Pharmacology of Chitraka (Plumbago zeylanica) Part 2
Pharmacology
of Chitraka (Plumbago zeylanica) Part
2
By
Dr.
Hemant Vinze M. S.
Actions
on CNS
Aqueous, ethanol, chloroform,
petroleum ether and acetone extracts of leaves of Chitraka (Plumbago zeylanica) were tested for
analgesic activity in rats. The study revealed that the acetone and petroleum
ether extracts significantly decreased pain only in the later phases of
formalin test, suggesting that the drug could be acting peripherally. The
analgesic action of Chitraka (Plumbago
zeylanica) was attributed to plumbagin. [58]
The plant callus is a growing
mass of unorganized plant parenchyma cells. The callus extract and the root
extract of Chitraka (Plumbago zeylanica)
were evaluated for central and peripheral analgesic activity. The study revealed
that at 200 mg/kg, the root extract and at 400 mg/kg the callus extract
displayed significant analgesic activity in experimental animal (mice) models. [59]
In Ayurveda herbs are grouped
according to their prominent pharmacological actions. The groups are called ‘Ganas’. Chitraka (Plumbago zeylanica) is grouped in ‘Aamalakyaadi Gana’. Manoj J et al, evaluated actions of ‘Aamalakyaadi Gana’ on CNS in Wistar
albino rats. The study showed that the ‘Gana’ showed antipyretic, analgesic
activity. As Chitraka (Plumbago zeylanica)
belongs to ‘Aamalakyaadi Gana’, it
was concluded that by inhibiting synthesis of prostaglandin locally Chitraka (Plumbago zeylanica) shows antipyretic
activity. Further, Chitraka (Plumbago
zeylanica) also has analgesic effect through central and peripheral
mechanism. These effects are dose dependent. [60]
The chloroform extract of root
of Chitraka (Plumbago zeylanica) at
200mg/kg body weight has shown promising memory enhancing effect in mice brain.
The antioxidant effect of Chitraka (Plumbago
zeylanica) was said to be effective in reversing amnesia induced by
scopolamine at 0.4mg/kg body weight. The herb also enhanced the learning
ability of mice. [61]
Some researchers have reported
anti-inflammatory and analgesic activity of hydro-alcoholic extract of leaf of
Chitraka (Plumbago zeylanica). [62]
The dried extract of root of
Chitraka (Plumbago zeylanica) may ameliorate Parkinsonism without
developing side effects. [63]
In an experimental study, single oral dose of 100, 200, 300 mg/kg
body weight of 50 % ethanol extract of root of Chitraka (Plumbago zeylanica) significantly
increased the spontaneous motility in animals. [64]
Actions on CVS
A study showed that plumbagin administered to hyperlipidaemic
rabbits, lowered total cholesterol by 53 to 86 percent and LDL-cholesterol by
61 to 91 percent. It lowered cholesterol/phospholipid ratio by 45.8 percent.
Plumbagin also elevated significantly the lowered level ofHDL-cholesterol.
Further, plumbagin prevented the accumulation of cholesterol and triglycerides
in liver and aorta. Plumbagin regressed the atheromatous plaque in thoracic and
abdominal aorta. Wheh treated with plumbagin, hyperlipidaemic subjects excreted
more cholesterol and phospholipids in faeces.
[65], [66]
Actions on RS
A study showed that plumbagin had the ability to suppress the
non-small cell carcinoma of the lung [67]
Actions
on GI System
Feeding of root of Chitraka (Plumbago zeylanica) has been shown to
proliferate coliform bacteria in mice. This activity is similar to that of
‘Mexaform’. Chitraka (Plumbago zeylanica)
normalizes gastrointestinal flora. Scientists attribute digestive stimulant and
appetizer activity of Chitraka (Plumbago
zeylanica) to this normalization of gastrointestinal flora. [68]
Recently Helicobacter pylori is shown to be associated with peptic
ulceration and gastric cancer. A study showed that Chitraka (Plumbago zeylanica) had the highest inhibitory
effect against Helicobacter pylori.
Thus Chitraka (Plumbago zeylanica)
prevents the development of peptic ulcer and gastric carcinoma. [69]
In another group the animals
given plumbagin along with the carcinogen had a lower incidence of tumors in
the entire intestine.
These data suggest that
plumbagin from Chitraka (Plumbago
zeylanica) could be a promising chemopreventive agent for human intestinal
neoplasia. [72]
Actions
on Liver
In a study plumbagin in
ethanolic extract of Chitraka (Plumbagin
zeylanica) protects liver from paracetamol-induced toxicity. Furthermore,
in rats, at 300mg/kg bodyweight plumbagin normalized the elevated levels of
liver enzymes in paracetamol-induced hepato-toxicity. Plumbagin also protected
the liver against paracetamol-induced hepatocellular injury as was evident on
histopathological study. [73]
In another study on Wistar
rats, the methanolic extract of aerial parts of Chitraka (Plumbagin zeylanica) protected the liver from carbon tetrachloride
(CCl4)-induced hepatotoxicity as was evident by normalization of elevated
levels of total serum bilirubin, SGOT and SGPT. Histological studies also displayed
the normalization of liver structure. The methanolic extract of aerial parts of
Chitraka (Plumbagin zeylanica) was
superior to 100 mg/kg bodyweight per animal of silymarine in hepatoprotection. [74]
A study showed that plumbagin
found in Chitraka (Plumbagin zeylanica)
inhibited cell proliferation of hepatocellular carcinoma and accelerated
apoptosis of Hep G2 cells. Plumbagin also inhibited Hep G2 cell invasion. The
effect was dependent on the dose used. [75]
By restraining the mRNA and
protein expression of α-smooth
muscle actin (α – SMA) plumbagin found in Chitraka (Plumbagin zeylanica) could inhibit the activation and proliferation
of human hepatic stellate-LX2 (HSC-LX2) cells.
Plumbagin can also have antihepatic fibrosis effect. [76]
Experimental
study on mice suggested that antihepatic cancer activity of plumbagin was due
to the elevated levels of cytokine IL-2 and TNF- α. Plumbagin also showed anti-tumor
activity in vivo. [77]
In
Kunming mice plumbagin prolonged the survival time of H22 ascites hepatoma
bearing animals. Plumbagin also stabilized or increased the body weight of
these animals. [78]
Actions
on Pancreas
In an experimental study in the
United States, administration of plumbagin isolated from root of Chitraka (Plumbagin zeylanica) was found to
inhibit, in vitro and in vivo, the growth of pancreatic cancer
cells. Plumbagin was found to induce apoptosis in pancreatic cancer cells.
Furthermore, intra-peritoneal administration of plumbagin in rats, at doses of
2 mg/kg bodyweight 5 days a week resulted in significant inhibition of tumor
both in weight and volume. These results suggest that plumbagin may be a useful
therapeutic agent against human pancreatic cancer. [79]
In experimentalstudy on
laboratory animals plumbagin isolated from Chitraka (Plumbagin zeylanica) inhibited the groth of pancreatic cancer
(Panc-1 and Bxpc-3) cells in a dose dependent manner. The degree of apoptosis
was assessed by measuring the proportions of sub-G (1), annexin V+/propidium
iodide, and terminal-deoxynucleotidyl-transferase-mediated-nick-end labeling
(TUNEL) + cells. A significant increase in apoptotic calls was observed.
Exposure to plumbagin caused upregulation of Bax, rapid decline in
mitochondrial transmembrane potential, apoptosis-induced factor over expression
in cytosol and cleavage of procaspage-9 and ADP-ribose polymerase. Pretreatment
with caspase inhibitors did not block plumbagin-induced apoptosis. [80]
A study conducted on obese
patients by Kotecha M and Rao K S (2007) in Gujarat, India showed that Chitraka
(Plumbagin zeylanica) powder at the
dose of 500 mg/kg bodyweight four times a day for 45 days with restricted, low
calorie diet showed that Chitraka (Plumbagin
zeylanica) was useful for the treatment of obesity. [81]
Sharma et al demonstrated
hypocholesterolemic activity of Chitraka (Plumbagin
zeylanica). The study was carried out in hyper-lipidemic rabbits with
active component plumbagin. The study showed that plumbagin lowered total serum
cholesterol by 53 to 86% and LDL-cholesterol by 61 to 91%. Furthermore
plumbagin prevented the accumulation of cholesterol and triglycerides in the
liver and aorta.
Another study on hyperlipidemic
rabbits showed that administration of ethanolic extract of roots of Chitraka (Plumbagin zeylanica) at doses of 500
mg/kg body weight with normal diet for two months significantly lowered total
cholesterol, LDL cholesterol and triglyceride. The reduction was almost double
when given in combination with Vitamin E.
[82]
A study on hyperlipidemic
rabbits showed that, treatment with plumbagin not only prevented the
accumulation of cholesterol and triglycyrides in the liver and aorta but also
regressed atheromatous plaque of thoracic and abdominal aorta. Treatment with plumbagin
helped excrete more cholesterol and phospholipids in faeces in hyperlipidemic
rabbits. [83], [84]
Actions
on Diabetes
To evaluate effects of plumbagin
isolated from Chitraka (Plumbagin zeylanica) in
streptozotocin-induced diabetic rats, plumbagin was administered orally at
doses of 15 and 30 mg/kg bodyweight to streptozotocin-induced diabetic rats for
28 days. The results showed that plumbagin significantly lowered raised blood
sugar and significantly altered all other parameters to near normal levels.
[In the paper, method of
isolation of plumbagin (aqueous, alcoholic or hydro-alcoholic) is not mentioned]
Some researchers observed
hyperglycaemia in rats treated with ethanolic extract of root of Chitraka (Plumbagin zeylanica), while most
researchers have reported antidiabetic (hypoglycaemic) activity. To evaluate
these contradictory results, Olangunju et al studied the biochemical basis of
the effects of ethanolic extract of Chitraka (Plumbagin zeylanica) on key enzymes of glycolysis and other
biochemical parameters in rats. The results showed that hexokinase,
phosphofructokinase, pyruvate kinase and lactate dehydrogenase activities in
thigh muscles were significantly reduced. The protein synthesis in the muscles
was not affected. The serum pyruvate and lactate were significantly lowered.
The reduction in the activities of the key enzymes of glycolysis and its end
products suggest a reduction in flux across the glycolytic pathway. This may be
a result of impaired delivery to, and utilizitation of, glucose by peripheral
tissue.
(In the study by Olangunju et
al it is not mention whether the animals treated with ethanolic extract of root
of Chitraka (Plumbagin zeylanica)
were diabetic, euglycaemic or hypoglycaemic)
Glucose transporter type-4
(GLUT-4) is a protein encoded in humans by the SLC 2A4 gene. It is
insulin-regulated glucose transporter. It is found primarily in adipose tissues
and skeletal and cardiac muscle (striated muscle). At the cell surface glucose
transporter type-4 (GLUT-4) facilitated diffusion of circulating glucose down
its concentration gradient into muscle and fat cells. Once within cells,
glucose is rapidly phosphporylated by glucokinase in the liver and hexokinase
in other tissues to form glucose-6-phosphate, which then enters glycolysis or
is polymerized into glycogen. Glucose-6-phosphate cannot diffuse back out of
cells, which also serves to maintain the concentration gradient for glucose to
passively enter cells.
These studies on hypoglycaemia
and hyperglycaemia caused by plumbagin/ Chitraka (Plumbagin zeylanica) led to a concept of “glucose homeostasis” in
cells, adipose tissue and muscle.
[Plumbagin/ Chitraka (Plumbagin zeylanica) enhanced GLUT4 transportation and contribution to glucose homeostasis.]
This makes Chitraka (Plumbagin zeylanica) an unique herb in
the treatment of diabetes. [87], [88], [89]
NADPH oxidase 4 (Nox 4) is
reported to be the major source of reactive oxygen species (ROS) in the kidneys
during the early stages of diabetic nephropathy. A study demonstrated that
plumbagin at a dose of 2mg/kg body weight prevents the development of diabetic
nephropathy through Nox 4 signaling pathways. [90]
Actions
on Male Reproductive System
For years Chitraka (Plumbagin zeylanica) has been used for
regulation of male fertility. [91]
Another study on mice showed
that administration of plumbagin from Chitraka (Plumbagin zeylanica) at 2mg/kg body weight, five days in a week for
eight weeks inhibited the growth of prostate cancer. There was a significant
inhibition of metastases also. These results were confirmed by histopathology
of these organs. [93]
Treatment
with plumbagin from Chitraka (Plumbagin
zeylanica) at the dose of 2mg/kg body weight also arrested or delayed the
development and growth of metastases from hormone refractory prostate cancer by
three weeks. Discontinuation of plumbagin for as long four weeks did not result
in progression of tumor growth or metastases. [94]
Actions
on Female Reproductive System
In female Wistar rats, plumbagin-free
alcohol extract of root of Chitraka (Plumbagin
zeylanica) at the doses of 300 and 500 mg/kg body weight exhibited
significant anti-implantation and abortificient activity. These effects were
dose-dependent. These effects were possibly through the changes in the
implantation site, altered hormonal levels, prolonged estrous cycle and
anti-estrogenic activity. The extract posseses reversible antifertility
activity without adverse toxicity in female rats. [95]
A study on female albino rats
showed that treatment of pregnant rats during first seven days of pregnany with
Chitraka (Plumbagin zeylanica) root
powder destroyed uterine luminal proteins the of molecular weights 13,000,
19,000, 26, 000 and 75,000 Da (Dalton) resulted in loss of embryo in
preimplantationary period. This suggested that these proteins influence the
implantation of embryo and continuation of the pregnancy; their destruction
results in abortion. [97]
Radiotherapy is the primary
line of treatment for cervical cancer. However radiotherapy is limited by total
dose that can be given without damaging normal tissue. In a study plumbagin
from Chitraka (Plumbagin zeylanica)
sensitized cervical cancer cells to radiation increasing the safety to normal
tissue. This supplementation of plumbagin from Chitraka (Plumbagin zeylanica) showed a five fold increase in the activation
of caspase 3 in C33A cells. Plumbagin also modulated the expression of
apoptotic regulatory molecules Bcl-2, Bax and Survivin. This study showed that
combination of plumbagin and radiation is a better way to inhibit the growth of
cervical cancer than higher dose of radiation alone. [98]
Another study showed that
plumbagin induced cell death in cervical cancer cell line ME-180. The cytotoxic
effect of plumbagin-induced cell death was said to be through the generation of
reactive oxygen species (ROS) and subsequent induction of apoptosis. Treatment
of cancer cells with plumbagin caused loss of mitochondrial membrane potential
and morphological changes observed in cell apoptosis such as nuclear
condensation, DNA fragmentation and translocation of phosphatidyl serine.
Moreover, plumbagin-induced apoptosis involved release of mitochondrial
cytochrome c and AIF (apoptosis inducing factor), thus activating caspase-dependent
and caspase-independent pathways. [99]
Antitumor
activity
In Swiss albino mice,
pretreatment with alcoholic extract of root of Chitraka (Plumbagin zeylanica) at doses of 250 and 500mg/kg body weight
orally for five days protected the animals from cyclophosphamide-induced
genetoxicity and oxidative stress. [100]
Plumbagin derived from Chitraka
(Plumbagin zeylanica) inhibited NF-
κB activation induced by tumor necrosis
factor (TNF), other carcinogens and carcinogenic inflammatory stimuli such as
H2O2, cigarette smoke condensate, okadaic acid, lipopolysaccharide,
interleukin-1 β
and phorbol 12-myristate 13-acetate. Plumbagin also suppressed activation of NF-
κB in certain tumor cells. Cellular
proliferation, carcinogenesis and radioresistence are regulated by the
activation of transcription factor NF-
κB. This suggests that plumbagin might
affect NF-
κB activation pathway. Plumbagin also
suppressed the direct binding of nuclear p65 and recombinant p65 to DNA.
Plumbagin down-regulated the expression of NF-
κB-regulated anti-apoptotic,
proliferative and angiogenic gene products. This may explain cell growth
modulatory, anticarcinogenic and radiosensitizing effects of plumbagin. [101]
Another
group of investigators identified and isolated important groups of cytotoxic
drugs from roots of Chitraka (Plumbagin
zeylanica): Plumbagic acid glucosides (3’-O- β-pyranosoyl plumbagic acid and 3’-O- β-pyranosoyl plumbagic acid
methylester) and five naphthaquinones (plumbagin, chitranone, maritinone,
elliptinone and isoshinanolone) and five coumarins (seselin, 5’-methoxyseselin,
suberosin, xanthyletin and xanthoxyletin). Of these, plumbagin suppressed
growth of Raji, Calu-1, HeLa and Wish tumor cell lines. [103]
Toxicity
In acute toxicity study, the
methanolic extract of Chitraka (Plumbagin
zeylanica) did not show toxicity up to the highest dose of 2000 mg/kg body
weight. However doses 100, 200 and 400 mg/kg body weight are selected for
pharmacolological use. [104]
Some researchers have reported
adverse brain toxicity of methanol extract of root of Chitraka (Plumbagin zeylanica) at dose of 160mg
/kg body weight, repeated during 15 days. Alteration in biochemical parameters
was noted with significant changes in levels of LPO, GOT andGPT activities.
There were significant changes in the histopathological studies in the brain. [105]
In Ethiopia Chitraka (Plumbagin zeylanica) used for skin
diseases was seen to show systemic and dermatotoxicity. Methanol extract of
root of Chitraka (Plumbagin zeylanica)
having 80% concentration produced moderate skin irritation and ear swelling in
rats.
Repeated dose administration
was associated with increased weight of testes, higher values of blood urea
nitrogen and potassium in both sexes of rats. These toxic effects were observed
at hightest dose 1000mg/kg body weight. [106]
Toxicity of plumbagin was not
found to be mediated by cell membrane but was mediated by oxidative stress.
[107]
Contraindications
Chitraka (Plumbago zeylanica) should not be used in women of child bearing
age and pregnant women.
Chitraka (Plumbago zeylanica) should not be used beyond recommended doses.
Chitraka (Plumbago zeylanica) should not be used in subjects having
neurological disorders. [108]
Traditional
and Ayurvedic uses
As anti-inflammatory and
anti-edema (Shothaghna)
As analgesic (Wedanana-shamak)
As antipyretic (Jwaraghna),
diaphoretic (Sweda-janana)
In impaired weak digestion as
appetizer and digestive (Deepana, Paachana)
As anthelmintic (Krimighna)
In diarrhea, dysentery (As
grahee in atisaar, in dysentery, in colitis)
Arsha (Piles, fissures in ano)
Udara/ Jalodara (Ascites,
cirrhosis of the liver)
As antitussive (Kaasaghna, in
bronchitis)
In bronchial asthma (Shwaasa)
In skin disorders, leucoderma,
leprosy (Kushtaghna)
In anaemia (Pandu roga)
In obesity for weight loss
(Lekhana)
As adaptogen (Rasaayana)
Boils, furuncles, abscesses
(Gulma)
Wounds, ulcers (Wrana)
Shleepada (Filariasis, filarial
edema) [109], [110], [111]
Additional
information:
Inflammations:
Chew
two leaves of Chitraka (Plumbago zeylanica) twice a day.
Alternatively apply paste of leaves to inflamed area.
Atisaar
(Diarrhea): Mix half a tablespoonful of powder of root of Chitraka
(Plumbago zeylanica) with one glass
of warm water, take it twice a day.
Piles:
Dust
the powder of the root of Chitraka (Plumbago
zeylanica) to affected area
Liver
Tonic: Crush dried Chitraka (Plumbago
zeylanica) plant to make powder, take two grams of powder with lukewarm
water twice a day.
Scrofula
(Tubercular lymphadenopathy): Crush leaves of Chitraka (Plumbago zeylanica), make paste, mix
with castor oil, warm it and apply to the affected part
Scabies:
Apply
milky juice of Chitraka (Plumbago
zeylanica) to the affected part
Skin
diseases: Crush leaves of Chitraka (Plumbago zeylanica) , make paste and apply to affected parts twice
a day
Leprosy:
To
powder of Chitraka (Plumbago zeylanica)
add water, make paste and apply to skin lesions.
Extensive
Skin disease: Sprinkle roor powder on affected areas.
Alternatively mix the powder of the root of Chitraka (Plumbago zeylanica) in bathing water and take bath with this
medicated water. [112]
Preparations and doses
Purification of Chitraka
Usually
purification of Chitraka (Plumbago
zeylanica) is not required and not done. Some authors recommend
purification of Red Chitraka (Plumbago
rosea)
Procedure
ofpurification: Cut roots of Red Chitraka (Plumbago
rosea) in small pieces, immerce them in 3-4% lime water, allow to steep for
3-4 hours, change lime water every 3 hours, repeat the process 3-4 times,
takeout the roots, they are ready to use now.
Some
authors have mentioned to steep roots for three days, changing lime water every
day. [113]
Dose: The usual dose of root powder is 1-3 grams once to thrice a
day.
Kushtha,
Twachaa roga: Root powder 1-3 grams with cow’s urine three
times a day
Atisaar:
Root
powder 1-2 grams three times a day
Arsha:
Root
powder 1-2 grams with butter milk three times a day
Medoroga,
medaatya: Root powder with honey 1-2 grams
Shleepad,
wounds, ulcers: The root paste is applied to affected parts
Twacharoga
(Dermatitis): Prepare paste by mixing root powder with water and apply to affected parts
Sandhiwaata,
Sandhishoth (Arthritis): Chitraka tailam (Medicated oil) prepared by
boiling chitraka moola (roots) with sarpagandha in mustard oil, is to be
applied to joints.
Scabies:
Prepare
paste of leaves or bark powder with haridraa (turmeric) and apply to the
affected areas.
Rasaayana
(Rejuvenator, Adaptogen): Root powder 1-2 grams to be consumes with
cow ghee and tila tailam (sesame oil) for one year.
Choorna (Powder): 1-2
gram
Kwatha Decoction: 25-50
ml
Chitrakaadi watee (Chitraka tablets): 2
tablets twice a day with water [114], [115]
References
from Ayurvedic Texts /Manuscripts
Grahanee
(Chronic diarrhea, dysentery, Colitis): Chitrakaadi Gutika (Pills),
Chitraka ghrita
[Charaka Samhitaa, chikitsaa
sthaana, 15/96-97]
Arsha:
Kalka
of chitraka mixed with shunthee and gruel is applied to fissures, piles. Pealed
bark is made into kalka, mixed with takram (buttermilk) to be taken orally
[Charaka Samhitaa, chikitsaa
sthaana, 14/68; Charaka Samhitaa, chikitsa sthaana, 14/76; Sushrut Samhitaa,
chikitsa sthana 6/13]
Pandu
(anaemia): Chitraka moola + Bala moola 10 grams to be taken
with warm water; or alternatively shigru beeja (seeds of drumstick) mixed with
equal salt (such a patient should be on milk diet)
[Sushrut Samhita, Uttar tantra,
44/26]
Udara
roga (Ascites): Chitrakadi ghrita
[Charaka Samhitaa, chikitsaa
sthaana, 13/116]
Shotha
(Inflammation, Edema): Local application of warm paste:
Chitraka+Devadaaru, Chitraka+
Powdered seeds of Drum stick with go-mootra (cow urine), Chitraka+ Sarshapa
(Mustard)
[Vr. Ma. 42/5]
Formulations:
Chitrakaadi ghrita [Charaka
samhita Da. 4/43]
Chitraka rasaayana
[Ashtaang Hridaya 3/39, 62-65]
Agnitundi watee
Chitrakaadi choorna: [Charaka
samhitaa, chikitsaa sthaana 12/58-59]
Chitraka Kashaaya: [Sushruta
samhitaa, chikitsasthaana 11/9]
Shaddharana Yoga: [Sushruta
samhitaa, chikitsasthaana 4/2] [116], [117]
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