Kutki

Picrorhiza kurroa (of the family scrophulariaceae), also known as Kutki or Katuki, is a perennial herb used in Ayurveda and sometimes used as a substitute for the herb gentiana kurroo; and tends to grow in the Himilaya region on rocky places within 3000-5000m above sea level.^[1] It is traditionally used for liver disorders, but has also been implicated in the treatment of upper respiratory tract, fevers, dyspepsia, chronic diarrhea, and scorpion stings^[1] as a part of the formulations Arogyavardhini, Tiktadya ghrita, Jatyadi ghrita, Punarnavasava and Nimbadi churna.^[2] It is sometimes used interchangeably with the similar herb Picrorhiza scrophulariiflora, which contains the same bioactives.^[3]

The plant is also known to be highly bitter (white root moreso than black root) which led to its name (as picros is greek for 'bitter') and appears to be endangered due to overharvesting.^[1] It should not be confused with picrotoxin, which is a completely different molecule that also happens to be better (hence the picros).

Picrorhiza kurroa is a bitter herb used in Indian medicine for the purpose of helping the liver and digestion, among other usages. It grows in a limited region and altitude, and is currrently overharvested to an endangered status

• The bitter principle known as 'Kutkin',^[4] which is a mixture of picroside I and picroside II (kutkoside).^[2] These are irioid glycoside structures^[5] present at 1.611% and 0.613% of the roots dry weight, respectively^[3]
• The α-methoxy substituted catechol Apocynin,^[6] structurally similar to vanillic and ferulic acids
• Androsin^[7]
• Cucurbitacin glycosides based on cucurbitacin B and dihydrocucurbitacin B^[8]

The main ingredients are the two molecules that make up the mixture called kutkin (or picroliv), which are picroside I and picroside II; both molecules are based off the same backbone, but one contains a cinnamic acid group and the other an apocynin group.

Storage of picrorhiza kurroa at 50°C for three to six months appears to not result in any significant degradation, although storage at 60°C for this time frame resulted in a 30-50% rate of degradation.^[9]

Higher than average temperatures may degrade the bioactives in the plant. While refrigeration does not appear to be necessary, it may be prudent to store it away from heat producing appliances

Picroliv is a mixture of kutkin (picroside I and picroside II) in a 1:1.5 ratio^[10] which has a slightly higher concentration of picroside II than does basic kutkin (45:55).^[2] 60% of the mixture by weight is picrosides I and II, with the other 40% being micellaneous irioid glycosides.^[11]

Picroliv is another name for kutkin, and while kutkin tends to have a more balanced profile picroliv tends to favor a higher concentration of picroside II

Picrolax is a brand name for an extract of Picrorhiza kurroa which is recommended for laxative purposes. This extract appears to confer 45mg picroside I (0.02%) and 17.6mg picroside II (0.01%) for every 1.585g of supplement^[2] suggesting that other bioactives play a more significant role.

Picrolax is a form of picrorhiza kurroa that is sold for its laxative purposes; it has a low concentration of kutkin but high enough doses may still be hepatoprotective

Irioid glycosides (picroside I and picroside II) are known to be able to be hydrolyzed in the intestines leading to their aglycones, as evidenced by aucubin.^[12] This is hypothesized to partly underlie the poor oral bioavailability of picrosides^[2] which is common among most irioid glycosides.^[13][14][15] Isolated kutkin has a poorer bioavailability than does the plant extract however,^[2] suggesting some synergism between components of the plant.

Like most irioid glycosides, the picrosides (components that make up kutkin) appear to be poorly absorbed. The exact bioavailability was not calculated

Following ingestion of Picrorhiza kurroa, picroside I has been detected in the blood at a C_max of 206.10+/-7.09ng/mL (45mg/kg via 100mg/kg kutkin), a C_max of 357.88+/-5.74ng/mL (same dose via 510mg/kg plant extract), and a C_max of 301.43+/-9.19ng/mL (same dose via 1.585g/kg picrolax).^[2] All T_max values were approximately one hour, and the half-life was 50-56m for mixtures and 37m for pure kutkin.^[2]

Following ingestion of Picrorhiza kurroa, picroside II has been detected in the blood at a C_max of 152.62+/-11.54ng/mL (55mg/kg picroside II via 100mg/kg kutkin), a C_max of 134.67+/-18.18ng/mL (32.3mg/kg via 510mg/kg plant extract), and a C_max of 76.64+/-3.69ng/mL (17.6mg/kg via 1.585g/kg picrolax).^[2] Picroside II also has a T_max of approximately one hour, but a shorter half-life between 15-30m.^[2]

Picrosides reach serum at a low nanomolar concentration

Picroside II appears to be predominately (80%) conjugated in the blood as either a glucoronide or sulfate, with 20% of circulating picroside II being eliminated in its free form.^[16]

Picrosides appear to be conjugated by Phase II metabolic enzymes

In mice given a high fat diet, 50-200mg/kg of picrorhiza kuroa daily for 12 weeks appears to be able to normalize most parameters of lipid metabolism (triglycerides, cholesterol, LDL-C) although without apparent influence on HDL-C; these changes were thought to be secondary to aiding the liver^[17] and has been seen elsewhere with lipid alterations induced by PX-407.^[18]

Secondary to helping the liver, there may be reductions in circulating triglycerides and LDL cholesterol

100-200mg/kg of a water extract of picrorhiza kurroa over the course of 14 days in diabetic rats (streptozotocin induced) is able to improve blood glucose and insulin levels in a dose-dependent manner, with the 200mg/kg dosage being nonsignificantly less potent than the reference drug of 10mg/kg glibenclamide.^[19]

There may be antidiabetic properties of the plant, but they are mostly unexplored and trend to underperform relative to the reference drug glibenclamide

Apocynin appears to be able to inhibit NADPH oxidase in neutrophils in vitro at 4µg/mL concentration, with a potency somewhat comparable to 20µg/mL vanillic and ferulic acids^[20] and appears to be effective in microglia at 500µM.^[21]

Oral ingestion of apocynin at 100mg/kg thrice daily alongside MPTP toxin (to induce parkinson's like effects via microglia activation) was able to alleviate symptoms, which was attributed to NADPH oxidase inhibition.^[6] NADPH oxidase activation is known to be involved in the pathology of MPTP^[21] and protective effects have been noted with other NADPH oxidase inhibitors such as Spirulina.^[22]

Apocynin appears to be an NADPH oxidase inhibitor, albeit significantly weaker than the reference supplement (C-phycocyanobilin from spirulina)

200mg/kg of the rhizome of kutki for 14 days prior to immunosuppression (cyclophosphamide) is able to partly preserve the reduction in antibody titer seen in immunosuppressed control and slightly increased antibodies in control mice.^[23]

There appears to be an increase in antibodies in mice given oral supplementation of the plant, and this may occur with and without immunosuppression

A phenolic glycoside known as androsin found in picrohiza kurroa appears to be able to reduce allergic reactions at an oral dose of 10mg/kg in guinea pigs an hour prior to inhalation challenge^[7] or 500µg inhalative.^[24]

One study using a combination supplement of picrorhiza kurroa (270mg of 30% apocynin), ginger (100mg of 5% gingerols), and ginkgo biloba (130mg of 24% ginkgoflavones) taken twice daily for 20 weeks failed to note any significant benefit on Peak Expiratory Flow Rate (PEF) or FEV1 and only trends to improve asthmatic symptoms.^[25]

No significant known interactions with asthma

An ayurvedic mixture of herbs (Arogya-wardhani) of which is 50% picrorhiza kurroa by weight has been noted to have efficacy against acute viral hepatitis^[26] and when 375mg of picrorhiza kurroa thrice daily for two weeks (daily dose of 8.16-8.64mg picroside I and 16.5-18mg picroside II) was able to reduce serum bilirubin and enzymes in a time dependent manner.^[9]

The lone human study noted that the well known hepatoprotective effects applied to humans with acute viral hepatitis over the course of two weeks of supplementation

Picroliv (25mg/kg) orally to rats for six weeks effectively abolished (over 90% normalization) the changes induced by aflatoxin despite not having a significant effect on rats not given aflatoxin^[27] and this potency against aflatoxin specifically has been replicated elsewhere with comparable potency to 20mg/kg silymarin (from milk thistle, comparable molar doses) although the 84-100% protection seen with picroliv was less variable than silymarin (53-100%) and while silymarin was more effective at reducing lipid peroxidation picroliv is more effective at reducing liver enzymes (GPT and ALP).^[28][11] Picroliv appears to be effective when given prior to the toxin^[27] and when given after toxin exposure for one week,^[29] two weeks,^[11] and six weeks.^[28]

Although most studies assess the protective effects of picroliv against aflatoxin it has also shown protective effects against oxytetracycline (at 1.2-12mg/kg picrolive),^[30] carbon tetrachloride (12mg/kg picroliv),^[31][32] thioacetamide,^[33] paracetamol,^[34][35] cadmium,^[36][37] ischemia^[38] and partial hepatectomy,^[39] monocrotaline,^[40] hydrazine,^[41] galactosamine (12mg/kg picroliv),^[42][9] and alcohol.^[43] Most notably, picroliv also appears to be protective against poisoning from the deathcap mushroom (Amanita phalloides) with protective effects comparable to silybinin yet greater rehabilitative effects.^[44]

When looking at the studies on alcohol specifically when thirty days of alcohol ingestion (3.76g/kg in rats) was followed up with coingestion of alcohol and 12mg/kg picroliv for 15 days, picroliv was able to attenuate the adverse changes (although not absolute protection)^[43] although 45 days of continuous ingestion at 12mg/kg caused full protection (3mg/kg causing 36% protection).^[45]

Picroliv (picrosides I and II) appears to be very potently protective of the liver in rats, in accordance with its claims in ayurvedic medicine. The protective effects seem to extend to pretty much every liver stressor tested, and seems to persist when taken either in a prophylactic (preventative) or rehabilitative manner

In general, when picroliv is used at the higher dosage (25mg/kg oral ingestion) and compared to an equimolar dosage of silymarin (20mg/kg) they are comparable in protective effects^[28][11] but when lower doses of picroliv (12.5mg/kg or less) are compared against an equimolar dose of silymarin (10mg/kg or less) picroliv appears to be more potent.^[30] Doses in the 50-100mg/kg range for picroliv are still comparable to equimolar doses of silymarin, and is also comparable to curcumin and ellagic acid.^[32][34]

When compared to other hepatoprotective agents, picroliv appears to be as potent as silymarins (from milk thistle) when they are compared at higher doses and stronger when they are compared at lower doses

Picroliv possesses chloretic and anticholestatic potential in rats treated with paracetamol and ethynyl estradiol,^[35] CCl₄,^[46] alcohol,^[45] and cadium.^[36][37] In this regard, supplementation of 3-6mg/kg to rats is effective yet there markers of cholestasis are fully normalized with prolonged ingestion (2 weeks or longer) of 12mg/kg picroliv^[46][45] and seems more potent than an equimolar dose of silymarins.^[35]

There appears to be an anticholestatic potential for picroliv in instances of liver damage which is maximized (absolute protection) at a chronic rat intake of 12mg/kg. This potency exceeds silymarins from milk thistle

When looking at fatty liver (steatohepatitis) in rats fed a high fat diet, 200-400mg/kg of a 50:50 ethyl alcohol:water picrorhiza kurroa extract (6.54% picrosides) is able to significantly reduce liver fat over the course of four weeks supplementation, with the higher dose having a greater potency than 50mg/kg silymarins.^[47] The increase in liver fat from changing to a high fat diet in rats was fully prevented, and the picrorhiza kurroa group ended up with 42% the liver fat seen in the control group.^[47]

Steatohepatitis induced by hydrazine is also prevented with supplementation of picrosides at 50mg/kg.^[41]

The liver protective effects seem to extend to reducing fatty liver, where picrorhiza kurroa seems very effective at preventing fatty liver (its benefits also seem general rather than specific for a particular cause of fatty liver)

In inflammatory bowel diseases (ulcerative colitis), the release of inflammatory cytokines such as IL-1β and TNF-α are involved in pathology^[48][49] and suppressing their release via inhibiting NF-kB is seen as therapeutic.^[50][51]

In a mouse model of dextran-sulfate-sodium (DSS) induced colitis, supplementation of 12.5mg/kg picroliv for seven days following DSS ingestion (for seven days prior to picroliv and continued throughout supplementation) was able to attenuate the reduction in colon length and improve histological scores by about half.^[10] These benefits correlated with less NF-kB mRNA induction and less release of inflammatory cytokines (IL-1β and TNF-α) and oxidation.^[10]

Appears to have moderately potent antiinflammatory effects in an animal model of ulcerative colitis

The alterations seen in kidney oxidative markers from aflatoxin are potently suppressed with ingestion of 25mg/kg picroliv in rats for 14 days after aflatoxin ingestion, with a potency somewhat comparable to 20mg/kg silymarin.^[11] When comparing the protective effects in the liver against the protective effects in the kidneys, picroliv seems slightly more effective in protecting the liver (in a model of cadmium toxicity).^[37]

The liver protective effects may also extend to the kidneys, suggesting a general protective effect against organ function

Two studies that noted protective effects in the liver against cadmium toxicity have confirmed that these protective effects may extend to the testes.^[52][53]

General protective effects may extend to the testes

Supplementation of 200mg of the dried rhizome twice daily alongside methoxsalen therapy was able to significantly reduce symptoms of vitiligo, with 10% of the group nonresponsive to picrorhiza kurroa intervention and 27% of the group experiencing complete resolution of symptoms.^[54]