Pharmacology of Mareecham-Black pepper (Piper nigrum)
Pharmacology of Mareecham-Black pepper (Piper nigrum) Part 3
Piperine is the
pharmacologically active phytochemical found in Mareecham-Black pepper (Piper
nigrum). Here I discuss in detail the phytopharmacology of piperine.
Molecular
formula: C17H19NO3
Structural
formula:
Piperine is the alkaloid found in Mareecham-Black
pepper (Piper nigrum). It is
responsible for the pungency of Mareecham-Black pepper (Piper nigrum).
Piperine was discovered in 1819 by Hans Chriastian
Orsted, who isolated it from the fruits of Mareecham-Black pepper (Piper nigrum). Piperine was first
synthesized in 1882 by mixing piperidine and piperoyl chloride. Piperine is now
extracted by using water, alcohol and dichloromethane.
Piperine is slightly soluble in water and highly
soluble in alcohol, ether and chloroform.
Till date four isomers of piperine reported are:
Chavicine, Isochavicine, Isopiperine and piperanine (dihydro form of
piperine)
The primary value of piperine in health supplements is
its ability to enhance the bioavailability of some bioactive phytochemicals.
This mechanism is still being studied, but piperine is known to inhibit enzymes
P-glycoprotein and CYP3A4. These enzymes are involved in the metabolism and
transport of various metabolites. [45],
[46], [47]
Pharmacokinetics of Piperine
To evaluate the potential of
piperine as a therapeutic agent, a group of researchers studied pharmacokinetic
characteristics of piperine. A single dose, 10mg/kg body weight was
administered intravenously and 20 mg/kg body weight by oral gavage to male
Wistar rats.
After intravenous
administration, the half life of piperine was found to be 7.999 hours, the
steady state of volume distribution 7.046L/kg and total body clearance
0.642L/kg/hr. After oral administration the half life was found to be 1.224 hour,
the steady state of volume distribution 4.692L/kg and total body clearance
2.656L/kg/hr. Two hours after oral administration, the peak plasma
concentration of piperine was found to be 0.983μg/ml. The absolute oral
bioavailability of piperine was found to be 24 percent. [48]
Researchers developed a
new method by which the solubility of piperine and rate of absorption improved.
[51]
Bioenhancer
activity of Piperine
Type of
activity
|
Drugs
|
Anti-inflammatory
|
Indomethacin,
Diclofenac, Nimesulide, Oxiphenylbutazone, Ibuprofen
|
Anti-oxidant
|
Curcumin,
Epigallocatechin Gallate (EGCG), Resveratrol
|
Analgesic
|
Diclofenac,
Nimesulide, Pentazocine
|
Antibacterial
|
Sulfadiazine,
Ciprofloxaxin, Norfloxacin, Pefloxacin, Gatifloxacin, Ampicillin,
Tetracyclines, Oxitetracycline,
|
Antitubercular
|
Rifampicin,
Isoniazid, Pyrazinamide
|
Antiviral
|
Nevirapine,
Acyclovir, Atazanvir, Saquinavir mesylate
|
Antihistaminic
|
Fexofenadine
|
Antiprotozoal
|
Metronidazole
|
Hypnotic, CNS sedative
|
Pentobarbitone
|
Anticonvulsant
|
Carbamazepine
|
Antiepileptic
|
Phenytoin
|
β-adrenoceptor
blocker
|
Propranolol,
Atenolol
|
Anti-arrhytmic
agent
|
Sparteine
|
Antihypertensives
|
Losartan
potassium
|
Antidiabetic
|
Nateglinide
|
Bronchodilator, Anti-tussive
|
Theophylline,
Vasicine
|
Anti-tumor
|
Paclitaxel
|
The
effective bioenhancing property of piperine differs from drug to drug. In
general it can be said that W/W 10% of the active drug or 15-20 mg /day could
be regarded as an appropriate bioenhancing dose of piperine. [52]
Ideal properties of the bioenhancer
(1)
It should be easily available and, cost effective
(2)
It should be safe, non-irritating, non-allergenic and nontoxic
(3)
It should be well tolerated by patients
(4)
It should be preferably a catalyst and should not exhibit its own, separate
pharmacological action
(5)
It should preferably have synergism with the drug with which it is combined
(6
It should be compatible with drugs with which it is combined and should not
interfere with actions of bioactive drugs
(7)
It should have rapid, predictable and reproducible action
(8)
It should be unidirectional in action
(9)
It should be stable with time
(10)
It should be easily formulated in various forms and dosages
The
exact mechanism of bioenhancer action of piperine is not known. Some mechanisms
proposed for this activity are as follows:
1. Increased Gastrointestinal
Absorption
It
observed that when combined with active drug, piperine increases the absorption
of the active drug. This is brought about by:
(a) By enhancing the solubility:
Bile acids are required for the absorption of fat soluble drugs. Piperine
enhances the secretion of bile acids thereby enhancing the solubility and
absorption of fat soluble drugs. [53]
(b) By increasing blood supply: Piperine
increases the blood supply of the gastrointestinal tract thereby causing
increased absorption of drugs. [54]
(c) By increasing permeability of
epithelial cell modification: Piperine increases the
permeability of intestinal mucosa and causes an increased absorption of amino
acids by epithelial cells. [55]
(d) By increasing brush border
membrane fluidity: It is suggested that piperine increases
brush border membrane fluidity, increases the length of microvilli thereby
enhancing the bioavailability of active drugs. [56]
2. Reduced efflux of drugs from the
site of action
Piperine
increases the stay of active drugs at the active site by inhibiting human
P-glycoprotein, which is a major efflux pump. [57]
3. Inhibition of solubilizer
attachment
When
substances are chemically linked to a highly water soluble substance their
entry in the cells is prevented. This is termed as solubilizer attachment.
Glucuronic acid is an important solubilizer. The substances bound to glucuronic
acid are excreted either in urine or in small intestine. It is suggested that
piperine inhibits glucuronic acid thus facilitating increased entry of
substances into the cell. [58], [59]
4. Reduced metabolism
Piperine
inhibits many different cytochrome P-450 enzyme isoforms like CYP1A1, CYP1A2,
CYP2C8, CYP2D6, and CYP3A4. Piperine is also found to inhibit various mixed
function oxygenases. By inhibiting functions of various enzymes piperine
reduces metabolism of various drugs. [60], [61], [62]
Advantages of Using Piperine as
Bioenhancer
(2)
Combination of bioenhancer with drug reduces the dosage.
(3)
Combination of bioenhancer with drug minimizes the chances of developing drug
resistance.
(4)
Combination of bioenhancer with drug minimizes the toxicity, adverse drug
reactions, side effects etc. of drugs. This is of great advantage while using
anticancer drugs like Paclitaxel (Taxol)
(5)
Many anticancer drugs are derived from plants; for example, Vincristine from periwinkle, Catharanthus roseus, Indirubin from Indigofera tinctoria, Irisquinone
from Iris lateapallasii, Camptothesin from Camptotheca accuminata, Taxol
from Taxus chinensis and many more.
The incessant search for newer, better and safer anticancer drugs from plants
will be a gracious contribution for humankind in cancer treatment and
chemoprevention. Alas! Many bioactive plants are on the brink of extinction.
Another somber story is, to treat one patient of ovarian cancer or breast
cancer with Taxol, six Pacific yew (Taxus
chinensis) trees, 25-100 years old need to be felled. Pacific yew (Taxus chinensis) is one of the slowest
growing trees in the world. Paucity of bioactive plants is one more threat for
the development of anticancer drugs. Hence the need to combine bioenhancers
with anticancer drugs [63]
Anti-inflammatory
activity of Piperine
To
evaluate anti-inflammatory activity of piperine, different acute and chronic
experimental models like carrageenin-induced rat paw edema, cotton pellet
granuloma and cotton oil induced granuloma pouch were employed. The results
showed that piperine acted as anti-inflammatory agent in early acute phase of
inflammation and in chronic granuloma phase. This activity was said to be
through stimulation of pituitary adrenal axis [64]
In
a study piperine was administered orally in 5, 10, 20, 40 mg /kg body weight
half an hour prior to subcutaneous injection of carageenin in the plantar
region of the hind paw of rats to induce local inflammation. Piperine showed
dose-dependent anti-inflammatory activity. The study revealed that 10 mg/kg
body weight was the lowest dose to produce significant activity. This dose was
used in adrenalectomized animals. The activity of piperine was lower in
adrenalectomized animals than in normal animals.
This
study was extended further with various phlogistic agents like histamine,
formalin and prostaglandin E1 (PGE1) to induce paw edema. In the histamine and
formalin induced paw edema, piperine showed 28.3% (+/- 4.2) and 32.8% (+/-5.6)
anti-inflammatory activity respectively. There was no effect of piperine
treatment on prostaglandin E1 (PGE1)-induced edema.
Formalin
ascites induced by intraperitoneal injection (IP) of 0.1 ml 1.5 % formalin
solution was treated with piperine. The ascetic fluid volume reduced following
piperine treatment.
The
treatment of animals having cotton pellet granuloma and granuloma pouch for
seven days with piperine showed that the weight of granuloma was significantly
less than that in control group. [65]
In another study in
albino rats, anti-inflammatory activity of piperine was compared with that of
hydrocortisone. The study showed that inhibition of paw edema by piperine was
57.23 % and that by hydrocortisone was 65.3% 3 hours after the treatment. [66]
Antioxidant
Activity of Piperine
Oxidative stress is an
important factor that is responsible for development of various disease
processes in our body. The root cause of oxidative stress is free radicals
generated during metabolic processes. The different kinds of free radicals
attack cell membrane, alter cell-membrane permeability, damage cell membrane,
oxidize lipids, disrupt enzyme activities and disrupt cell physiology which
might cause cancer. Hence there is a need to counter them to arrest the genesis
of disease process. The antioxidant system of our body includes enzymes like as
ascorbate, catalase, peroxidase and superoxide dismutase which scavenge the
free radicals and oxygen species, but at times this system is insufficient.
Plants are a rich source of antioxidants. Piperine from Mareecham-Black pepper
(Piper nigrum) maintains superoxide
dismutase, glutathione, glutathione peroxidase, glutathione-s-transferase and
catalase levels and reduces high fat diet induced oxidative stress. Many
screenings, using different solvents proved that the ethanolic extract of
Mareecham-Black pepper (Piper nigrum)
showed highest antioxidant potency. [67], [68]
At low concentrations
piperine acts as a hydroxyl radical scavenger, but at higher concentrations
piperine activated Fenton reaction resulting in increased generation of
hydroxyl radicals. [Fenton reaction is a catalytic process that converts
hydrogen peroxide, a product of mitochondrial oxidative respiration into a
highly toxic hydroxyl free radical.] Piperine is a powerful superoxide
scavenger. Piperine possesses direct antioxidant activity against various free
radicals. [69]
At the dose of 15 μM
piperine inhibited the proliferative response induced by Lipo- Poly- Saccharide
(LPS) and α-IgM antibody and secretion of IgM antibody in vitro. Piperine at 3 μM
and 15 μM reduced the CD86 expression on B cells stimulated with Lipo-Poly-Saccharide
(LPS) and α-IgM antibody in vitro. However, piperine at 2.5 and 4.5 mg/kg body
weight did not modulate antibody production for T-independent in vivo. Piperine
was unable to modify in vivo thymus-independent antigen-induced antibody response.
[70]
A study showed that by
alteration in oxidative stress cadmium at 25 μM/ml induced apoptosis in
thymocytes in 6 hours. The phenotypic changes occurred at 18 hours and
blastogenesis at 72 hours. Piperine at 1, 10 and 50 μM/ml when added with
cadmium caused a dose and time dependent amelioration in thymic apoptosis.
Piperine reduced cadmium induced apoptosis in lymphocytes. [73]
In
murine model of Mycobacterium
tuberculosis infection, piperine enhanced the bioavailability and efficacy
of rifampicin. In mice infected with Mycobacterium
tuberculosis, piperine at 1mg/kg body weight exhibited proliferation of T
and B cells, increased Th-1 cytokines and enhanced macrophage activation. Thus
combination of rifampicin and piperine exhibited better efficacy and reduction
in lung colony forming units as compared to rifampicin alone. [74]
In
an experimental study bronchial asthma was induced in Balb/c mice by ovalbumin.
They were treated by administering orally 2.25 and 4.5 mg/kg body weight
piperine 5 times a week for 8 weeks. The results showed that piperine suppressed
eosinophil infiltration, relieved allergic inflammation and hyperresponsiveness
of airways. These effects were attributed to suppression of the production of
interleukin-4, interleukin-5, immunoglobulin E and histamine. In addition there
was marked reduction of activation of thymus, eotaxin-2 and interleukin-13 mRNA
expression in lung tissue. [75]
Hematological,
biochemical, morphological and histopathological analyses of various tumors and
organs including liver, spleen and kidney showed that piperine had synergistic
effect with 5-fluorouracil (5-FU) in inhibiting the tumor growth. [76]
Oxidative stress and activation
of caspase dependent pathways are involved in deltamethrin (DLM), a pyrethroid
insecticide-induced thymic apoptosis. The results of in vitro study showed that piperine at 1, 10 and 50 μg /ml
increased the viability of thymic cells and ameliorated thymic cell apoptosis
in a concentration dependent manner. [77]
A morphological and
histopathological study on 60 female Swiss mice transplanted with sarcoma 180
showed that administration of 50-100mg/kg body weight of piperine
intraperitoneally from day 1 of inoculation to 7 days inhibited the development
of sarcoma. The inhibition rate after 7 days was 56.8 percent. [78]
Antiallergic activity of Piperine
To
evaluate antiallergic effect of piperine, mice were sensitized with ovalbumin
on 1, 3, 5, 7, 9, 11 and 13th day. Mice developed allergic rhinitis.
From 14th to 20th day they were treated with piperine
(10, 20, 40 mg/kg body weight) or montelucast (10 mg/kg body weight).
Piperine
acts by stabilizing mast cells. In addition piperine exhibits anti-inflammatory
and immunomodulatory activity thereby providing an effective treatment for
allergic rhinitis. [79]
Antimicrobial activity
of Piperine
Piperine was known for its antibacterial activity against Gram
positive and Gram negative bacteria. In a study ciprofloxacin and piperine
showed synergistic activity against Bacillus
subtilis and Escherichia coli. In
combination with ciprofloxacin, piperine was active against these organisms
even at a very low concentration. [80]
Another
study showed antibacterial activity of piperine and black pepper oil at the
concentration of 0.5% against Staphylococcus
aureus and Bacillus subtilis. At
high concentrations piperine showed its antibacterial activity against Gram
negative bacteria (Escherichia coli) by altering the permeability
of the cell wall of the microorganism which contains high level of lipid
material. [81]
In combination with ciprofloxacin piperine is active
against Escherichia
coli and Bacillus subtilis even at a very low concentration 20 μg/mL [82]
Combination
of piperine with rifampicin and tetracycline widened the antibacterial spectrum
of these antibiotics. It improved the bioavailability, reduced the requirement
of doses and toxicity of these antibiotics. [83]
Administration of piperine boosts activity of peritoneal
macrophages, thus enhancing their phagocytic ability. Further, piperine also
has the capacity to fortify the innate functions of peritoneal macrophages
against bacterial infection. This activity was attributed to enhanced
production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) by
activated macrophages. [84]
Antiviral
activity of Piperine
The pandemic of
influenza of 1918 to 1919 was extremely severe killing 40 million people
worldwide. Since then search was on to find a safe anti-influenza drug; but in
vain as researchers found none. The recent study showed that piperine isolated
from Mareecham-Black pepper (Piper nigrum)
is a new anti-influenza drug. [85]
Acyclovir and atazanvir
are antiviral drugs. When they were combined with piperine at the dose 30mg/kg
bodyweight, the bioavailability of these drugs increased, doses required to
treat viral infections reduced, the duration of action of these drugs lengthened
and their toxicity reduced. [86], [87]
Antifungal activity of Piperine
In another study
piperine and 10 piperine-like synthetic compounds showed anti-fungal activity
against Aspergillus flavus and
aflatoxin B1. The activity of synthetic compounds was remarkable because
thiabendazole had no inhibitory effect on the fungus and aflatoxin B1. [89]
Antiparasitic activity of Piperine
Chagas’
disease or American trypanosomiasis is the incurable human disease caused by a
protozoan parasite Trypanosoma cruzi.
Like other synthetic antiparasitic drugs, piperine a natural product, isolated
from Mareecham-Black pepper (Piper nigrum)
showed trypanocidal activity. The activity was tested on proliferative forms of
Trypanosoma cruzi. [90]
The alcoholic extract
of the dried fruits of Mareecham-Black pepper (Piper nigrum) showed anthelmintic
properties. In experimental study earthworm (Pheritima prosthuma) is replaced for round worm (Ascaris lumbricoides). Piperine at
concentrations of 2.5mg/ml, 5mg/ml and 10mg/ml showed helminthicidal activity
against earthworm (Pheritima prosthuma).
So it was inferred that piperine is ascaricidal. Piperine was more effective
than albendazole 20mg/ml against earthworm (Pheritima
prosthuma). Needless to say that the helminthicidal activity was dose
dependent [91], [92]
Actions of Piperine on the skin
Peperine
also enhances skin permeation of curcumin. This property of piperine is taken
advantage of for skin care preparations using curcumin. [95]
A wide range of
piperine analogues has been synthesized. They stimulated melanocyte
proliferation. They increased total melanin in cell cultures, though melanin
content per cell was not significantly altered. [96]
That piperine
stimulates melanocye proliferation in vitro was well documented. This property
renders it its use for the treatment of vitiligo. Exposure of vitiligo patients
receiving piperine to ultraviolet (UV) radiation improved the pigment deposition
in depigmented areas. This can be a promising future treatment for vitiligo. [97]
At concentrations of
2.5, 5 and 10 μg/ml piperine inhibited collagen matrix invasion of B16F-10
melanoma cells in a dose dependent manner. Piperine could inhibit the matrix
metalloproteinase production. Thus piperine could inhibit the growth of
melanoma cells. Piperine can be a future drug to control melanoma. [98]
By using
various solvents, phytochemicals were extracted from berries of Mareecham-Black
pepper (Piper nigrum). Further study
demonstrated that the extracts (0.32-1.0 μg/ml) encouraged the proliferation of epidermal keratinocytes.
This suggested that Mareecham-Black pepper (Piper
nigrum) helps wound healing. [99]
Actions
of Piperine on Mouth
A study on hamster’s buccal pouch showed that piperine
prevented and retarded the development of squamous cell carcinoma. This effect
was attributed to the antioxidant activity of piperine. [100]
Osteoclasts are responsible for bone resorption and
development of osteoporosis. Being a potent anti-resorptive agent, curcumin
prevents osteoporosis. Piperine not only enhances the bioavailability of
curcumin but also increases the activity of curcumin. The effect of this
combination was studied on periodontal ligament cells. The results suggest that
the combination is useful for the prevention and treatment of replacement
resorption in replanted avulsed teeth. Curcumin below the concentration of 10 μmol/L
and piperine up to 30 μmol/L did not show toxicity. [101]
Actions of Piperine on the Breast
Anti-neoplastic activity of
pierine was wellknown. Using MIT, a colorimetric assay, anti-epithelial breast
cancer cell (anti-proliferative) activity of piperine was demonstrated in mice.
Anti-inflammatory and antiangiogenic activities of piperine were found to
arrest/ prevent cancer cell growth. Further piperine is said to regress breast
cancer metastases in experimental animals. Regression of breast carcinoma
syngraft was seen in mice following treatment with piperine in combination with
Thymoquinone. [102]
On investigation it was found
that piperine inhibited the growth and motility of triple negative breast
cancer cells (TNBC). Further an in vitro study
showed that piperine also inhibited the growth of hormone-dependent breast
cancer cells, without affecting normal mammary cell growth. Interestingly,
combined treatment with γ radiation and piperine was more cytotoxic for triple
negative breast cancer cells (TNBC) than γ radiation alone. Intratumoral
injection of piperine inhibited the growth of triple negative breast cancer
cells (TNBC) xenografts in immune-deficient mice. [103]
When the effect of paclitaxel alone and in combination
with piperine was investigated on MCF-7 breast cancer cell line, it was found
that piperine not only works in synergy with paclitaxel but potentiates its
anti-breast cancer effect. This led to hypothesize that piperine may not only
improve the bioavailability of paclitaxel but potentiate the antitumor effect
of paclitaxel. [104]
Therapeutic applications of piperine are limited
because of immunotoxicity, reproductive toxicity and poor water solubility. To
overcome these limitations, piperine encapsulated polyethylene glycol-Polylactide-co-glycolide
nanoparticles (P-PEG-PNP) are developed. They kill MCF-7 breast cancer cells by
apoptotic mechanism. For the first time this demonstrates the targeted delivery
of piperine to MCF-7 breast cancer cells by utilizing polyethylene
glycol-Polylactide-co-glycolide nanoparticles. [105]
Actions
on Hematopoetic system
A human study showed
that piperine inhibited proliferation of peripheral blood mononuclear cells
(PBMCs). Piperine inhibited production of interleukin-2 (IL-2) and interferon-γ
(IFN- γ). This study suggests that piperine has a potential as an immunomodulatory agent. [106]
In a study, piperine
inhibited mouse B cell proliferation by causing G0/G1 phase cell cycle arrest.
In addition, piperine inhibited synthesis of interleukin-6 (IL-6) and
interleukin-10 (IL-10) cytokines as well as IgM, IgG2b and IgG3 immunoglobulin.
The inhibitory effect of piperine on B lymphocyte activation and effector
function warrants further investigation for possible application in the
treatment of pathologies related to inappropriate immune responses. [107]
Actions of Piperine on
Musculo-skeletal System
In a study in rats, Mareecham-Black pepper (Piper nigrum) extract containing
piperine at concentrations of 10-100 μg/ml was administered to arthritic rats.
Even at the concentration of 10 μg/ml piperine reduced
the production of prostaglandin E2 (PGE-2). Piperine inhibited the migration of
activator protein-1 (AP-1) but not nuclear factor kappa B (NF κB) in
synoviocytes in rats. Further piperine significantly reduced nociceptive
symptoms at 8 days and arthritic symptoms at 4 days. Histological study showed
that piperine significantly reduced the inflammatory area in the ankle joints.
[108]
Osteoclasts are responsible for bone resorption and
development of osteoporosis. Being a potent anti-resorptive agent, curcumin
prevents osteoporosis. Piperine not only enhances the bioavailability of
curcumin but also increases the activity of curcumin. The effect of this
combination was studied on periodontal ligament cells. The results suggest that
the combination is useful for the prevention and treatment of replacement
resorption in replanted avulsed teeth. Curcumin below the concentration of 10 μmol/L
and piperine upto 30 μmol/L did not show toxicity. [109]
Actions
of Piperine on Nervous System
Midazolam belongs to a class of
drugs called benzodiazepines. Midazolam is a quick acting, short acting,
hypnotic, sedative, anxiolytic, muscle relaxant and anticonvulsant drug. It has
amnesic property. Thus midazolam is an unique benzodiazepine. These facts make midazolam
very suitable for use in dentistry, some cardiac procedures and endoscopic
procedures, as pre-anaesthetic medication and as an adjunct to local
anaesthesia. Administration of 15 mg of piperine with 10 mg of midazolam,
enhanced the plasma concentration, increased the duration of sedation,
increased the half life of midazolam. It is suggested that piperine exhibits
these effects by inhibition of Cytochrome P450 3A4 (abbreviated CYP3A4) enzyme
activity in liver microsomal system. [110]
Carbamazepine is an anticonvulsant
that can relieve certain neuralgias. The effects of piperine 3.5 to 35 mg/kg
bodyweight on the metabolism of carbamazepine were evaluated in rats. The
results revealed that combination of high doses of piperine inhibited the metabolism
of cabamazepine and decreased rCYP3a2 mRNA and protein expression. [111]
Micro-sleepiness (MS) is a temporary biological disorder,
which can last from fraction of second to 30seconds. During micro-sleepiness
(MS), an individual fails to respond for some arbitrary sensory inputs. Micro-sleepiness
(MS) has become a major social issue that causes fatalities. It impacts
productivity, quality, dilapidation and economic losses. According to available
statistical data, over 1.3 million people die on road, 20-30 million people
suffer non fatal injuries and 100,000 vehicles crash. To combat
micro-sleepiness (MS) while driving, studying and working; plant-based,
effective, low cost and chewable confectionaries have been developed using Mareecham-Black pepper (Piper longum), beans of Arabian coffee (Coffea arabica), Cinnamon (Cinnamomum varum) and Ginger (Zingiber officinale). The developed
confectionaries were capable of suppressing and controlling micro-sleepiness
(MS) in a large number of subjects, but they failed to control micro-sleepiness
(MS) in about 15 percent of subjects. The confectionaries were well tolerated
without any adverse effects or allergies. [112]
At a dose of 5mg/kg body weight, piperine and at a dose of
15mg/kg body weight, ethanol extract of fruit of Mareecham-Black pepper (Piper nigrum L) after 120 minutes
exhibited anti-inflammatory and analgesic activity; and at a dose of 10mg/kg
body weight the hexane extract of Mareecham-Black pepper (Piper nigrum L) exhibited anti-inflammatory and analgesic activity
in 60 minutes in rats. The anti-inflammatory activity was evaluated by
carrageenan-induced paw edema and analgesic activity was evaluated by
tail-emersion method, hot plate and acetic acid induced writhing test. [113]
That piperine is a bioenhancer is well established. By
inhibiting the metabolism of drugs, piperine improves the bioavailability of
drugs. When piperine (10mg/kg body weight) was combined with ibuprofen the
nociceptive activity of ibuprofen increased significantly. This can be
attributed to increased plasma concentration of ibuprofen by piperine. [114]
Analeptics are medications
that stimulate central nervous system. The research shows that piperine is an
analeptic. This is due to its effect on nerve impulse transmission in the brain
stem. Piperine elevates mood, alertness, energy, stamina and muscle power. In
athletes it enhances physical stamina. The repeated use of analeptics can
produce serious psychophysiological side effects such as paranoia, hostility
and addiction. [115]
Sertaline hydrochloride is the drug used to treat
depression. Administration of piperine by oral and parenteral route enhances
the plasma level of sertaline, reduces its antidepressant dose and delays its
excretion. [116]
Haloperidol is an antipsychotic drug that decreases
excitement in the brain. It is used to treat psychotic disorders like
schizophrenia, severe behavioral problems in children, motor tics and verbal
tics (e.g. Tourette’s syndrome). However haloperidol has inbuilt neurotoxicity
that can result in neuronal death. Co-administration of piperine and curcumin
prevented haloperidol neurotoxicity. [117]
Morphine is a very potent analgesic, but respiratory
depression is a serious side effect associated with morphine. Nalorphine
antagonizes respiratory depression, but nalorphine can also antagonize
analgesia induced by morphine. In rats, piperine produced respiratory
stimulation, antagonized morphine induced respiratory depression but not morphine
induced analgesia. Thus piperine is better than nalorphine in this regard.
[118]
Loss of
memory is a disabling condition. Every subject attempts to restore his memory.
Even subjects with normal memory try to enhance it. A study on male Wister rats
piperine was administered to the animals at doses ranging from 5, 10 and 20
mg/kg body weight per day for 4 weeks. The results showed that piperine at all
doses possessed mood enhancing, anti-depression, cognition enhancing and memory
stabilizing effect. The memory enhancing property of piperine is useful for the
treatment of Alzheimer’s disease. These effects are attributed to antioxidant
activity of piperine. [119], [120]
The protective effect
of piperine on ischaemia-reperfusion injury of brain was evaluated in Wister
rats. Piperine was administered by oral route to Wister rats at 10mg/kg body
weight once daily for 15 days. After this pretreatment the
ischemia-inflammation was induced in the animals by occluding the right middle
cerebral artery for 2 hours followed by reperfusion for 22 hours. The maximum
infarct volume observed was 57.80 % in animals that were not pretreated with
piperine. However in animals pretreated with piperine the infarct volume was
significantly reduced to 28. 29 % and neuronal loss was 12.72%. A significant
improvement in behavior was observed in animals pretreated with piperine.
Piperine successfully reduced the level of pro-inflammatory cytokines
interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor-necrosis-factor- α
(TNF- α). Usually the ischemic brain shows edematous morphology with vacuolated
architecture and pyknotic nuclei on hematoxylin and eosin staining procedure.
Pretreatment with piperine ameliorated these changes. Piperine also lowered the
expression of cyclooxygenase-2 (COX-2), nitric oxide synthase-2 (NOS-2) and
nuclear factor-κB (NF- κB). This suggests that piperine is able to salvage the
neurons in ischemic penumbral zone by virtue of its anti-inflammatory property
thereby limiting the ischemic cell death. [121]
Actions of Piperine on Respiratory System
Oral
administration of water extract of Mareecham-Black pepper (Piper nigrum) at the dose of 50mg/kg body weight to guinea pigs
showed antitussive activity comparable to 10 mg/kg of codein phosphate. An in vivo study shows that piperine is a
potent antitussive agent. This activity was attributed to smooth muscle
relaxing property of piperine. [122]
A study was designed to evaluate the effect of
piperine on the hypersensitiveness of airway, eosinophilic infiltration,
various immune cell phenotypes, Th2 cytokine production, immunoglobulin E (Ig
E) and histamine production in murine model of bronchial asthma. By using
ovalbumin bronchial asthma was induced in Balb/c mice. Piperine was then
administered orally at 2.25 and 4.5 mg/kg bodyweight five times a day for eight
weeks. The results showed that piperine suppressed eosinophil infiltration,
allergic inflammation of the airway, production of interleukin-4 (IL-4),
interleukin-5 (IL-5), histamine and immunoglobulin E (Ig E); and reduced
hypersensitiveness of the airway [123]
Oxidative stress plays an important role
in chronic pulmonary diseases. Antioxidant activity of piperine can alleviate
the symptoms of oxidative stress in pulmonary diseases. The combination of curcuminoids
1500 mg/day with piperine 15 mg/day was more effective than only curcuminoids
or only piperine. [124]
A study was arranged to study the chemopreventive
effect of piperine against lung cancer. Lung cancer was induced in experimental
animals by using Benzo(a)pyrene B(a)p. Oral supplementation of piperine 50mg/kg
body weight effectively suppressed lung carcinogenesis. The chemopreventive
effect of piperine was by modulating lipid peroxidation and augmenting
antioxidant defense system. [125]
Actions
of Piperine on Cardiovascular System
Some researchers observed that piperine
can cause a significant decrease in blood pressure in normotensive rats. They
attributed this activity to calcium channel blockade. Taking a cue from this,
some researchers induced hypertension in Wistar rats by administering 40mg/kg
body weight/day N(G)-nitro-L-arginine methyl ester (L-NAME) for six weeks. As
expected the animals developed hypertension; systolic more than diastolic.
Piperine, 20mg/kg body weight/ day in corn oil was then administered by oral
gavage (fed directly into the stomach) to hypertensive rats. As expected the
blood pressure decreased markedly, systolic more than diastolic. The drop in
systolic blood pressure suggests that piperine lowers blood pressure by
blocking calcium channel. [126]
Inhibition of nitric oxide synthase (NOS)
produces vasoconstriction and hypertension. N ώ-Nitro-L-arginine methyl ester
hydrochloride (L-NAME) is a pharmacological agent that can induce hypertension.
In a study hypertension was induced in rats by oral administration of N
ώ-Nitro-L-arginine methyl ester hydrochloride (L-NAME) at a dose of 40mg/kg
body weight for 4 weeks. Treatment of these animals with piperine restored the
concentration of nitric oxide (NO) metabolites. Piperine also restored
anti-oxidant concentration and decreased the levels of lipid peroxidation
markers. Histopathological findings confirmed the biochemical findings of this
study. This showed that oxidative stress can cause hypertension in nitric oxide
(NO) deficient rats and by its antioxidant property piperine attenuate
hypertension in nitric oxide (NO) deficient rats. [127]
A study was arranged to evaluate the effect of
piperine on myocardial ischemia/infarction. Baseline levels of cholesterol,
phospholipids, triglycerides and lipoproteins were determined in serum and
heart tissues. Then by using isoproterenol (ISO) researchers induced myocardial
infarction in male Wister rats. The isoproterenol (ISO) treatment increased
levels of thiobarbituric acid reactive substances (TBARS), prothrombin complex
concentrate (PCC), serum markers of cardiac ischemia; depleted antioxidant
status (GSH, SOD, CAT, GPx and GST) in serum and heart tissues. Pretreatment
with piperine prevented the myocardial damage; increased antioxidant status in
the heart tissues of isoproterenol (ISO) administered rats. The study showed
that piperine, with its antioxidant and anti-dyslipidemic effects can be a
potent therapeutic agent against isoproterenol (ISO) induced myocardial
infarction. [128]
Curcumin is a well-known cardioproctective
phytochemical used to protect the myocardium against cyclophoshphamide induced
toxicity. But its bioavailability is very poor. Incorporation of piperine
20mg/kg body weight with curcumin 50 mg/kg body weight was the best effective
combination. This result was supported by levels of serum biomarkers, decrease
in lipid profile, ECG and histopathological studies. [129]
Piperine inhibits platelet aggregation by attenuating
(Platelet Cytosolic Phospholipase A2 (cPLA2 ) and
Thrombxane A2 (TXA2) synthase activities rather than
through the inhibition of cyclooxigenase-1 (COX-1) activity. [130]
Piperine showed positive chronotropic and inotropic
effects on isolated rat-atria. The responses were not affected by
norepinephrine, acetylcholine, histamine and serotonin. According to
researchers piperine causes positive chronotropic and inotropic effects by releasing
calcitonin gene-related peptide (CGRP) from nonadrenergic noncholinergic
nerves. [131]
Actions of Piperine on
Gastro-Intestinal System
Administration of 0.02% piperine to Wistar rats
significantly enhanced the activities of antioxidant enzymes in gastric and
intestinal mucosa suggesting gastro-intestinal protective role of piperine. [132]
Stress, excessive secretion of gastric hydrochloric acid
(HCl) with subsequent peptic digestion, ligation of pylorus, drugs like
indomethacin damage gastric mucosa and cause ulceration. Gastric ulcers were
induced by these factors in rats or mice. Rats or mice were then treated with
oral administration of piperine at doses 25, 50, 100 mg/kg body weight per
animal. Pretreatment with piperine prevented the ulceration while treatment of
animals with ulceration showed marked regression of ulcers. Needless to say
that these effects were dependent on the dose. The inhibitory rates were: 16.9,
36.0 and 48.3% in stress ulcers; 4.4, 51.1 and 64.4 % in indomethacin ulcers;
19.2, 41.5 and 59.6% in hydrochloric acid (HCl) ulcers; 4.8, 11.9 and 26.2% in
pyloric ligation ulcers respectively [133]
Oral administration of piperine inhibited gastric emptying
(GE) of solids/liquids in rats and gastrointestinal transit (GT) in mice in a
dose dependent manner. At 1mg/kg bodyweight piperine significantly inhibited
gastric emptying of solids in rats and at 1.3mg/kg body weight delayed
gastrointestinal transit of solids in mice. However, at the same doses the
effect was insignificant for gastric emptying of liquids. The gastric emptying
activity is independent of gastric acid and pepsin secretion. [134]
Acyclovir loaded floating microspheres were prepared by emulsification
solvent evaporation method. Piperine was added to it. Addition of piperine
enhanced the bioavailability of microsphere loaded acyclovir. This drug
delivery system was specially designed to target upper gastrointestinal tract. [135]
For an experimental study guinea pig ileum was isolated.
When tested in isolated guinea pig ileum preparation, the crude extract of
Mareecham-Black pepper (Piper nigrum)
at the concentration 1-10mg/mL and piperine at the concentration 3-300 μM
relaxed the ileum. In isolated rabbit jejunum preparation, 0.01 to 3.0 mg/mL Mareecham-Black pepper (Piper nigrum) extract and
30-1000 μM piperine relaxed
spontaneous contractions, similar to loperamide and nifedipine.
This relaxant effect was partially
inhibited in the presence of naloxone 1 μM similar to that of loperamide, suggesting the naloxone-sensitive
effect in addition to calcium channel blocking effect.
In mice, at lower doses, Mareecham-Black pepper (Piper nigrum) extract and piperine
exhibited partially atropine-sensitive laxative effect whereas at higher doses
they caused antisecretory and antidiarrheal activities. This study illustrates
the spasmodic (cholinergic) and antispasmodic (opiod agonist and Ca2+ antagonist)
effects, thus providing the possible explanation of the use of Mareecham-Black
pepper (Piper nigrum) extract and
piperine in gastrointestinal motility disorders. [136]
In a study on mice, piperine at the dose of 10mg/kg body
weight provided complete protection from castor oil induced diarrhea, similar
to that of loperamide. In isolated rabbit jejunum preparation, piperine
exhibited concentration dependent spontaneous contractions. Piperine also
inhibited high potassium (K+)-induced sustained contractions which
suggests calcium channel blocking activity similar to that of verapamil. These
studies suggest that piperine exhibits antidiarrheal and antispasmodic
activities mediated through calcium channel blockade. [137]
Helicobacter
pylori is known to induce gastritis and
gastric carcinoma. Eradication of Helicob
acter pylori is a daunting task. A study showed that piperine could inhibit
Helicobacter pylori. [138]
Piperine exhibits anti-tumor activities both in vitro and in vivo. In tumorogenesis, especially in gastric cancer,
interleukin-6 (IL-6) plays an important role. Interleukin-6 not only activates
the mechanism of genesis of gastric cancer but also promotes metastasis.
Piperine inhibits interleukin-6 expression in a dose dependent manner. In
addotion piperine inhibits interleukin-6 (IL-6) promoter activity. Thus
piperine can be partly useful to control gastric carcinoma. [139]
In experimental study piperine at 75- 150 μM doses inhibited
the growth of HT-29 colon carcinoma cell proliferation by causing G1 phase cell
cycle arrest. The study also showed that piperine inhibited the growth of
several colon cancer cell lines but had little effect on the growth of normal
epithelial cells and fibroblasts. Piperine caused hydroxyl radical production
and apoptosis dependent on the production of reactive oxygen species. Piperine
inhibited the colony formation by HT-29 cells. Piperine treated cells showed
loss of mitochondrial membrane integrity. [140]
Actions
of Piperine on Liver
In vitro
and in vivo piperine protects the
liver against the carbon tetrachloride and terbutyl hydroperoxide. However
piperine has lower hepatoprotective potency than silymarine a commonly used
drug for liver protection. [141]
D-galactosamine
is a hepatotoxic agent. It is used in animal models to evaluate the
hepatoprotective activity of drugs. To evaluate hepatoprotective activity of
piperine, hepatotoxicity was induced in mice by a single dose of 700mg /kg body
weight of galactosamine administered intra-peritoneally. As expected, levels of
serum glutamate oxaloacetate transferase (SGOT), serum glutamate pyruvate
transferase (SGPT), alkaline phosphatase (ALP), bilirubin, tumor necrosis
factor-α (TNF-α) and lipid peroxidation increased. Treatment with 25mg/kg body weight of
piperine, restored elevated levels to normal. The hepatoprotectetive activity
of piperine was found to be superior to the standard drug silymarin. [142]
A
study on seventy subjects showed that administration of a combination of curcuminoids
and piperine significantly improved nonalcoholic fatty liver disease (NAFLD)
compared with the placebo group. [143]
In
thirty five rats, hepatic damage was induced by double ligation and section of
the common bile duct (CBD). Some animals received piperine 20, 40 or 80mg/kg
body weight, some silymarine 25mg/kg bodyweight and some normal saline orally,
starting one day after the surgery for one month. At the end of the treatment,
in rats treated with piperine, the elevated levels of liver chemicals reduced:
Alanine Amino-transferase (ALT) by 16.5 to 37.5 %, Aspartate Amino-transferase
(AST) aka SGOT by 15.4 to 26.8 %, alkaline phosphatase (ALP) by 60.5 to 72.7 %
and bilirubin by 28.4 to 46.3 % respectively. The histopathological study
showed that following treatment with piperine liver fibrosis reduced in a dose
dependent manner. Further piperine also increased the amount of collagenous
fibers in the matrix of bone tissue. Thus piperine protects against
hepatocellular injury and liver fibrosis. Piperine was found to be better than
silymarin. [144]
In vitro
and in vivo study showed that
antioxidant property of piperine attenuated the progression of
diethylnitrosamine (DEN) induced hepatocellular carcinoma. Piperine also
mitigated the progression of hepatocellular carcinoma. Histopathological study
showed partial regression of hepatocellular carcinoma. [145]
The
hepatocellular carcinoma (HCC) was induced in rats by supplying 0.01%
diethylnitrosamine (DENA) in drinking water for 10 weeks. The rats were then
treated by oral administration with the combination of 100mg/kg body weight of curcumin
with 20 mg/kg body weight of piperine for 4 weeks. The treatment with this
combination significantly attenuated the morphological and histopathological
changes in the liver. The elevated levels of chemicals in the serum reduced.
The combination showed better suppression than curcumin alone. [146]
Actions
of Piperine on Pancreas
To
study the influence of dietary spices or their active principles on digestive
enzymes of pancreas, the experimental rats were fed in diet with a single spice
for 8 weeks. The study showed that piperine stimulated the secretion of trypsin
while there was no significant increase in the secretion of chymotrypsin. [147]
In
a study acute pancreatitis was induced by administering cerulein.
Administration of piperine reduced severity of acute pancreatitis lowered the
elevated levels of pancreatic enzymes and reduced myeloperoxidase (MPO)
activity. Histological study showed that piperine reduced the structural damage
of the pancreas. Furthermore, pretreatment with piperine reduced the production
of tumor necrosis factor-α (TNF- α), interleukin (IL)-1β and interleukin-6
(IL-6) during cerulein-induced acute pancreatitis (AP). In isolated pancreatic
acinar cells, piperine reduced cell death, amylase and lipase activity and
cytokine production. In addition, piperine inhibited the activation of
mitogen-activated protein kinases (MAPKs). These findings suggest that the
anti-inflammatory activity of piperine has protective effect against acute
pancreatitis (AP) [148]
Actions of Piperine against Diabetes
Piperine and piperine analogues showed a significant
anti-diabetic activity which was higher than that of rosiglitazone, a standard
anti-diabetic drug commonly used. Piperine and its derivatives did not show
adverse side effects. [149]
At the dose of 10 mg/kg body weight piperine lowered
elevated blood sugar in glucose challenged models and in alloxan induced
diabetics. This was comparable to hypoglycemic activity of nateglinide. When
piperine was administered with nateglinide piperine increased the plasma
concentration of nateglinide. Thus bioenhancer property of piperine could be
used to potentiate hypoglycemic activity of nateglinide and reduce the dose of
nateglinide. [150]
In another study, administration of piperine at 25 and 50 mg
/kg body weight to streptozotocin induced diabetic rats for 28 days
significantly lowered the elevated blood sugar. This was comparable to
administration of 0.06 mg/kg body weight for similar period of glibenclamide.
[151]
Actions of
piperine on Metabolism
Daily administration of 2.50 mg/kg body weight of
piperine for 15 days lowered thyroid hormones, serum glucose and hepatic lipid
activity in male mice. [152]
Piperine lowered the elevated levels of cholesterol in
hyperlipidemic rats. When combined with other lipid lowering agents piperine
enhanced their bioavailability and reduced their effective lipid lowering dose.
[153]
A study showed antiadipogenic activity of
Mareecham-Black pepper (Piper nigrum) extract and its constituent
piperine. Both the Mareecham-Black pepper (Piper
nigrum) extract and piperine strongly
inhibited adipocyte differentiation of 3T3-L-1 cells without showing any
toxicity. Piperine attenuates fat cell differentiation by down-regulating PPARγ
activity as well as suppressing PPARγ expression. Therefore piperine can be
useful for the treatment of obesity-related diseases. [154]
After induction of obesity in Sprague Dawley rats,
piperine was supplementd in 20, 30 and 40mg/kg body weight with high fat diet
(HFD) for 42 days. The study showed that supplementation of piperine reduced
obesity and alleviated symptoms of metabolic syndrome associated with obesity
in a dose dependent manner. The maximum therapeutic effect being noted at a
dose of 40 mg/kg body weight. Thus piperine can be an effective bioactive
molecule to reduce body weight, improve insulin and leptin sensitivity,
ultimately leading to regulate obesity. [155]
To asses the effects of piperine on metabolic
syndrome, rats were fed high carbohydrate, high fat (HCHF) diet. They received
high carbohydrate, high fat (HCHF) diet consisting of carbohydrate 52%, fat 24%
and fructose 25% in drinking water or corn starch (CS) diet for 16 weeks. As
expected they developed hypertension, elevated oxidative stress, impaired
glucose tolerance, abdominal obesity, intrahepatic and perihepatic fat
deposition with hepatic fibrosis, increased plasma liver enzymes,
inflammation-induced cardiac changes such as infiltration of inflammatory cells
in heart, increase in count and degranualation of mast cells in heart, cardiac
fibrosis with ventricular stiffness and reduced responsiveness of aortic rings
(metabolic syndrome). Supplementation with piperine at the dose of 375 mg/kg
body weight reduced the symptoms of metabolic syndrome. This suggests that
piperine can be used to treat metabolic syndrome in humans. [156]
Actions of Piperine on Male Reproductive System
To assess the effect of
Mareecham-Black pepper (piper nigrum)
on sex function in male mice, mice were fed with pellets containing aqueous and
ethanol extract of Mareecham-Black pepper (piper
nigrum) with 1:1 ratio. The pellets were given once every day for 90 days.
The animals showed shorter courtship latency and increased mounting frequency.
This showed that Mareecham-Black pepper (piper
nigrum) increased sexual drive and improved sexual function in male mice. [157]
When rats were treated with piperine for thirty days
there was a significant increase in serum testorone levels without affecting
luteinizing hormone (LH) concentrations. However the treatment with piperine
reduced folliclestimulating hormone (FSH) levels. Consistent with increase in
serum testorone, piperine increased the number and size of Leyding cells.
Piperine also increased multiple steroidogenic pathway proteins, including
steroidogenic acute regulatory protein, cholesterol side-chain cleavage enzyme,
3β-hydroxysteroid dehydrogenase 1, 17α-hydroxylase/20-lyase and sterodogenic factor
1 expression levels. Piperine in vitro
and in vivo also increased androgen
production. Interestingly, piperine inhibited spermatogenesis. Therefore many
Ayurvedic practitioners use Mareecham-Black pepper (Piper nigrum) as a herbal contraceptive agent. Thus in pubertal age
piperine stimulates Leyding cell development and promotes its maturation while
it inhibits spermatogenesis in rats. [158]
In another study, a group of
researchers administered piperine orally at doses of 5 and 10mg/kg body weight
for 30 days to male albino rats. The treatment with the dose of 10 mg/kg body
weight caused a significant reduction in size and weight of testes and
accessory sex organs. Histological study showed that piperine at 5mg/kg body
weight caused partial degeneration of germ cells, whereas at the dose of 10
mg/kg body weight piperine caused severe damage to seminiferous tubules,
decrease in diameters of nuclei of seminiferous tubule and Leyding cells,
desquamation of spermatocytes and spermatids. Correlated to the structural
changes, there was a fall in epididymal sperm concentration. At the dose of 10
mg/kg body weight piperine also caused a marked increase in serum gonadotropins
and a decrease in intratesticular testosterone concentration, despite normal
testorone titres. [159]
Maricham-Black pepper (Piper nigrum) has been a popular oral
male contraceptive used by Ayurvedic practitioners. Recently piperine has been
identified as a bioactive chemical responsible for this activity. To validate
this concept, bucks (male rats) received 10 mg/kg body weight of piperine daily
for 60 days. The results showed that piperine decreased the weights of
reproductive organs, induced hormonal imbalance by altering the serum levels of
follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone
bindibg globulin and levels of serum and testicular testorone. Furthermore,
piperine decreased the activity of germ cell markers and
Leyding-cell-steroidogenic enzymes leading to contraceptive effects in the
bucks. Histological findings also supported these findings. All the
above-altered values returned to normal levels after withdrawal piperine. Hrom
the above data it can be inferred that Mareecham-Black pepper (Piper nigrum)/ piperine can be a good
lead molecule for the development of oral male contraceptive due to its
reversible activity. [160]
The inferences of the study of
effects of piperine on sperms of goat are:
At doses of 40 μmol/L, 60
μmol/L, 80 μmol/L and 100 μmol/L piperine exhibited a significant reduction in
viability and motility of spermatozoa in the epididymis of goat. At the doses
mentioned here piperine significantly disturbed the structural integrity,
caused significant damage to DNA and significantly decreased the activity of
superoxide dismutase (SOD) and catalase (CAT) of the sperms of goat. [161]
Actions
of Piperine on Female Reproductive System
In
female rats, piperine given by various routes effectively inhibited the
implantation of embryo and produced abortions and delayed labour. At the same
dose level which interrupts pregnancy, piperine did not affect the estrous
cycle. Neither uterotropic, antiestrogenic nor antiprogestational property was
observed. [162]
An
in vitro study showed that piperine
causeed apoptosis in human cervical adenocarcinoma cells without harming normal
cells. This activity was attributed to antioxidant property of Mareecham-Black
pepper (Piper nigrum). Further in vivo
and clinical studies will be needed for its validation. [163]
Paclitaxel
is a commonly used chemotherapeutic agent to treat human ovarian
adenocarcinoma. Piperine a wellknown bioenhancer is used to compliment and
potentiate the action of paclitaxel. [164]
Antitumor activity of Piperine
In experimental study
piperine suppressed human fibrosarcoma HT-1080 cells. Piperine also exhibited
anti-invasive effect. Thus piperine is a potent anticancer drug for the
treatment and prevention of metastasis of fibrosarcoma. [165]
Angiogenesis plays an important
role in tumor progression. Piperine inhibits angiogenesis in tumor tissues.
This suggests that piperine can be used as an inhibitor of angiogenesis in the
treatment of cancers. [166]
Drug
interactions of Piperine
Piperine has been
reported to interact with carbamazepine, diclofenac and fexofenadine, digoxin,
chlorzoxazone, propranolol and theophylline. [167]
Toxicity
of Piperine
Administration of piperine upto
the dose of 100mg/kg bodyweight for 7 days was found to be nontoxic. [168]
Doses of piperine
The recommended
dose of piperine is 5 to 2o mg/kg body weight per day. However in some special
circumstances it is used upto 4omg/kg bodyweight or even upto 80 mg/kg body
weight.
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