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]

Another study showed that after oral administration to male albino rats at 170 mg/kg body weight, piperine was detected in plasma as early as fifteen minutes after administration. Of this dose 97% of piperine was absorbed and 3% was excreted in faeces and urine up to 4 days. During absorption from the gut piperine did not undergo any metabolic change. Later it was metabolized in the liver. Half life of piperine was found to be 18.26 hours. About 36% of piperine was excreted in urine as conjugated phenols and 62% as methylenedioxyphenyl metabolites. [49]     

Extensive study on the pharmacokinetics of piperine showed that piperine enhances the bioavailability of many pharmacological agents. The bioavailability enhancer activity of piperine was said to be via inhibition of CYP3A and P-glycoprotein. The drugs tested were: rosuvastatin, puerarin, domperidone, curcumin, resveratrol, propranolol, theophylline, β lactam antibiotics, amoxicillin trihydrate, cefotaxime sodium, rifampicin, isoniazid, phenyton, nevirapine, docetaxel (DOX) and many more. [50]

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 

Proposed Mechanism of Bioenhancer Action of Piperine

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

(1) The efficacy of drugs increases due to increase in bioavailability
(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]

Immunomodulatory activity of Piperine

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]     

To evaluate immunomodulatory activity of piperine, human peripheral blood mononuclear cells (PMBCs) were exposed to piperine. The study showed that, after exposure for 72 hours, piperine significantly inhibited phyto-hemagglutinin- stimulated human peripheral blood mononuclear cell (PMBC) proliferation. Piperine inhibited the production of interleukin-2 (IL-2) and interferon-γ (IFN- γ) mRNA expression. [71]

Cadmium, a potent immunotoxic agent affects both humoral and cell mediated immunity. In mice it induces apoptosis and suppresses immune functions. A study showed that pretreatment of mice with piperine prevented the damage caused by cadmium. Treatment with piperine also reversed the damage caused by cadmium. [72]

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).

Animals treated with piperine showed a significant dose dependent protection with respect to nasal rubbing, sneezing and nasal redness. The clinical findings were supported by reduction in histamine levels. Histopathology showed inhibition of eosinophil infiltration and hyperplasia of nasal mucosa.

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

Gas Chromatography with Electron Impact Mass Spectrometry (GC-EIMS)/ Gas Chromatography and Electron Ionization Mass Spectrometry (GC-EIMS) analysis showed that ethanolic extract of Mareecham-Black pepper (Piper nigrum) fruit containing piperine had antifungal and anti-aflatoxigenic activity. [88]
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]

Antiprotozoal activity of Piperine

Synthetic anti-malarial drugs are associated with many side effects. Moreover the parasites have started developing drug resistance. Hence search is on for natural and safer antimalarial drugs. Recent evaluation shows that piperine is safe antimalarial drug effective against chloroquin-resistant Plasmodium falciparum clones. Piperine is active against the asexual stage of Plasmodium falciparum       malarial parasite. [93] 

Kala azar or visceral leishmaniasis (VL) is a life-threatening protozoal infestation. It is rife in tropical and sub-tropical countries. Despite successful formulation of vaccine against canine leishmaniasis, no licensed vaccine is available for human visceral leishmaniasis (VL). Chemotherapy is in appalling state and development of new anti-leishmanial drug is painfully slow. Mother Nature is generous to unravel the wealth of natural products for the wellbeing of humankind. Piperine from the seeds of Mareecham- Black pepper (Pepper nigrum) is a promising new anti-leishmanial drug as it shows leishmanicidal activity. [94]  

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]

Actions on wound healing

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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98. C. R. Pradeep et al,  Piperine is a potent inhibitor of nuclear factor-κB (NF- κB), c-Fos, CREB, ATF-2 and proinflammatory cytokine gene expression in B16F-10 melanoma cells, International Immunopharmacology, Volume 4, Issue 14, 20 December 2004, Pages 1795-1803   
         
99. Chin Mee Wong, Jing Jing Ling, In Vitro Study of Wound Healing Potential in Black Pepper (Piper nigrum L.) Pharmaceutical and Biosciences Journal, [Formerly known as UK Journal of Pharmaceutical and Bioscience] 2013-2018; https://www.ukjpb.com/article_details.php?id=41

100. Manoharan S et al, Chemopreventive efficacy of curcumin and piperine during 7, 12-dimethylbenz [a]anthracene-induced hamster buccal pouch carcinogenesis, Singpore Med J 2009; 50 (2): 139
101. Martins CA et al, Curcumin in Combination with Piperine Suppresses Osteoclastogenesis In Vitro, J Endod, 2015 Oct; 41(10): 1638-45  

102. Wamidh H. Talib, Regressions of Breast Carcinoma Syngraft Following treatment with Piperine in Combination with Thymoquinone, Sci Pharm. 2017; 85(3): 27
103. Anna L Greenshields et al, Piperine inhibits the growth and motility of triple-negative breast cancer cells, Cancer Letters, Volume 357, Issue 1, 1 February 2015, Pages 129-140 
104. M. N. Motiwala, V. D. Rangari, Combined effect of paclitaxel and piperine on a MCF-7 breast cancer cell line in vitro: Evidence of a synergistic interaction, Synergy, Volume 2, Issue 1, May 2015, pages 1-6
105. Mamendra Pachauri et al, Piperine loaded PEG-PLGA nanoparticles: Preparation, characterization, and targeted delivery for adjuvant breast cancer chemotherapy, Journal of Drug Delivery Scienceand Technology, Volume 29, October 2015, Pages 269-282

106. Chuchawankul S et al, Piperine inhibits cytokine production by human peripheral blood mononuclear cells, Genet Mol Res. 2012 Mar 14; 11(1): 617-27 

107. Soutar DA et al, Piperine, a Pungent Alkaloid from Black Pepper, Inhibits B Lymphocyte Activation and Effector Functions; Phytother Res. 2017 Mar; 31(3): 466-474
 
108. Bang JS et al, Anti-inflammatory and antiarthritic effects of piperine in human interleukin 1 beta-stimulated fibroblast-like synoviocytes and in rat arthritis models, Arthritis Res Ther, 2009; 11(2): R49  

109. Martins CA et al, Curcumin in Combination with Piperine Suppresses Osteoclastogenesis In Vitro, J Endod, 2015 Oct; 41(10): 1638-45  

110. Rezaee MM et al, The effect of piperine on midazolam plasma concentration in healthy volunteers, a research on the CYP3A-involving metabolism, Daru. 2014 Jan 7; 22(1):8

111. Tianjing Rena et al, Time dependent inhibition of carbamazepine metabolism by piperine in antiepileptic treatment, Life Sciences 218 (2019) 314-323

112. Rumesh Liyange et al, Development of Plant Based Confectionary to Combat Micro-sleepiness due to Fatigue in Hectic Life-styles and Cerebral Relaxation, Pak. J. Nutr., 15(12): 1017-1025, 2016     
113. Tasleem F et al, Analgesic and anti-inflammatory activities of Piper nigrum L, Asian Pac J Trop Med, 2014 Sep; 7S1:S461-8  

114. Sama Venkatesh Kowuru Devi Durga, Influence of piperine on ibuprofen induced  antinociception and its pharmacokinetics; Arzneimittelforschung 2011; 61(9): 506-509
115. Kulshreshtha VK et al, A study of central stimulant effect of Piper longum, Indian J Pharmacol 1969; 1:8-11  

116.  S Atal et al, Evaluation of the interaction of piperine with antidepressant sertaline and analgesic pentazocine, using different routes of administration in albino mice. Asian J Pharm Clin Res, Vol 9 Issue 1, 2016, 193-197
117. Bishnoi M et al, Protective effect of curcumin and its combination with piperine (bioavailability enhancer) against haloperidol-associated neurotoxicity: cellular and neurochemical evidence, Neurotox Res. 2011 Oct; 20 (3): 215-25
118. Singh N et al, A comparative evaluation of piperine and nalorphine against morphine induced respiratory depression and analgesia, J Res Indian Med 1973; 8: 21-6

119. Jintanaporn Wattanathorn et al, Piperine, the potential functional food for mood and cognitive disorders, Food and Chemical Toxicology 46(9): 3106-10; September 2008

120. Hanumanthachar Joshi et al, Effects of piperine on memory and behavior mediated via monoamine neurotransmitters, Journal of Traditional Medicine, 2005 Volume 22, Issue 2+3 Pages 39-43   

121. Kumar Vaibhav et al, Piperine suppresses cerebral ischemia-reperfusion-induced inflammation through the repression of COX-2, NOS-2 and NF-κB in middle cerebral artery occlusion in rats, Molecular and Cellular Biochemistry; August 2012, Volume 367, Issue 1-2, pp 73-84.     
122. Sadhana Khawas et al, In vivo cough suppressive activity of pectic polysaccharide with arabinogalactan type II side chains of Piper nigrum fruits and its synergistic effect with piperine, International Journal of Biological Macromolecules, Volume 99, June 2017, Pages 335-342

123. Senug-Hyung Kim et al, Piperine inhibits eosinophil infiltration and airway hypersensitiveness by suppressing T cell activity and Th2 cytokine production in ovalbumin-induced asthma model, Journal of Pharmacy and Pharmacology, 08 January 2010.
124. Yunes Panhai et al, Effects of Curcuminoids-Piperine Combination on Systemic Oxidative Stress, Clinical Symptoms and Quality of Life in Subjects with Chronic Pulmonary Complications Due to Sulfur Mustard: A Randomized Controlled Trial; Journal of Dietary Suppliments, Volume 13, 2016-Issue 1   
125. K. Selvendiran et al, Modulatory effect of Piperine on mitochondrial antioxidant system in Benzo(a)pyrene-induced experimental lung carcinogenesis, Phytomedicine, Volume 11, Issue 1, 2004, Pages 85-89        
126. Hlavackova L et al, Piperine, active substance of black pepper, alleviates hypertension induced by NO synthase inhibition, Bratisl Lek Listy 2010; 111(8): 426-31 
127. Kumar S et al, Efficacy of piperine, an alkaloidal constituent of pepper on nitric oxide, antioxidants and lipid peroxidation markers in L-NAME induced hypertensive rats, Int J. Res. Pharm. Sci. Vol. 1, Issue 3, 300-307, 2010  
128. Velumani Dhivya et al, Piperine modulates isoproterenol induced myocardial ischemia through antioxidant and anti-dyslipidemic effect in male Wistar rats, Biomedicine & Pharmacotherapy, Volume 87, March 2017, Pages 705-713

129. Manodeep Chakraborty et al, Cardioprotective effect of curcumin and piperine combination against cyclophosphamide-induced cardiotoxicity, Indian j pharmacol, 2017 Jan-Feb; 49(1): 65-70    
130. Dong Ju Son et al, Piperine Inhibits Activities of Platelet Cytosolic Phospholipase A2 and Thromoxane A2 Synthase without Affecting Cyclooxigenase-1 Activity: Different Mechanisms of Action Are Involved in the Inhibition of Platelet Aggregation and Macrophage Inflammatory Response, Nutrients. 2014 Aug; 698): 3336-3352
131. T Miyauchi et al, Involvement of calcitonin gene-related peptide in the positive chronotropic and inotropic effects of piperine and development of cross-tachyphylaxis between piperine and capsaicin in the isolated rat atria; Journal of Pharmacology and Experimental Therapeutics, February 1989, 248 (2): 816-824
132. Usha N. S. et al, Gastrointestinal protective effect of dietary spices during ethanol-induced oxidant stress in experimental rats, Applied Physiology, Nutrition and Metabolism, Volume 35, Number 2, April 2010

133. Bai YF and Xu H, Protective action of piperine against experimental gastric ulcer, Acta Pharmacologica Sinica, 01 April 2000, 21(4): 357-359
134. Sunil Bajad et al, Piperine Inhibits Gastric Emptying and Gastrointestinal Transit in Rats and Mice, Planta Med 2001; 67(2): 176-179 

135. Smriti Khatri and Rajendra Awasthi, Piperine containing floating microspheres: an approach for drug targeting to the upper gastrointestinal tract, Drug Delivery and translational research, June 2016, Volume 6, Issue 3, pp 299-307

136. Malik Hassan Mahmood, Pharmacological Basis for the Medicinal Use of Black Pepper and Piperine in Gastrointestinal Disorders, Journal of Medicinal Food, Volume 13, No. 5; Published on line : 1 Oct 2010  
137. Syed Intasar Hussain Taqui et al, Insight into the possible mechanism of antidiarrheal and antispasmodic activities of piperine, Journal of Pharmaceutical Biology Volume 47, 2009, Issue 8 

138. Nagendra Tharmalingam et al, Inhibitory effect of piperine on Helicobacter pylori growth and adhesion to gastric adenocarcinoma cells, Infectious Agents and Cancer, Volume 9, Article number 43, 2014

139. Yong Xia Pham Ngoc Khoi Hyun Joong Yoon, Piperine inhibits IL-1β-induced IL-6 expression by suppressing p38 MAPK and STAT3 activation in gastric cancer cells, Molecular and Cellular Biochemistry, January 2015, Volume 398, Issue 1-2, pp 147-156

140. Paul B. Yaffe et al, Piperine, an alkaloid from black pepper, inhibits growth of human colon cancer via G1 arrest and apoptosis triggered by endoplasmic reticulum stress, Molecular Carcinogenesis, 13 may 2014

141. Indu Bala Koul and Aruna Kapil, Evaluation of the Liver Protective Potential of Piperine, an Active Principle of Black and Long Peppers, Planta Med 1993; 59(5): 413-417 
142. Evan Prince Sabina et al, Ameliorative Effect of Piperine from Piper nigrum on D-Galactosamine-Induced Hepatotoxicity in Mice, Int. J. Pharm. Sci. Res., 21(2), Jul-Aug 2013; 44, 240-245

143. Yunes Panahi et al, Curcuminoids plus piperine improve nonalcoholic fatty liver disease: A clinical trial. Journal of Cellular Biochemistry, 06 June 2019

144. O Abdel Salam et al, Effect of Piperine on Liver Damage and Bone Changes Caused by Bile Duct Ligation in Rats, The Internet Journal of Pharmacology, Volume 5 Number 2

145. Gunasekaran V et al, Targeting hepatocellular carcinoma with piperine by radical-mediated mitochondrial pathway ofapoptosis: An in vitro and in vivo study, Food Chem Toxicol 2017, Jul; 105: 106-118

146. Patil V et al, Synergistic effect of curcumin and piperine in suppression of DENA-induced hepatocellular carcinoma in rats, Environ Toxicol Pharmacol 2015 Sep; 40(2): 445-452  
147. K Platel, K Srinivasan, Influence of dietary spices and their active principles on pancreatic digestive enzymes in albino rats, Molecular Nutrition, Volume 44, Issue 1, January 2000, Pages 42-46 

148. Bae GS et al, Piperine ameliorates the severity of cerulean-induced acute pancreatitis by inhibiting the activation of mitogen activated protein kinases, Biochem Biophys Res Commun 2011 Jul 8; 410(3): 382-8

149. Chetna K harbanda et al, Novel Piperine derivatives with Antidiabetic effect as PPAR-γ Agonists, Chemical Biology and Drug Design, Volume 88, Issue 3, September 2016 Pages 354-362 

150. V. Sama, Effect of piperine on Antihyperglycemic Activity and Pharmacokinetic profile of Nateglinide, Arzneimittelforschung 2012; 62(08): 384-388

151. Suresh Kumar et al, Screening of antidiabetic and antihyperlipidemic potential of oil from Piper longum and piperine with their possible mechanism; Journal Expert Opinion on Pharmacotherapy, Volume 14, 2013, Issue 13
152. S. Panda and A. Kar, Piperine Lowers the Serum Concentrations of Thyroid Hormones, Glucose and Hepatic Activity in Adult Male Mice, Horm Metab Res 2003; 35(9): 523-526
153. Sneha Nawale et al, Data of antihyperlipidaemic activity for methanolic extract of Tagetes patula Linn, flower head along with piperine as bioavailability enhancer, Data Brief. 2018 Dec; 21: 587-597
154.Park UH et al, Piperine, a component of black pepper, inhibits adepogenesis by antagonizing PPARγ activity in 3T3-L-1 cells, J Agric Food Chem 2012 Apr 18; 60(15): 3853-60
155. Brahma Naidu P et al, Mitigating efficacy of piperine in the physiological derangements of high fat diet induced obesity in Sprague Dawley rats, Chem Biol Interact 2014 Sep 25; 221: 42-51.
156. Vishal Diwan, Hemant Poudyal, Piperine Attenuates Cardiovascular, Liver and Metabolic Changes in High Carbohydrate, High Fat-Fed Rats; Cell Biochemistry and Biophysics, November 2013, Volume 67, Issue 2, pp 297-304
157. Sutyarso et al, Effects of Black Pepper (Piper nigrum Linn.) Extract on Sexual Drive in Male Mice, Research Journal of Medicinal Plants, Volume 9(1): 42-47, 2015 
158. Chen X et al, Diverged Effects of Piperine on Testicular Development: Stimulating Leyding Cell Development but Inhibiting Spermatogenesis in Rats, Front Pharmacol. 2018 Mar 28; 9: 244          
159. T Malini et al, Effects of piperine on testis of albino rats, Journal of Ethnopharmacology, Volume 64, Issue 3, March 1999, Pages 219-225
160. Chinta G et al, Reversible Testicular Toxicity of Piperine on Male Albino Rats, Pharmacogn Mag 2017 Oct; 13 (Suppl 3): S525-S532   
161. Rajesh Janarthanan et al, Effect of piperine on goat epididymal spermatozoa: An in vitro study; Asian J Pharm Clin Res, Volume 7, Issue 5, 2014, 57-61.  
162. P. Piyachaturawat et al, Postcoital antifertility effect of piperine, Contraception, Volume 26, Issue 6, December 1982, pages 625-633.

163. Asif Jafri et al, Induction of apoptosis by piperine in human cervical adenocarcinoma via ROS mediated mitochondrial pathway and caspase-3activation, CXCLI J; 2019, 18: 154-164

164. Pal MK et al, Synergistic effect of piperine and paclitaxel on cell fate via cyt-c, Bax/Bcl-2-caspase-3 pathway in ovarian adenocarcinomas SKOV-3 cells; Eur J Pharmacol. 2016 Nov 15; 791: 751-762

165. Yong PilHwang et al, Suppression of phorbol-12-myristate-13-acetate-induced tumor cell invasion by piperine via the inhibition of PKC α/ERK1/2-dependent matrixmetalloproteinase-9 expression, Toxicology Letters, Volume 203, Issue 1, 30 May 2011, Pages 9-19

166. Carolyn D et al, Piperine, a dietary phytochemical, inhibits angiogenesis, J Nutr Biochem, 2013 Jan; 24(1): 231-239  

167. John R Horn et al, https://www.pharmatimes.com/issue July 2017
168. Mhaske DB et al, Role of Piperine as an Effective Bioenhancer in Drug Absorption; Pharmaceutica Analytica Acta; Volume 9, Issue 7



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