test for hypersensitivity in which a strip of smooth muscle is removed from a sensitized animal and exposed to specific antigen, resulting in contraction is known as Schultz-Dale reaction. The effect of picroliv was also studied in sensitized guinea pig ileum (Schultz-Dale study). The study showed that picroliv inhibited Schulz-Dale response in sensitized guinea pig ileum. But picroliv could not relieve bronchospasm induced by histamine. This showed that picroliv does not have post-synaptic histamine blocking activity. [63]

Wound Healing

Wound healing is a complex process involving inflammation, granulation and remodeling granulation tissue. Angiogenesis palys a central role in wound healing. Picroliv improves neovascularization, re-epithelialization, migration of various cells such as endothelial cells, dermal myofibroblasts and fibroblasts in to the wound bed, thus accelerating the process of wound healing. Histological study showed increased vascular endothelial growth factor, number of microvessels and α-smooth muscle actin in granulation tissue. This study suggests that picroliv can be developed as a therapeutic angiogenic agent for various ischemic diseases. [64]

Anti-Inflammatory Activity

Anti-inflammatory capability of apocynin is attributed to its ability to selectively prevent the formation of reactive oxygen ions, and scavenge free radicals. Apocynin has been studied to determine its disease-fighting applications. In laboratory animals, apocynin inhibited the formation of thromboxane A2, but stimulated the release of prostaglandins E2 and F2. It inhibited platelet-aggregation. It inhibited neutrophil oxidative burst in vitro without affecting beneficial activities such as chemotaxis, phagocytosis, and intracellular bactericidal activity. It may also enhance T-cell, B-cell, and phagocytic function. Apocynin inhibited arachidonic acid-induced aggregation of bovine platelets possibly through inhibition of thromboxane formation. Apocynin from the root extract of Kutakee (Picrorhiza kurroa) may be a valuable tool in the development of new anti-inflammatory and anti-thrombotic drugs.  [65]
Kutakee (Picrorhiza kurroa) is a very potent anti-inflammatory agent. This action is by β adrenergic blockade. Cyclohexamide is an inhibitor of protein biosynthesis. Pretreatment with cyclohexamide reduces the anti-inflammatory effect of Kutakee (Picrorhiza kurroa). This suggests that the anti-inflammatory effect of Kutakee (Picrorhiza kurroa) is mediated through protein. Selective influence of Kutakee (Picrorhiza kurroa) on membrane linked activation events in inflammatory effector cells could be the basis of anti-inflammatory activity of the herb. [66]
In mice and rats Kutkin inhibited acetic acid induced vascular permeability and leukocyte migration. Picroside-I and Kutkoside are scavengers of superoxide anions.

To evaluate anti-inflammatory activity of Kutakee (Picrorhiza kurroa) in mice, formalin was injected to induce chronic inflammation. They were then treated with extracts of the plant administered orally to mice at 125, 250 and 500mg/kg body weight once a day for 10 days. The results showed that inflammatory changes decreased dramatically at all three doses. The anti-inflammatory effects were slightly less than those of dexamethasone. [67]

Nuclear factor-κB (NF-κB) plays a major role in inflammation. In an experimental study on inflammation, researchers found that picroliv inhibited NF-κB activated inflammation. (IκB-kinase is an enzyme complex that is involved in propagating the cellular response toinflammation). Picroliv also inhibited the activation of IκBA-kinase, leading to inhibition of phosphorylation and degradation of IκBA. Picroliv also inhibited phosphorylation and nuclear translocation of p65. Picroliv directly inhibits the binding of p65 to DNA. Thus picroliv exerts anti-inflammatory activity by acting on various inflammatory pathways.  [68]

Antioxidant Activity

Ethanol, ethyl acetate and butanol extracts of leaves of Kutakee (Picrorhiza kurroa) were evaluated for antioxidant activity. All extract showed antioxidant activity but butanol and ethyl acetate showed greater antioxidant activity than that of ethanol extract. [69]

By employing radical scavenging assays aqueous and methanolic extracts of Kutakee (Picrorhiza kurroa) were shown to exhibit antioxidant activity. The study concludes that Kutakee (Picrorhiza kurroa) possesses diverse therapeutic potential which might be useful in the development of new drugs or their preccursors.  [70] 
The powerful antioxidant activity of Kutakee (Picrorhiza kurroa) is attributed to apocynin, a catechol that can prevent neutrophil oxidative burst.[71]

Kutakee (Picrorhiza kurroa) possesses a strong nitric oxidescavenging property. This makes it a potent antioxidant therapeutin agent. [72]

In a study, picroliv and two glycosides viz. picroside-I and kutkoside inhibited non-enzymatic generation of O2-anions which makes them powerful antioxidants. [73]

Resuscitation from hemorrhagic shok initiates profound changes in the liver that can culminate into target organ damage and resultant dysfunction after hemorrhagic shock. Pretreatment with 12mg/kg body weight of picroliv for 7 days, protects the liver, inhibits lipid peroxidation and nitric oxide release that occurs after hemorrhage- resuscitation. These effects are due to antioxidant activity of picroliv. [74]

Immunomodulatory activity

Kutakee (Picrorhiza kurroais a potent immunostimulant of both cell mediated and humoral immunity. The purported anti-inflammatory effects seem to be due to increased sensitivity of beta-adrenergic receptors and impairment of the functions of neutrophils, macrophages and mast cells.  The immunomodulatory effect is attributed to iridoid glycoside.
A 50% ethanolic extract of leaf of Kutakee (Picrorhiza kurroa) was found to stimulate the cell mediated and humoral components of immune system. The extract also stimulates phagocytic function of the reticuloendothelial system in rats and other experimental animals. [75]

Immune System Regulation through Enhanced Liver Protection

For centuries Kutakee (Picrorhiza kurroa) was in use worldwide for the treatment of bronchial asthma and liver diseases especially jaundice. Some of the patients experienced dramatic relief from their rheumatic pains. This convinced doctors to use Kutakee (Picrorhiza kurroa) to treat ankylosing spondylitis, cervical spondylitis and osteoarthritis. All cases showed marked relief without recurrence for up to half a year. This inspired researchers to treat other autoimmune diseases like vitiligo, psoriasis and some other conditions like peptic ulcer, neuralgia, malignant tumor pain. However the pain not connected with immunological disorders like sciatica was never relieved. This led to the conclusion that Kutakee (Picrorhiza kurroa) by regulating immune system relieves inflammation and pain. Researchers then looked at the liver more closely and hypothesized that it was linked to immunological functions. They therefore reasoned, if the extract of the root or rhizome of Kutakee (Picrorhiza kurroa) were routinely administered, then not only the health of the liver would substantially improve but also would lead to greater harmony of the immune system. Only the extracts of Kutakee (Picrorhiza kurroa) containing 4% of the glycoside kutkin are able to accomplish both tasks of immune regulation and liver protection. Picroliv capsules 400 mg daily on empty stomach show maximum effectiveness. [76]

Mycobacterial (tubercolosis and leprosy) diseases are characterised by a deficiency in antigen specific host T cell responses. The researchers have studied the effect of Picroliv, a standardised fraction of root and rhizome of Kutakee (Picrorhiza kurroa), on proliferative T cell response to the mycobacterial PPD (Purified Protein Derivative) antigen in subjects infected with or exposed to mycobacteria. The study suggests that Picroliv could be useful as an adjunct to chemotherapy or as a short term prophylactic antigen.  [77], [78] 

Aqueous and alcoholic extracts of Kutakee (Picrorhiza kurroa) show protective effects on cyclophosphamide-induced immunosupression in mice. The alcoholic extract is more potent than the aqueous extract in this regard.  [79] 
In a study anti-leishmanial effect of picroli is significantly enhanced when used in combination with paromycin and miltefosine. With the combinaton increased toxic oxygen metabolite generation and phagocytosis were witnessed. The study suggests that picroliv can be used as an adjunct to chemotherapy for the treatment of leishmaniasis. [80]
To evaluate the immunosrimulant activity of picroliv, the phytochemical was administered orally to mice at 10mg/kg body weight for 7 days prior to immunization with sheep red blood cells. This resulted in a significant increase in haemagglutinating antibody titre, plaque forming cells and delayed hypersensitivity response to sheep red blood cells. Picroliv increased non-specific immune response. Picroliv also induced a high degree of protection in golden hamsters against Leishmania donovani infection. [81] 

Antimicrobial Activity

Methanolic and aqueous extract of Kutakee (Picrorhiza kurroa) possess antibacterial activity. They can be used to treat infections due to Pseudomonas aeruginosa, Staphylococcus aureas, Bacillus subtilis, Micrococcus luteus, Escherichia coli. Methanolic extract has significant activity against Pseudomonas aeruginosa and Staphylococcus aureus. But the effectiveness of the extract was less than the convential antibiotic ciprofloxacin.  [82]


Antifungal activity

Methanolic and aqueous extract of Kutakee (Picrorhiza kurroa) exhibit antifungal activity against Candida albicansand Aspergillus niger. [83]


Antiprotozoal activity

Currently used antileishmanial drugs are hepatotoxic. Kutakee (Picrorhiza kurroa) is now used as an adjuvant tochemotherapy or in combination therapy along with sodium stibogluconate. Kutakee (Picrorhiza kurroa) not only protects the liver but also enhances the efficacy of antileishmanial drugs. 

Recent studies have shown that picroliv while acting as an adjunct to sodium stibogluconate protects the liver against the hepatotoxicity caused by the antileishmanial drug and enhances the efficacy of sodium stibogluconate. [84]
When administered at 3-12mg/kg body weight dose to Mastomys natalensis rats infected with the parasitePlasmodium bergheri, the alcoholic extract of Kutakee (Picrorhiza kurroa) protected the hepatic damage in rats. This hepatoprotective activity was attributed to antioxidant activity of picroliv. Picroliv has no action against parasitePlasmodium bergheri [85]


Administration of picroliv at 6mg/kg body weight to Mastomys natalensis rats infected with the parasite Plasmodium bergheri prevented the liver and brain damage in the animals. [86]

Anti-parasitic Activity

The methanolic extract of Kutakee (Picrorhiza kurroa) shows trypanocidal activity against Trypanosoma evansi. [87]

Actions on Hematopoietic System

Phenylhydrazine is known to cuase iotrogenic anemia. Researchers have evaluated the effect of the ethanolic extract of leaves of Kutakee (Picrorhiza kurroa) on animal model of rats. They induced anemia in rats by intraperitoneal injection of phenylhydrazine at 40mg/kg body weight for 2 days. Kutakee (Picrorhiza kurroa) extract was then administered orally at 100 mg/kg body weight/ day and 200mg/kg body weight/day. Following this treatment there was a significant increase in the haemoglobin concentration, in the number of Red Blood Cells and the haematocrit and reticulocytes. [88]        


Kutakee (Picrorhiza kurroa) may inhibit leucopenia. Caution is advised when taking Kutakee (Picrorhiza kurroa) with other immunosupressants. [89]

Actions on Nervous System

A study on mice, hot water extract of Kutakee (Picrorhiza kurroa) revealed that the extract is centralnervous system depressant. Depressant action of the extract is slightly better than that of diazepam in terms of the duration of sleep. This action may be attributed to the cerebral mechanism involved in the regulation of sleep. The phytochemicals present in the extract are water soluble substances, therefore triterpenoids and flavonoids might be present in glycoside forms that are responsible for this activity. Other classes of phytochemicals not evaluated in this study can also be able to exert depressant action the nervous system. Further study in this regard is necessary.  [90] 

Antipyretic Activity

To evaluate antipyretic activity of Kutakee (Picrorhiza kurroa), fever was induced in animal models by using DNP (2, 4-Dinitrp Phenol), D-amphetamine and brewer’s yeast. The extract was then administered. The test results were compared with antipyretic activity of paracetomol. The extract showed a significant antipyretic activity which justifies its use in traditional medicine (ethnomedicine).  [91] 

Actions on CVS

Oral pretreatment with 80mg/kg bodyweight/day for 15 days with ethanol extract of roots and rhizomes of Kutakee (Picrorhiza kurroa) significantly prevented the isoproterenol-induced myocardial infatction and maintained the rats in near normal status.  [92]

Myocardium contains an abundant amount of endogenous enzymatic and non- enzymatic antioxidants to protect the cardiomyocytes from deleterious effects of reactive oxygen species and peroxides. Isoproterenol is a potent synthetic catecholamine with β-adrenergic activity. In a study on Wistar rats administration of injection of isoproterenol to experimental rats brought about depletion of these antioxidants along with significant rise in methylenedioxyamphetamine simulating myocardial infarction. However long term treatment with 200mg/kg body weight with Kutakee (Picrorhiza kurroa); of experimental rats, significantly preserved the myocardium as indicated by marked reduction in necrosis of the myocardium, edema and infiltration of inflammatory cells. [93]
Adriamycin is an anthracycline antibiotic used in the treatment of various malignancies. It is cardiomyotoxic. In an experimental study on rats, oral administration of 50mg/kg body weight/day of Kutakee (Picrorhiza kurroa) extract significantly prevented adriamycin-induced toxicity. This effect was attributed to membrane stabilizing and antioxidant property of Kutakee (Picrorhiza kurroa) [94]

Actions on RS

For centuries Kutakee (Picrorhiza kurroa) has been used for the treatment of bronchial asthma world wide. Recent study has shown that tablets of Kutakee (Picrorhiza kurroa) 300 mg three times a day offer good relief for asthmatics. [95]

Actions on GI System

Kutakee (Picrorhiza kurroa) reduces the excessive gastric acid secretion (hyperacidity) and exhibits prokinetic activity.
Ethanol extract of rhizome of Kutakee (Picrorhiza kurroa), (dose: 20 mg/kg body weight), accelerated the healing of indomethacin induced gastric ulcers in patients. [96]

In another study ethanolic extract of rhizome of Kutakee (Picrorhiza kurroa) at a dose of 20mg/kg body weight, for 10 days was found to increase the healing speed on Indomethacin-indiced gasric ulceration in mice, compared to the mice having gastric ulcer but without any treatment. This effect was attributed to the free radical scavenging property of the plant. [98]


Free radicals and proinflammatory cytokines play a major role in the pathogenesis of ulcerative colitis. Antioxidant and anti-inflammatory activity of picroliv ameliorates dextran sulphate sodium (DDS) induced colitis. The results of the study suggest that picroliv may provide a therapeutic approach for ulcerative colitis. [99]


Actions on the Liver

(A). Hepatoprotection


In a study, in mice, Kutakee (Picrorhiza kurroa) reversed the toxic effects of aflatoxin B2 (a potent hepatocarcinogen), as demonstrated by elevated enzyme levels coming back to their normal levels.

In another study, galactosamine was used to induce liver injury in rats. Administration of Kutakee (Picrorhiza kurroa) at a dose of 200mg/kg body weight significantly reduced the elevated levels of SGOT, SGPT [100]
In yet another study in rats, oral pre-treatment with alcoholic extract of rhizome and root of Kutakee (Picrorhiza kurroa) at 50mg/kg body weight/day prevented the D-galactosamine-induced alterations in respiration and oxidative phosphorylation of liver mitochondria. [101]

In a study conducted by Dwivedi et al on rats, intraperitoneal injection of D-galactosamine at a dose of 800mg/kg body weight caused a significant liver damage and increased serum levels of various liver enzymes. Oral administration of picroliv at 12mg/kg body weight/day for 7 days significantly prevented the liver damage and alterations in enzyme levels. Kutkoside at 12mg/kg body weight/day for 7 days also had similar effect. Picroside-I at the same doses could only prevent D-galactosamine induced toxicity. The mixture of picroside-I and kutkoside in the ratio 1:1.5 at a dose of 12mg/kg body weight elicited lesser response than Picroliv. [102]

In a further study on rats toxicated with galactosamine or thioacetamide, Dwivedi et al found that perfusion of liver with a 0.02% solution of picroliv (1ml/minute) for 30 minutes, reversed the changes induced by toxicanrs. [103]
Picroliv exerts choleretic (anti-cholestatic) effect against paracetamol and ethynylestradiol-induced cholestasis. In antagonizes the changes in bile volume as well as the contents viz. bile salts and bile acids. Picroliv was found to be more potent choleretic agent than silymarin. [104]

Pretreatment with Picroliv administered orally at 3-12mg/kg body weight for 7 days prevents galactosamine induced liver damage. [105]

Investigation by Singh V et al on effect of picroliv from rhizome and root of Kutakee (Picrorhiza kurroa) showed reversal of LDL (Low Density Lipoprotein) binding to paracetamol-induced damaged hepatocytes of rats. Picroliv at different doses prevented the changes in levels of glutamic pyruvate transaminase, glutamic oxaloacetic tranaminase, alkaline phosphatase and lipids of hepatocytes. These effects were comparable to a known hepatoprotective agent, silymarin. [106]
In another study the hepatocytes damaged by CCl4thioacetamide and galactosamine were incubated with Kutakee (Picrorhiza kurroa) extract. They recovered to normal depending upon the concentrations used.
Picroside I and kutkoside are potent choleretic and anticholestatic agents especially in cholestasis induced by alcohol, CCl4, oxytetracycline, paracetamol and [107], [108]


Administration of carbon tetrachloride (CCl4) to normal rats induces hepatotoxicity. Administration of picroliv at doses of 6 and 12 mg/kg body weight provides significant protection against biochemical alterations produced by carbon tetrachloride (CCl4). The degree of protection offered by picroliv when administered imultaneously with carbon tetrachloride (CCl4) or as a pretreatment is almost the same. [109]

Administration of carbon tetrachloride (CCl4) to normal rats induces hepatotoxicity. Cholestasis is associated hepatotoxicity. Administration of picroliv at doses 3-12 mg/kg body weight for 7 days increases the bile flow. The effect is dose dependent. Further, researchers observed that the effect of picroliv was more than that of silymarin. [110]

Liver damage due to amoebiasis is commonly observed in tropical countries. Picroliv does not show amoebicidal activity. Amoebiasis may coexist with carbon tetrachloride poisoning. When administered with other drugs, picroliv prevents liver damage caused due to both carbon tetrachloride amoebiasis. [111]

Cadmium an industrial and environmental pollutant is toxic to several tissues, most notably to liver on short term exposure and kidney on long term exposure. In a study, administration of picroliv at 6 mg/kg and 12 mg/kg body weight/day for 4 weeks to subjects with cadmium poisoning; improved liver and kidney functions. At higher doses picroliv enhanced excretion of urinary proteins, cadmium, calcium, lactate dehydrogenase and N-acetyl-β-D-glucosaminidase. Picroliv not only reduced the levels of accumulated cadmimum, calcium and zinc but also enhanced the bile flow and excretion of cadmium in bile. Picroliv was less effective in restoring urinary parameters as well as oxidative stress indices in the renal tissue and renal morphology.  [112]

Oral administration of picroliv at 25mg/kg body weight/ day for 15 days, 6 weeks after aflatoxin B1 intoxication, prevented the biochemical changes induced in the liver of rats. The protective effect of picroliv was comparable to a well known hepatoprotective agent silymarin.  [113]

A study was undertaken to evaluate the efficacy of picroliv derived from Kutakee (Picrorhiza kurroa) in protecting against ischemia-reperfusion injury in vivo. Picroliv was administered orally to male Sprague Dawley rats in a dose of 12mg/kg body weight once a day for 7 days prior to hepatic ischemia. Later hepatic ischemia was induced by occluding hepatic pedicle for 30minutes. Thereafter by releasing clamps reperfusion was allowed for 15-20 minutes. The study showed that picroliv protected the liver from ischemia-reperfusion injury. [114] 

Thioacetamide 200µg/ml, galactosamine 400µg/ml and carbontetrachloride 3µg/ml are known hepatotoxic agents. In a study these toxic agents produced a 40-62% inhibition of cell viability reduction of biochemical parameters. The damaged cells were incubated with picroliv at 370C for 48 hours. Depending upon the dose, picroliv exerted ‘curative’ effect as the viability of the cells was restored. [115]

Lipid peroxidation and reactive oxygen species are instrumental in producing hepatocellular injury. Kutakee (Picrorhiza kurroa) exerts hepatoprotective action by scavenging free radicals and modulating lipid peroxidation. To validate these, by administering 50mg/kg body weight 2-acetylaminofluorene (2-AAF) to Wistar rats, hepatotoxicity was induced. There was an increase in the levels of trans-aminase enzymes and LDH; enhanced ornithine decarboxylase (ODC) activity and thymidine incorporation into hepatic DNA. Pretreatment of rats with Kutakee (Picrorhiza kurroa) protected the liver from 2-AAF-induced liver injury.  [116]

Picroliv at 1.5- 12 mg/kg body weight shows hepatoprotective activity against oxytetracycline-induced hepatotoxicity in rats. The effect was dependent on the dose of picroliv used. The researchers observed that picroliv was more potent than silymarin. [117] 

What is commonly known as “ Death cap” is a mushroom botanically. It is also known as toad-stool. Its taxonomic name isAmantia phylloides. What is known as “Soma” in ancient Indian literarure is identified to be Amantia phylloides by some researchers. It is described in “Rigved” and “Atharvaveda”. It is a very poisonous mushroom. It is potent hepatotoxic. [118]

Amantia phylloides at 50mg/kg body weight causes a significant hepatotoxicity. Administration of Picroliv at 25mg/kg body weight per day for 10 days protects the liver from the toxicity of Amantia phylloides. [119] 

When administered to rats at 100/kg body weight thioacetamide caused severe liver damage. Administration of picroliv in doses of 12.5 and 25mg/kg body weight exerts hepatoprotective effect. This effect is comparable with that of silymarin. [120] 

Monocrotaline is a crystalline alkaloid found in leguminous plants of the genus crotalaria that is poisonous to livestock and humans. Administration of monoctotaline to rats induces hepatotoxicity. In an experimental study, researchers Dwivedi Y et al observed hepatotoxicity in rats after 12 days on administration of a single dose of 120mg/kg body weight of monocrotiline. Simultaneous administration of Kutakee (Picrorhiza kurroa) in a dose of 25mg/kg body weight prevented the hepatic damage as was evident by alterations in biochemical parameters and histological studies of the liver. [121] 

Additional Information: 

Oral administration of kutkoside and/or picroside-I, standardized iridoid glycosides of Kutakee (Picrorhiza kurroa), at the dose of 12 mg/kg/day for 7 days, protect the liver against ischemic and galactosamine-induced liver damage in rats. But their mixture picroside-I and kutkoside in the ratio of 1:1.5 at the dose of 12mg/kg is less effective. Kutakee (Picrorhiza kurroa) protects the liver against many hepato-toxic agents.

Kutakee (Picrorhiza kurroa) seems to alter cytochrome P-450 enzyme levels in the liver. Therefore, possible interactions with the drugs metabolized in the liver must be borne in mind while the patient is being treated with Kutakee (Picrorhiza kurroa). 
Experimentally Kutakee (Picrorhiza kurroa) has following actions:
(1) It increases the volume of secretion of bile from the liver without increasing the amount of solids secreted (hydrocholeretic effects) in rats and dogs.
(2) It exerts antinecrotic effect in CCl–induced damage in rats and rabbits.
(3) It reduces fatty infiltration and lipid deposits in galactosamine-induced liver damage.
(4) It protects the liver from paracetamol toxicity and heals paracetamol-induced liver damage.
(5) It inhibits lipidperoxidation. [122]

Mechanism of Hepatoprotection: 

The mechanism by which Kutakee (Picrorhiza kurroaoffers hepatoprotection is not established. It is probably multifactorial. However there are certain conjectures:
1. Kutkin seems to play a major role in this regard. Kutkin alters the structure of the membrane of the hepatocytes. This prevents the penetration of hepatotoxic agents into the interior of the hepatocytes.  
2. Kutkin stimulates the action of polymerase A in the hepatocytes. This results in ribosomal protein synthesis which results in the regeneration of the hepatocytes and formation of new hepatocytes.
3. Anti-inflammatory action of apocynin and other constituents of Kutakee (Picrorhiza kurroa) is important in hepatoprotection.  
4. Kutakee (Picrorhiza kurroa) not only inhibits the formation of reactive oxygen species but also scavenges free radicals, thus protecting the hepatocytes.  
5. Kutakee (Picrorhiza kurroa) probably acts as a free-radical scavenger and an inhibitor of lipid peroxidation of liver cell membrane.
6. Picroliv in Kutakee (Picrorhiza kurroa) is a potent choleretic and anticholestatic agent. 

(B). Viral Hepatitis

In animal studies, the ethanol extract of Kutakee (Picrorhiza kurroa) has demonstrated potent anti-oxidant effect by protecting the liver against oxidative injury. It is effective against liver damage secondary to viral hepatitis. Kutakee (Picrorhiza kurroa)was found to have anti-hepatitis B surface antigen activity during an in vitro study. 
In a randomized, double blind placebo controlled trial in patients diagnosed to have HBs Ag negative viral hepatitis, root powder of Kutakee (Picrorhiza kurroa), at the dose 375mg thrice a day for 2 weeks (n=15) or a matching placebo (n=18) was administered. Difference in values of bilirubin, SGOT and SGPT was significant between Kutakee (Picrorhiza kurroa) and placebo groups. The duration required for total serum bilirubin to drop to average 2.5mg% was 27.44 days in patients treated with Kutakee (Picrorhiza kurroa) as against 75.9 days in placebo group. This study has shown the efficacy of Kutakee (Picrorhiza kurroa) as supported by clinical trial in viral hepatitis, hepatoprotection in animal model and an approach for standardizing extraxts based on picroside content. [123]

(C). Alcoholic Liver disease

Binduja Saraswat et al evaluated the efficacy of picroliv as a hepatoprotective agent against alcohol-induced liver injury in rats. Alcohol feeding to rats at a dose of 3.75g/kg body weight for 45 days produced 20-114% alterations in serum levels of aspertate aminitransferase, alanine transaminase, alkaline phosphatsae, lipids, glycogen and proteins; alcohol metabolizing enzymes (aldehyde dehydrogenase 41%, acetaldehyde dehydrogenase 52%); and produced cholestasis (41-53%).  Further, alcohol reduced the viability of hepatocytes by 44-48%. Treatment with picroliv at 3-12 mg/kg body weight per animal for 45 days restored the altered parameters by 36-100%. The effect was dependent on the dose used. [124], [125]

Sinha S et al used aqueous extract of Kutakee (Picrorhiza kurroa) to treat the deleterious effects of alcohol. They concluded that due to its potent antioxidant property Kutakee (Picrorhiza kurroa) significantly restored the liver functions and reduced lipid peroxidation. [126] 

(D) Non-Alcoholic Fatty Liver Disease (NAFLD)

The liver bears the major brunt of body metabolism. It is therefore exposed to a variety of metabolic insults. Some of them are obesity and insulin resistance (type 2 diabetes) that culminate into Non-Alcoholic Fatty Liver Disease (NAFLD). In male Wistar rats,  a team of researchers developed NAFLD showing several features akin to the malady in humans. The rats were subsequently treated with hydroalcoholic extracts of Kutakee (Picrorhiza kurroa). The extract was given orally (p.o. = per oral) in two doses viz. 200mg/kg body weight and 400mg/kg body weight twice a day for 4 weeks.
There were three control groups (n=6). Group 1 received vehicle with a regular diet, Group 2 rceived vehicle with a high fat diet (HFD) and Group 3 received high fat diet with with silymarin a known hepatoprotective agent.

Histopathology showed that the extract of Kutakee (Picrorhiza kurroa) brought about complete reversal of fatty infiltration. The hepatic enzymes returned to normal levels when treated with the dose of 400 mg/kg twice a day. Further the effect of Kutakee (Picrorhiza kurroa) was better than that of silymarine. Kutakee (Picrorhiza kurroa) should be investigated for the treatment of NAFLD and metabolic syndrome. [127] 

(E). Hepato-carcinogenesis

N-Nitrosodiethylamine (NDEA) is a known hepatocarcinogenic agent. To investigate anti-hepatocarcinogenic activity of Kutakee (Picrorhiza kurroa), NDEA was administered to rats. The animals developed nodules in the liver. Oral administration of picroliv at 200mg/kg body weight reduced the liver weight and restored the elevated bilirubin and liver enzymes to normal. Histopathological study showed normal structure of the liver. [128], [129]

DMH (1, 2-dimethylhydrazine hydrochloride) is a known hepatocarcinogenesis. To evaluate anti-hepatocarcinogenic effect of picroliv Rajeshkumar NV and Kuttan R used DMH to induce hepatocarcinogenesis in Sprague-Dawley rats. Subsequently the animals were treated with Picroliv (40 and 200 mg/kg body weight). They observed that DMH-induced hepatic carcinogenic response and necrosis were inhibited by oral administration of picroliv. Histological study showed that picroliv treated liver resembled normal liver except a few degenerating cells. [130]

Actions on metabolism
In a study on mice aqueous extract of Kutakee (Picrorhiza kurroa) was administered orally to mice at 50, 100 and 200mg/kg body weight once a day for 12 weeks. A hypolipidemic effect of Kutakee (Picrorhiza kurroa) was observed. While serum levels of total cholesterol, low density lipoproteins and triglycerides were significantly reduced, the serum levels of high density lipoproteins were not affected. [131]
In another study aqueous, alcoholic and chloroform extracts of root of Kutakee (Picrorhiza kurroa) at varying doses from 50mg/kg body weight to 200mg/kg body weight were found to exert hypolipidemic effect. [132]

Administration of 50mg/kg body weight to rats caused increase in triglyceride, free fatty acids and total lipids in both plasma and liver tissue of rats. Simultaneous administration orally of picroliv 50mg/kg body weight prevented these effects caused by hydrazine. [133]

Antidiabetic activity

An alcoholic extract of Kutakee (Picrorhiza kurroa) was found to lower basal blood sugar and after aheavy load of glucose in normal rats. The maximum reduction in blood sugar was observed 2 hours at a dose of 75 mg/kg body weight of the extract. The extract also lowered the blood sugar in alloxan-induced diabetic rats. The extract was also found to reduce blood urea nitrogen and serum lipid peroxides in alloxan –induced diabetic rats. [134]

In a study, water extract of Kutakee (Picrorhiza kurroa) was administered orally at 100 and 200mg/kg body weight/day to alloxan-induced diabetic rats. The researchers observed that plasma insulin level significantly increased along with glucose transporter type 4 protein content in the total membrane fractions of muscles. The researchers also observed β cells regeneration in pancreatic islets. [135]

Actions on Urinary System

To evaluate nephroprotective and nephrotective activity of Kutakee (Picrorhiza kurroa) researchers administered Cisplatin 5mg/kg body weight to female Wister rats and induced nephrotoxicity. The ethanolic extract of Kutakee (Picrorhiza kurroa) showed nephroprotective and nephrocurative effect on Cisplatin-induced toxicity. [136]
A study on rats showed that Picroliv at a dose of 12mg/kg body weight for 7 days protects the kidney from ischemia-reperfusion injury. The probable mechanism of action is free radical scavenging (antioxidant) property of Picroliv.[137] 
Picroliv at doses of 6 and 12 mg/kg body weight protects the kidney from Cadmium-induced nephrotoxicity. [138]
Picroliv protects the kidney from deleterous effects of aflatoxin B1. [139]

Actions on Male Reproductive System

Picroliv at 6 and 12mg/kg body weight for at least 4 weeks ameliorated Cadmium-induced early testicular damage in male rats. [140]

Antitumor activity

In experimental studies the hydroalcoholic mother extract of Kutakee (Picrorhiza kurroa) showed cytotoxic potential. While aqueous and hexane fractions did not show cytotoxicity against breast and cervical cancer cells, dichloromethane (DCM) fraction was found as the best active fraction. This might be due to the phytochemicals cucurbitacin B and E, betulinic acid, picrosides 1 and 2 and apocynin. [141], [142], [143], [144], [145]
K. L. Joy et al found that administration of 20-methylcholanthrene (20-MC) to mice, induced sarcoma in mice. Oral administration of Kutakee (Picrorhiza kurroa)  extract at doses of 150 and 750 mg/kg body weight reduced the tumor burden. The extract was also found to reduce the volume of transplanted solid tumors inducedby Dalton's lymphoma ascites tumor cell lines. [146]

Culinary uses

Not used.

Medicinal Actions and Uses

Traditional Uses

The rhizome has been used in traditional medicinal systems of Bhutan, China, India and Nepal to treat disorders of the liver and upper respiratory tract, reduce fevers, and to treat dyspepsia, chronic diarrhea, constipation, worms and scorpion sting.

Decoction of Kutakee (Picrorhiza kurroa) root with honey is used to cure stomach ache. To cure fever, 10 g o  Kutakee root powder and 1 g black pepper mixed with honey is given to adult patients. To cure stomach in new born and infants 0.25 g of Kutakee powder with mother's milk is advised. [147]

In Kashmir, Kutakee (Picrorhiza kurroa) is used for a variety of purposes.

In Bhutan, Kutakee (Picrorhiza kurroa) is used as a medicine for cough, cold, fever. To develop various formulations, the rhizome is used as an ingredient by the National Institute of Traditional Medicines and some local hospitals. [148]

In China, Kutakee (Picrorhiza kurroa) is used to cure fever, jaundice, diarrhea, dysentery and malnutrition due to digestive disorders. [149] 

In Nepal, the rhizome of Kutakee (Picrorhiza kurroa) is widely used to treat cough, cold, fever, skin diseases, jaundice, liver diseases. indigestion and metabolic disorders. 
In Kathmandu, the rhizome is as purgative and to treat scorpion bites. [150]

Rhizome of Hutakee (Picrorhiza kurroa) is used to treat high blood pressure, intestinal colic, ophthalmic disorders, gastritis,  respiratory diseases and fever. [151]
In Pakistan, Kutakee (Picrorhiza kurroa) is used in the Ayurvedicand Greek-Arab system of medicine as a stimulant, carminative, remedy for coughs, bronchial asthma, disorders of blood, liver, kidney and skin, debility, tremors, tetanus and gout [152]

Usages in Ayurveda

It is used for flatulent dyspepsia, digestive disorders, PUO, coughs, bronchial asthma, persistent hiccups, diseases of the liver, spleen, kidney, diabetes and skin disorders (especially leucoderma and leprosy) and as aphrodisiac tonic. 
In Ayurvedic Samhitaas Kutakee (Picrorhiza kurroa) is classified in accordance with its bioactivity. It is mentioned as an ingredient in several complex formulations, though Kutakee (Picrorhiza kurroa) is not a prime active agent of the formulation.
Charak Samhitaa recommends these formulations for skin disorders, blood disorders, disorders of throat, intestinal helminthiasis, snake poisoning etc.
In Sushrut Samhitaa, the formulations are prescribed for wound healing and wound dressing, skin disorders, leukoderma, elephantiasis, dental disorders, sinusitis, pharyngitis,  bronchitis, hepatobiliary disorders, dyspepsia, jaundice, chronic fevers, cervical spondylitis, rheumatism (rheumatoid arthritis, osteoarthritis), and pain relief. [153]  

Usages in Modern Medicine

Human studies on Kutakee (Picrorhiza kurroaare not prolific. Its current usages are focused on its hepatoprotective, anticholestatic, antioxidant, and immune-modulating activity.
It is used to treat viral hepatitis and for hepatoprotection.
It is used to treat respiratory allergies and bronchial asthma.
In combination with methoxsalen it is used to treat vitiligo.
It is used to enhance response to vaccinations.
It is used to speed up the wound healing. 
A landmark double blind clinical trial was conducted on Aarogyawardhanee in viral hepatitis by Antarkar DS, Vaidya AB, Doshi JC, Athavale AV et al.
The clinical response was positive within 4-7 days in terms of relief from anorexia, nausea, liver tenderness etc. ‘A double blind-blind clinical trial of Aarogyawardhanee – an Ayurvedic drug in acute viral hepatitis’
The root is used to treat inflammations, allergies, to boost immunity and reduce platelet aggregation, chronic diarrhea, dyspepsia, jaundice, respiratory disorders such as asthma, autoimmune diseases such as vitiligo, psoriasis, Amantia mushroom poisoning, to reduce serum cholesterol, diabetes and complications of diabetes and leishmaniasis. [154]

Toxicity

Loose stools and intestinal colic have been reported when unprocessed Kutakee (Picrorhiza kurroa) is used as medicine. However alcoholic extracts have much less tendency to cause such adverse effects. [155], [156]
The use of Kutakee (Picrorhiza kurroais not discouraged during pregnancy and breast-feeding by Ayurvedic physicians in India and there is little information to determine its safety during these times. But due to lack of comprehensive safety evaluation, modern physicians strongly recommend against the use of Kutakee (Picrorhiza kurroa) in pregnant women, lactating women and young children. One test tube study found apocynin of Kutakee (Picrorhiza kurroa) to be non-mutagenic. [157]

Isoniazid is said to interact with Kutakee (Picrorhiza kurroa). (Palo Alto Medical Foundation)
There have been no published reports of toxicity in humans in Ayurvedic medicine. A long history of its traditional use is suggestive of its safety when used at recommended dosages. The LD50 of Kutkin in rats is greater than 2600 mg/kg.
Kutakee (Picrorhiza kurroa) seems to alter cytochrome P-450 enzyme levels in the liver. Therefore, possible interactions with the drugs metabolized in the liver must be borne in mind while the patient is being treated with Kutakee (Picrorhiza kurroa).  
Precaution should be taken before using any herbal medicine. [158] '> is not discouraged during pregnancy and breast-feeding by Ayurvedic physicians in India and there is little information to determine its safety during these times. But due to lack of comprehensive safety evaluation, modern physicians strongly recommend against the use of Kutakee (Picrorhiza kurroa) inpregnant women, lactating women and young children. One test tube study found apocynin of Kutakee (Picrorhiza kurroa) to be non-mutagenic. [157]

Preparations and dosages

Compound Picrorrhiza Tincture: It contains Picrorhiza, cardamom and 45% alcohol. Dose: 1 - 4 ml per day.
Powder: A typical recommended dose of powdered Kutakee (Picrorhiza kurroa) ranges from 400 mg to 1,500 mg daily or 1–2 ml of fluid extract twice a day which is said to be equivalent of powder form. As laxative powder can be given up to 3 to 6 gm
As antipyretic and antiperiodic: 3-4 gm per day.
As bitter tonic: 0.6-1.2 gm.
In Nepal, Root paste is applied for speedy healing of wounds. [159]
Various formulations of the plant are widely used to treat jaundice.
Decoction of roots in water is given with salt to cattle as antipyretic.
Some Kutakee (Picrorhiza kurroa) extracts are standardized to contain desired amount of one or more of its chemical constituents (usually 4% Kutkin). However, since no constituent has any medicinal benefit accepted by medical fraternity, such standardization has no known practical usage.
Picrorhiza Tea: Picrorhiza tastes quite bitter. Tea made by combining it with ginger and honey or sugar as sweeteners can improve palatability. 
Aarogyawardhanee Rasa AKA Aarogyawardhanee, Aarogyavardhini Rasa (Watikaa or Gutikaa) (AW). This is avery famous Ayurvedic formulation used for viral hepatitis and liver ailments.
500mg of Aarogyawardhanee Rasa contains:
11.4 mg each of shuddha mercury-sulphur (purified Ayurvedic way), iron, mica and copper
22.8 mg each of the fruits of Terminalia chebula, Terminalia belerica and Emblica officinalis (Triphalaa meaning combination of three fruits)
34.0 mg of Shilajeet
44.4 mg each of the gum of Commiphora mukul (guggulu) and the powder of the root of Plumbago zeylanica (Chitraka)
250 mg powder of the root of Picrorhiza kurroa (Kutakee)
Dose: 750 mg thrice a day for 3 weeks.
Punarnawaadi Kwath 

SOME IMPORTANT FORMULATIONS –

Aarogyavardhini Gutika, Tiktaka Ghrita, Sarvajvarahara Lauha, Mahatikataka Ghrita. [160]
Aarogya Wardhanee Watee: Tablet is used for treating hepatic disorders, skin diseases and PUOs
Saariwaasawa: Used for diabetes, gout, skin disorders
Mahaatiktaka Ghrita: Medicated ghee used for skin disorders.
Patolaadi Choorna: A mixture of powders containing Patol, Kutakee etc
Mahaayogaraaja Guggul: Used for musculo-skeletal disorders [161]

(2). Recommended dosages: 

Picroliv: 12-24mg/kg body weight 
Some experts recommend: 
130 mg for a 150 lb person
170 mg for a 200 lb person
220 mg for a 250 lb person
However lower doses are also effective. A lone human study used a total picroside I and Picroside II at dosages of around 25 mg.
The dosages mentioned above refer to the total picroside I and II, kutkin or picroliv content in the extract and not the weight of the plant itself.
Thus if the plant extract weighs 1000 mg containing 4% picroliv, the actual quantity of picroliv in 1000 mg of extract would be 40mg. [162], [163]

(3). Dosages and Administration 

Kutakee (Picrorhiza kurroa) does not easily release its contents into water. Therefore standardized encapsulated powder containing 4% kutkin is better than tea.
Now recommended adult dose is 400-1500 mg/day. For some fevers the recommended dose may be as high 3.5 g/day.
As anti-periodic: 3-4 g
As bitter tonic: 0.6-1.2 g [164], [165], [166]

References: 

[1] Vaidya Antarkar Memorial Volume 
[2] https://en.wikipedia.org/wiki/Picrorhiza_kurroa 
[3] Singh H. et al, Why uproot Picrorhiza kurroa, an endangered medicinal herb, Curr Sci 100 (7): 1055-1059 (2011) 
[4] Patil V et al, Propagtion of Picrorhiza kurroa Royale ex Benth: An important medicinal plant of Western Himalaya, J Med Plants Res 6(34): 4848-4860, 2012 

[5] http://www.gits4u.com/agri/agri5kutki.htm
[6] http://www.ayurveda.hu/api/API-Vol-2.pdf
[7] http://en.wikipedia.org/wiki/Picrorhiza_kurroa
[8] http://easyayurveda.com/2014/07/17/Kutki-picrorrhiza-kuroa-benefits-dose-side-effects-research/   
[9] Bhattacharjee S et al, A Review on Medicinally Important Species of Picrorrhiza, Intl J pharm Res Biosc 2 (4): 1-16
[10] Bishen Singh Mahendra Pal Singh, Wild flowers of Kashmir, Vol. 2, (Reprint) 1984, pp8 9-90
[11] The Ayurvedic Pharmacopoeia of India, Part I, Volume III 
[12] Bhattacharjee S et al, A Review on Medicinally Important Species of Picrorrhiza, Intl J pharm Res Biosc 2 (4): 1-16
[13] Google images      
[14] http://en.wikipedia.org/wiki/picrorrhiza_kurroa
[15] http://www.ayurveda.hu/api/API-Vol-2.pdf
[16] http://ayudrug.blogspot.in/2010/06/katuki-consists-of-dried-rhizome-with.html
[17] Pharmacopoeia of the People’s Republic of China (2005), Beijing, Chemical Industry Press.
[18] http://www.ayurveda.hu/api/API-Vol-2.pdf 
[19] www.motherherbs.com/Picrorrhiza- kurroa-extract.html  
[20] Illustrated Dravyaguna Vijnana, Vol. II, by Dr JLN Shastry 
[21] http://easyayurveda.com/2014/07/17/kutki-picrorhiza-kurroa-benefits-dose-side-effects-research/    
[22] Chemistry: NMR papers, PubMed ID: 10395515 
[23] Medicine: Physiology Papers, PubMed ID: 17191857 
[24] http://www.ayurveda.hu/api/API-Vol-2.pdf 
[25] http://www.ayurveda.hu/api/API-Vol-2.pdf 
[26] Ravinder Raina et al, Reproductive Biology of Picrorhiza kurroa- a Critically Endangered High Value Temperate Medicinal Plant, Open Access Journal of Medicinal and Aromatic Plants, Vol 1, No 2 (2010)
[27] Sud A et al, Mass Spectroscopic Analysis of Differentially Expressed proteins in an Endangered Medicinal Herb, Picrorhiza kurroa, Bio Med Res Int Vol. 2014
[28] http://easyayurveda.com/2014/07/17/kutki-picrorhiza-kurroa-benefits-dose-side-effects-research/
[29] http://www.ayurwiki.info/wiki/katuka, www.evaidyaji.com 
[30] http://easyayurveda.com/2014/07/17/kutki-picrorhiza-kurroa-benefits-dose-side-effects-research/ 
[31] http://ayudrugs.blogspot.in/2010/06/katuki-consists-of-dried-rhizome-with.html 
[32] www.chemical book.com 
[33] http://www.lookchem.com/Picroside-III
[34] Kawoosa T et al, Light and temperature regulated terpene biosynthesis: hepatoprotective monoterpene picroside accumulation in Picrorhiza kurroa, Funct Integr Genomics 2010 Aug 10(3): 393-404
[35] Li P et al, Picrosides I and II, selective enhancers of the mitogen-activated protein kinase-dependent signaling pathway in the action of neuritogenic substances on PC12D cells, Life Sci, 2002 Aug 30; 71(15): 1821-1835  
[36] Ray, Arun and et al; Antioxidant activity of Rhizome of Picrorhiza kurroa on healing, Indian Journal of Clinical Biochemistry, 2002, 17 (2): 44-51 
[37] www.motherherbs.com/Picrorrhiza- kurroa-extract.html   
[38] http://www.ethnoleaflets.com/leaflets/kutkin.htm 
[39] Verma PC, Basu V, Gupta V, Saxena G, Rahman LU;   Pharmacology and chemistry of a potent hepatoprotective compound Picroliv isolated from the roots and rhizomes of Picrorhiza kurroa royle ex benth (kutki), Curr Pharm Biotechnol 2009 Sep; 10 (6): 641-9 
[40] Vanita Singh-Gupta et al, Effect of picroliv on protein and nucleic acid synthesis, Indian Journal of Experimental Biology, 30 (1): 68-69, February 1992 
[41] Ray S., Mjumder HK, Chakravarty AK, Mukhopadhya S, Gil RR, Cordell G, J Nat prod 27, 1996, 59
[42] Mittra B, Saha A, Roy Chowdhury A, Bandhyopadhy S, Majumder HK, Molecular medicine, 6, 2000, 527 
[43] Monday May 16th 2016; http://www.evolutionary.org/picroliv/ 
[44]Rajeshkumar NV et al, Protective effect of Picroliv, the active constituent of Picrorhiza kurroa, against chemical carcinogenesis in mice, Teratog Carcinog Mutagen, 2001; 21(4): 303-313  
[45] http://www.chemicalbook.com 
[46] http://www.chemicalbook.com 
[47] http://www.ncbi.nlm.nih.gov/pubmed/1718906 
[48] http://en.wikipedia.org/wiki/Apocynin 
[49] http://en.wikipedia.org/wiki/Apocynin 
[50] http://en.wikipedia.org/wiki/Apocynin 
[51] J. Stefanska and R. Pawliczak; Apocynin: Molecular Aptitudes; Mediators Inflamm 2008, Published online 2008, December 2.  
[52] http://en.wikipedia.org/wiki/Dimer_(chemistry)
[53] J. Stefanska and R. Pawliczak; Apocynin: Molecular Aptitudes; Mediators Inflamm 2008, Published online 2008, December 2. 
[54] Biochemical Pharmacology Volume 73, Issue 1, 1 January 2007 
[55] Biochemical Pharmacology, Volume 72, Issue 1, 28 June 2006. 
[56] Jose M. Escandell; Department of Pharmacology, University of Valencia, Spain 
[57] Kumar N et al, Phytopharmacological review on Genus Picrorhiza, Int J Universal Pharma Bio Sci 2 (4): 334-347 
[58] Dilawar Upadhyay et al, Comparative pharmacokinetic profiles of picrosides I and II from kutkin, Picrorhiza kurroa extract and its formulation in rats, Fitoterapia, 85 (2013): 76-83 
[59] Jia Dewei, et al, Methodology to nanocapsulatr hepatoprotective components from Picrorhiza kurroa as food supplement, Food Bioscience, Volume 9: pages 28-35
[60] Hardik Chandasana et al, Pharmacokinetic, bioavailability, metabolism and plasma protein binding evaluation of NADPH-oxidase inhibitor apocynin using LC-MS/MS; journal of Chromatography B 985 (2015): 180-188     
[61] Jaya P, Gaddipatti et al, Picroliv-a natural product protects cells and regulates the gene expression during hypoxia/reoxigenation, Molecular and Cellular Biochemistry, April 1999, Volume 194, Issue 1, pp 271-281 
[62] K. L. Bedi et al, Picrorhiza kurroa, an ayurvedic herb, may potentiate photochemotherapy in vitiligo, Journal of Ethnopharmacology, Volume 27, Issue 3, December 1989, Pages 347-352  
[63] C. C. Baruha et al, Anti-Allergic and Anti-Anaphylactic activity of Picroliv- A Standardized Iridoid Glycoside Fraction of Picrorhiza kurroa, Pharmacological Research, Volume 38, Issue 6, December 1998, Pages 487-492 
[64] Singh AK et al, Picroliv accelerates epithelialization and angiogenesis in rat wounds, Planta Med, 2007, Mar; 73(3): 251-256 
[65] Ferdi Engles et al, Effects of apocynin, a drug isolated from the roots of Picrorhiza kurroa, on arachidonic acid metabolism, FEBS Letters, Volume 305, Issue 3, 6 July 1992, pages 254-256     
[66] Pandey BL, Das PK, Immunopharmacological studies on Picrorhiza kurroa Royle-ex-Benth. Part IV: Cellular mechanisms of anti-inflammatory action, Indian J Physiol Pharmacol 1989 Jan-Mar; 33 (1): 28-30 
[67] Ji-Young Lee metal, Effects of Picrorhiza Rhizome Aqueous extracts on Paw Chronic Inflammation in Mice, J Korean Med 2015, 6, 21-35  
[68] Preetha Anand et al, Modification of Cysteine Residue in p65 Subunit of Nuclear Factor-KB (NF-KB) by Picroliv Supresses NF-KB-Regulated Gene Products and Potentiates apoptosis, Cancer Research, 68: 21, November 1, 2008 
http://www.dbpia.co.kr/Journal/ArticleDetail/NODE06387938
[68] Preetha Anand et al, Modification of Cysteine Residue in p65 Subunit of Nuclear Factor-KB (NF-KB) by Picroliv Supresses NF-KB-Regulated Gene Products and Potentiates apoptosis, Cancer Research, 68: 21, November 1, 2008 
http://www.dbpia.co.kr/Journal/ArticleDetail/NODE06387938
[69] K. Kant et al, Evaluation of Antioxidant activity of Picrorhiza kurroa (leaves) Extracts, Indian J Pharm Sci. 2013 May-Jun; 75(3): 324-329
[70] V. Rajkumar et al, Antioxidant and anti-neoplastic activities of Picrorhiza kurroa extracts, Food and Chemical Toxicology, Volume 49, Februry 2011, Pages 363-369 
[71] Simons JM et al, (1990) Metabolic activation of natural phenols into selective oxidative burst agonist by activated human neutrophils, Free Radical Bio and Med 8: 251-258
[72] Jagetia GC, Baliga MS, The evaluation of nitric oxide scavenging activity of certain Indian medicinal plants in vitro: a preliminary study, J Med Food 2004; 7(3): 343-348
[73] Chander R, KapoorNK, Dhawan BN, Picroliv, picroside-I and kutkoside from Picrorhiza kurroa are scavengers of superoxide anions, Biochem Pharmacol 1992 Jul 7; 44(1): 180-3
[74] Seth P et al, picroliv modulates antioxidant status and down-regulates AP1 transcription factor after hemorrhage and resuscitation, Shock, 2003 Feb; 19(2): 169-75
[75] M. L. Sharma, C. S. Rao, P. L. Dutta’ Immunostimulatory activity of Picrorhiza kurroa leaf extract, Journal of Ethnopharmacology, Volume 41, Issue 3, February 1994, pages 185-192
[76] http://www.detoxinternational.com/default.aspx?menuitemid=161&AspxAutoDetectCookieSupport=1,
504-415-9042-Wellnessstool@detoxinternational.com
[77] Sudhir Sinha et al, Immunopharmacology and Immunotoxicology, Volume 20, Issue 4, 1998.
[78] Sinha S et al, Picroliv, the iridoid glycoside fraction of Picrorhiza kurroa selectively augments human T cell response to mycobacterial protein antigens, Immunopharmacol and Immunotoxicol. 1998 Nov; 20(4): 579-588
[79] Arshad Hussain et al, Protective effects of Picrorhiza kurroa on cyclophosphamide-induced immunosupression in mice, Pharmacognosy Res, 2013, Jan-Mar; 5(1):30-35 
[80] Sane SA, Shakya N, Gupta S, Immunomodulatory effect of picroliv on the efficacy of paromycin and miltefosine in combination in experimental vvisceral leishmaniasis, Exp Parasitol. 2011 Feb; 127(2): 376-381
[81] Puri A et al, Immunostimulant Activity of Picroliv, the Iridoid Glycoside Fraction of Picrorhiza kurroa, and its Protective Action against Leishmania donovani infection in Hamsters, Planta Med. 1992 Dec; 58 (6): 528-532
[82] Deepti Rathee et al, Phytochemical screening and antimicrobial activity of Picrorhiza kurroa, an Indian traditional plant used to treat chronic diarrhea, Arabian Journal of Chemistry, Available online 10 March 2012
http://dx.doi.org/10.1016/j.arabic.2012.02.009 
[83] Deepti Rathee et al, Phytochemical screening and antimicrobial activity of Picrorhiza kurroa, an Indian traditional plant used to treat chronic diarrhea, Arabian Journal of Chemistry, Available online 10 March 2012
http://dx.doi.org/10.1016/j.arabic.2012.02.009 
[84] Navdha Mittal et al, Protective effect of picroliv from Picrorhiza kurroa against Leishmania donovani infections in Mesocricetus auratus, Life Sciences, Volume 63, Issue 20, 9 October 1998, Pages 1823-1834
http://www.com/science/article/pii/S0024320598004561
[85] Chander R et al, Evaluation of hepatoprotective activity of picroliv from Picrorhiza kurroa in Mastomys natalensis infected with Plasmodium berghei, Indian J Med Res. 1990 Feb; 92: 34-37 
[86] Chander R et al, Evaluation of picroliv on glutathione metabolism in liver and brain Mastomys natalensis infected with Plasmodium berghei, Indian J Exp Bio. 1992 Aug; 30(8): 711-714 
[87] S. Peter et al, I vitro trypanocidal activity of methanolic extract of Picrorhiza kurroa rhizome against Trypanosoma evansi, Planta Medica, 73(9): Jan 2007 
[88] Turaskar A. et al., Inhibitory potential of Picrorrhiza kurroa Royle ex. Benth extract on phenylhydrazine induced reticulogytosis in rats, Asian Journal of Pharmaceutical and Clinical Research, 2013; 6(2): 215-216 
[89] www.livingnaturally.com/ns/DisplayMonograph.asp?
[90] Tasmina Rahaman et al, Preliminary study on the central nervous system depressant effect of Picrorhiza kurroa Royle. (Scrophulariaceae) in mice models, Oriental Pharmacy and Experimental Medicine 2008 8(4): 448-451
[91] A. Rajani et al, Anti-pyretic activity of methanolic extract of Picrorhiza kurroa Royle ex Benth, International Journal of Pharma and Bio Sciences 5 (1): 340-343, January 2014
[92] SHS Kumar et al, Cardioprotective effect of Picrorhiza kurroa against isoproterenol-induced myocardial stress in rats, Fitoterapia, Volume 72, Issue 4, May 2001, pages 402-405
[93] Mukesh Nandave et al, Cardioprotective effect of root extract of Picrorhiza kurroa (Royle ex Benth) against isoproterenol-induced cardiotoxicity in rats, Indian Journal of Experimental Biology, Volume 51, September 2013, pp 694-701
[94] D. Rajaprabhu et al, Protective effect of Picrorhiza kurroa on antioxidant defense status in adriamycin-induced cardiomyopathy in rats, Journal of Medicinal Plants research, Volume 1 (4), pp 080-085, November 2007 
[95] Doshi VB, Shetye VM, Mahasur AA et al, Picrorhiza kurroa in bronchial asthma, J Postgrad. Med 1983; 29(2): 89-95
[96] Arun Ray, Susri Ray Chaudhuri, Biswajit Majumdar & Sandip K Bandyopadhyay; Antioxidant Activity of Ethanol Extract of Rhizome of Picrorhiza Kurroa on Indomethacin Induced Gastric Ulcer During Healing Indian Journal Of Clinical Biochemistry, 2002, 17 (2) 44-51
[97] Rangaswamy Anandan et al, Protective effects of Picrorhiza kurroa against HCl/ethanol-induced ulceration in rats, Fitoterapia, Volume 70, Issue 5, 1 October 1999, Pages 498-501
[98] Ray A. et al, Antioxidant Activity of Ethanol Extract of Rhizome of Picrorhiza kurroa on Indomethacin Induced Gastric Ulcer during Healing, (2002), Indian J Biochem 17 (2): 44-51.
[99] De-Kui Zhang et al, A Picrorhiza kurroa Derivative Picroliv, Attenuates the Development of Dextran-Sulphate-SodiumiInduced Colitis in Mice, Mediators of Inflammation Volume 2012 (2012), Article ID 751629, 9 pages.
[100] AB Vaidya, DS Antarkar et al, Picrorhiza kurroa (Kutki) Royle ex Benth as a hepatoprotective agent—experimental and clinical studies, Journal of Postgraduate Medicine, Year: 1996, Volume: 42, Issue 4, Page 105-108
[101] Rangasmy Anandan et al, Biochemical studies on the hepatoprotective effect of Picrorhiza kurroa on changes in liver mitochondrial respiration and oxidative phosphorylation in D-glucosamine-induced hepatitis in rats, Fitoterapia Volume 70, Issue 6, 1 December 1999, 548-551
[102]Dwivedi Y et al, picroliv and its components Kutkoside and Picriside-I protect liver against galactosamine-induced damage in rats, Pharmacol Toxicol. 1992 Nov; 71 (5): 383-387
[103] Dwivedi Y et al, Perfusion with picroliv reverses biochemical changes induced in livers of rats toxicated with galactosamine or thioacetamide, Planta Med. 1993 Oct; 59 (5): 418-420
[104] Shukla B et al, Choleretic effect of picroliv, the hepatoprotective principle of Picrorhiza kurroa, Planta Med. 1991 Feb; 57 (1): 29-33 
[105] Visen PK et al, Prevention of galactosamine-induced hepatic damage by picroliv: study on bile flow and isolated hepatocytes (ex vivo), Planta Medica 1993, 59(1): 37-41
[106] Singh V et al, Effect of picroliv on low protein receptor binding of rat hepatocytes in hepatic damage induced by paracetamol, Indian Journal of Biochemistry & Biophysics, 1992, 29(5):428-432  
[107] Santra A, et al, Prevention of carbon tetrachloride-induced hepatic injury in mice by Picrorhiza kurroa, Indian Journal of Gastroenterology; 1998, 17(1):6-9
[108] http://europepmc.org/abstract/med/9465504
[109] Dwivedi Y et al, Hepatoprotective activity of picroliv against carbontetrachloride-induced liver damage in rats, Indian J Med Res. 1990 Jun; 92: 195-200
[110] Saraswat B et al Anticholestatic effect of picroliv, active hepatoprotective princilple of Picrorhiza kurroa, against carbon tetrachloride induced cholestasis, Indian J Exp Biol. 1993 Apr; 31(4): 316-318
[111] Singh M et al, Protective activity of picroliv on hepatic amoebiasis associated with carbon tetrachloride toxicity, Indian J Med Res. 2005 May; 121 (5)676-682
[112] Neelam Yadav, Shashi Khandelwal, Therapeutic efficacy of Picroliv in chronic cadmium toxicity, Food and Chemical Toxicology, Volume 47, Issue 4, April 2009, Pages 871-879   
[113] Rastogi R et al, Hepatoprotective effect of picroliv and silymarin against aflatoxin B1 induced hepatotoxicity in rats, Planta Medica, 2000, 66(8): 709-713,  http://europepmc.com/abstract/med/11199126 
[114] Anoop K Singh et al, Picroliv preconditioning protects the rat liver against ischemia-reperfusion injury, European Journal of Pharmacology, Volume 395, Issue 3, 3 May 2000, pages 229-239 
[115] P. K. S. Visen, Binduja Saraswat, B. N. Dhavan, Curative effect of picroliv on primary cultured rat hepatocytes against different hepatotoxins: an in vitro study.Journal of Pharmacological and Toxicological Methods, Volume 40, Issue 3, October 1998, Pages 173-179
[116] Sahar Rahaman, Protective effect of Picrorhiza kurroa Extract against 2-Acetylaminofluorene-induced Hepatotoxicity in Wistar Rats, Journal of Environmental Pathology, Toxicology and Oncology, pages 195-205  
[117] Saraswat B et al, Protective effect of picroliv, active constituent of Picrorhiza kurroa, against oxytetracycline induced hepatic damage. Indian J Exp Biol. 1997 Dec; 35 (12): 1302-5
[118] Nipum Verma et al, Wild Mushroom Poisoning in North India: Case Series with Review of Literature, J Clin Exp Hepatol. 2014 Dec; 4(4): 361-365
[119]Dwivedi Y et al, Effects of picriliv, the active principle of Picrorhiza kurroa, on biochemical changes in rat liver poisoned by Amamtia phylloides, Zhongguo Yao Li Xue Bao, 1992 May; 13 (3): 197-200 >[120] Dwivedi Y et al, Picroliv affords (offers?) protection against thioacetamide-induced hepatic damage in rats, Planta Med. 1991 Feb; 57(1): 25-28.
[120] Dwivedi Y et al, Picroliv affords (offers?) protection against thioacetamide-induced hepatic damage in rats, Planta Med. 1991 Feb; 57(1): 25-28.
[121] Dwivedi Y et al, Picroliv protects against monocrotaline-induced hepatic damage in rats, Pharmacol Res. 1991 May; 23 (4): 399-407
[122] Vaidya Antarkar Memorial Volume page 81
[123] AB Vaidya, DS Antarkar et al, Picrorhiza kurroa (Kutki) Royle ex Benth as a hepatoprotective agent—experimental and clinical studies, Journal of Postgraduate Medicine, Year: 1996, Volume: 42, Issue 4, Page 105-108
[124] Binduja Saraswat, P. K. S. Visen, G. K. Patnaik, B. N. Dhawan, Ex Vivo and in vivo investigations of picroliv from Picrorhiza kurroa in an alcohol intoxication model in rats, Journal of Ethnopharmacology, Volume 66, Issue 3, September 1999, Pages 263- 269.
[125] Rastogi R et al, Picroliv protects against alcohol-induced chronic hepatotoxicity in rats, Planta Medica, 1996, 62(3): 283-285
[126] Sinha S et al, (2011), Hepatoprotective Activity of Picrorhiza kurroa Royle ex Benth Extract against Alcohol Cytotoxicity in Mouse Liver Slice Culture, Int J Green Pharm 5: 244-253 
[127] Sapna N Shetty, Sushma Mengi, Rama Vaidya, Ashok D. B. Vaidya, A study of standardized extracts of Picrorhiza kurroa Royle ex Benth in experimental nonalcoholic fatty liver disease, J Ayurveda Integr Med 2010 Jul-Sep; 1(3) 203-213. 
[128] Rajeshkumar NV, Kuttan R, Inhibition of N-nitrosodiethylamine-induced hepatocarcinigenesis by Picroliv, Journal of Experimental & Clinical Cancer Research: CR (2000), 19(4): 459-465 
[129] Jeena KJ, Joy KL. Kuttan R, Effect of Emblica officinalis, Phyllanthus amarus and Picrorhiza kurroa on N-nitrosodiethylamine-induced hepatocarcinigenesis, Cancer Letters, 1999 Feb 8; 136(1): 11-6  
[130] Rajeshkumar NV, Kuttan R, Modulation of carcinogenic response and antioxidant enzymes of rats administered with 1, 2-dimethylhydrazine by Picroliv, Cancer Lett. 2003 Mar 10; 191(2): 137-143
[131] Hyeung Sik Lee, Choon Bo Yoo, Sae Kwang Ku, Hypolipidemic effect of Picrorhiza kurroa in high fat diet treated muuse, Fitoterapia Volume 77, Issues 7-8, December 2006, Pages 579-584 
[132] Vijender Singh, Ashok Chaudhary, Gunjan, Anti-Hyper Lipidemic activity of Picrorhiza kurroa Royle ex Benth Roots, International Journal of Drug Development and Research, Accepted: 29 June 2012. 
[133]Vivekanandan P et al, Protective effect of picroliv against hydrazine-induced hyperlipidemia and hepatic steatosis in rats, Drug Chem Toxicol. 2007; 30 (3): 241-252 
[134] K. L. Joy, R. Kuttan, Anti-diabetic activity of Picrorhiza kurroa extract, Journal of Ethnopharmacology Volume 67, Issue 2, November 1999, Pages 143-148 
[135]Gulam Mohammed Husain et al, Potential mechanism of anti-diabetic activity of picrorhiza kurroa, TANG/ www. E-tang.org2014/Volume 4/Issue 4/e27
[136] Yagmar S et al, Studies on Nephroprotective and Nephrocurative Activity of Ethanolic Extract of Picrorhiza kurroa Royle and Arogyawardini Bati in Rats. Int J Pharm Technol, 2010; 2(3): 472-489. 
[137] Seth P et al, Prevention of renal ischemia-reperfusion-injury in rats by picroliv, Biochem Pharmacol, 2000 May 15; 59(10): 1315-1322 
[138] Yadav N, Khandelwal S, Effect of Picroliv on Cadmium-induced hepatic and renal damage in the rat, Hum Exp Toxicol. 2006 Oct; 25(10): 581-591 
[139] Rastogi R, Srivastava AK, Rastogi AK, Long term effect of aflatoxin B(1) on lipid peroxidation in rat liver and kidney: effect of picroliv and silymarin, Phytother Res. 2001 Jun; 15 (4): 307-310 
[140] Neelam Yadav, Shashi Khandelwal, Effect of Picroliv on cadmium induced testicular damage in rats, Food and Chemical Toxicology, Volume 46, Issue 2, February 2008, Pages 494-501. 
[141] A. A. Patil et al, Supercritical CO2 assisted extraction and LC-MS identification of picroside I and picroside II from Picrorhiza kurroa, Phytochemical Analysis, 2013, vol. 24, no. 2, pp.97-104 
[142] H. Stuppner, H. Wagner, New cucurbitacin glycosides from Picrorhiza kurroa, Planta Medica, 1989, vol. 55, no. 6, pp. 559-563 
[143] S. Sturm, H. Stuppner, Analysis of cucurbitacins in medicinal plants by high-pressure liquid chromatography-mass spectrometry, Phytochemical Analysys 2000, vol. 11, no. 2, pp. 121-127
[144] N. Sindhu et al, Isolation of a cucurbitacin from picrorhiza kurroa by column chromatography and its characterization, Research Journal of Pharmaceutical, Biological and Chemical Sciences, 2011, vol. 2, no. 3, pp. 149- 156.
[145] F. Engels et al, Effects of apocynin, a drug isolated from theroots of Picrorhiza kurroa, on arachidonic acid metabolism, FEBS Letters 1992, vol.2, no. 3, pp. 254-256
[146] K. L. Joy et al, Effect of Picrorhiza kurroa extract on transplanted tumors and chemical carcinogenesis in mice, Journal of Ethnopharmacology, Volume 71, Issues 1-2, July 2000, Pages 261-266.
[147] Arya D et al, Studies on natural resources, trade and conservation of Kutki (Picrorhiza kurroa Royle ex Benth. Scrophulariaceae) from Kuman Himalaya. Scientific Res Essays 2013, 8(14): 575-580. 
[148] Mulliken TA (2000). Implementing CITES for Himalayan Medicinal Plants Nardostachys grandiflora and Picrorhiza kurroa. In: TRAFFIC Bulletin 18, 63-72.    
[149] Zhang YJ et al, Chinese-English Chinese Traditional Medicine World Dictionary. Shanxi People’s Press, Shanxi, China.
[150] Amatya G. Medicinal and Aromatic Plants and NTFPs Project, IUCN Nepal, 2005: in litt. To TRAFFIC International
[151] Lama YC et al, (2001). Medicinal Plants of Dolpa: Amchis Knowledge and conservation. 150 pp, WWF Nepal Program and People & Plant Initiative, Kathmandu, Nepal
[152] Hamdard (1968), Qarabadain-eHamdard, Pharmaceutical Advisory Council, Hamdard Academy, Karachi, Pakistan
[153] http://easyayurveda.com/2014/07/17/kutki-picrorhiza-kurroa-benefits-dose-side-effects-research/ 
[154] http://www.herbal-supplement-resource.com/picrorhiza-kurroa-root.html 
[155] J Res Ind Med 1966; 1: 1-13 
[156] http://www.diagnose-me.com/treatment/picrorhiza.php 
[157] Pfuhler S et al, Investigation of genotoxic effects of the antihistaminic and anti-inflammatory drugs Apocynin and Acetosyringenin in the Salmonella typhimurium mutagenicity assay and the SCE-test with human lymphocytes, Phytomedicine. 1995 Apr; 1(4): 319-322 
[158] http://www.herbal-supplement-resource.com/picrorhiza-kurroa-root.html
[159] http://ayurdrugs.blogspot.in/2010/06/katuki-consists-of-dried-rhizome-with.html
[160] http://www.ayurveda.hu/api/API-Vol-2.pdf 
[161]  http://easyayurveda.com/2014/07/17/kutki-picrorhiza-kurroa-benefits-dose-side-effects-research/ 
[162]https://examine.com/suppliments/picrorhiza-kurroa/
[163] http://www.herbal-supplement-resource.com/picrorhiza-kurroa-root.html
[164] http://www.herbal-suppliment-resource.com/picrorhiza-kurroa-root.html
[165] Elizabeth WM: Major herbs of Ayurveda, The Dabur Research foundation and Dabur Ayurved Limited. 2002; p. 220-222 
[166] Anonymous: The Ayurvedic Pharmacopoeia of India. Part-I, Government of India, Ministry of Health and Family welfare Department of Ayush. 2007; 2: 91-93 




Comments

Popular posts from this blog

Bhumyamalaki (Phyllanthus amarus, Phyllanthus niruri)

AMALAKI (Phyllanthus emblica, Emblica officinalis)

Methee-Fenugreek (Trigonella foenum-graecum L)