Mareecham-Black pepper (Piper nigrum) Part 4

Mareecham-Black pepper (Piper nigrum) Part 4
In this article, I discuss the phytopharmacology of some more phytochemicals found in Mareecham-Black pepper (Piper nigrum)

Piperidine
Molecular formula: (CH2)5NH, C5H11N
Structural formula:


 [169]


  
Piperidine is heterocyclic amine. It is a colorless liquid with a disagreeable or objectionable odor. Piperidine was first reported in 1850 by the Scottish chemist Thomas Anderson and in 1852 by the French chemist Auguste Cahorus. Both obtained piperidine by reacting piperine with nitric acid. Pyridine can also be reduced to piperidine via a modified Birch reduction using sodium in ethanol. Piperidine itself has been obtained from Mareecham-Black pepper (Piper nigrum) [170]  
Pharmacokinetics of Piperidine
Piperidine a colorless liquid can be absorbed through intestine via breath, skin and all mucous membranes. While piperidine is metabolized in the liver and excreted by kidney, it can damages both the organs.   
Anti-inflammatory and Antioxidant activity of Piperidine
To investigate anti-inflammatory activity of piperidine, paw edema was induced in rats by using carrageenan. To one group, piperidine was administered orally at 100, 250 and 500mg/kg body weight doses. To another group, dexamethazone was administered intraperitoneally (IP) at the dose of 2mg/kg body weight. The study indicated that piperidine had a potent anti-inflammatory activity comparable to that of dexamethasone.
Furthermore antioxidant activity of piperidine was investigated by standard methods. The study revealed that piperidine exhibited antioxidant activity comparable to ascorbic acid, a commercial synthetic antioxidant. [171]
Immonomodulatory activity of Piperidine
Piperidine and its derivatives display glycosidase inhibiting and immunosuppressive activities. Glycosidase inhibitory activity was studied against α-glucosidase, α-galactosidase and α-mannosidase with reference to known standard N-hydroxyethyl 1-Deoxynojirimycin (DNJ: trade name Miglitol). Immunosuppressive activity was evaluated in vitro by the ability of piperidine derivatives to inhibit the proliferation of human lymphocytes in the Mixed Lymphocyte Reaction (MLR) and to inhibit the production of Immunoglobulin G (IgG). [172]
Antibacterial activity of Piperidine        
Piperidine, sodium piperidine and some of its synthetic derivatives showed in vitro antibacterial activity against Staphylococcus aureus ATCC 1501, Bacillus subtilis ATCC 6633, Yersinia enterococolitica ATCC 1501, Escherichia coli ATCC 11230 and Klebsiella pneumoniae [173]
Recently six novel derivatives (No. 5 to10) have been synthesized. They show strong antioxidant activity. Due to this they are potent antibacterial agents. Of these compound 6 showed the strongest inhibitory activity against seven bacteria tested. [174]
Piperidine-4-one, a new derivative of piperidine has been synthesized recently. Its antimicrobial activity was characterized by using Fourier-transform infrared spectroscopy (FTIR), hydrogen-1 nuclear magnetic resonance (1H-NMR), 13C nuclear magnetic resonance (13C NMR), mass spectroscopy and zone of inhibition. It was found to be a potent antibacterial agent against Bacillus subtilis. [175]
Antiviral activity of Piperidine
Researchers have developed a series of N(2)-(1-(substituted-aryl)piperidin-4-yl)-N(6)-mesityl-9H-purine-2,6-diamine derivative (piperidine derivative). Further study revealed that the compound showed antiviral activity against HIV, influenza A/H1N1 (strain A/PR/8/34) in Madin-Darby canine kidney cells. [176]

Antifungal activity of Piperidine
Piperidine, sodium piperidine and some of its synthetic derivatives showed in vitro antifungal activity against Candida albicans. [177]
Recently six novel derivatives (No. 5 to10) have been synthesized. They show strong antioxidant activity. Due to this they are potent antifungal agents. Compounds 5, 6, 9 and 10 reveal varying degree of inhibition against Aspergillus niger, Aspergillus flavus, Saccharomyces cervisiae and Candida albicans. At 1000 μg/ml compound 8 demonstrates the highest scavenging capacity of 78% and compound 6 the least scavenging potential of 49%. [178]
Piperidine-4-one, a new derivative of piperidine has been synthesized recently. Its antimicrobial activity was characterized by using Fourier-transform infrared spectroscopy (FTIR), hydrogen-1 nuclear magnetic resonance (1H-NMR), 13C nuclear magnetic resonance (13C NMR), mass spectroscopy and zone of inhibition. It was found to be a potent antifungal agent against Candida albicans. [179]
Actions of Piperidine against Parasites
A series of 44 derivatives of 4-aminipiperidine was screened in vitro for antiprotozoan activity. The study showed that they were active against Trypanosoma brucei rhodesienses, Trypanosoma cruziLeishmania donovani and Plasmodium falciparum. [180]
Piperidine derivative R. D. 7098 was tested for its efficacy against intestinal amoebiasis in 30 patients. R. D. 7098 showed a definite clinical improvement in 73% of patients. The clinical improvement was supported by stool examination and sigmoidoscopic examination. Toxic reactions were nausea and epigastric pain. [181]
Piperidine and its derivatives were found to be effective against the human parasite Giardia intestinalis. [182]
Actions of Piperidine on wound healing
Naturally occurring piperidine, synthetic piperidine and synthetic derivatives of piperidine were screened for their wound healing activity on Swiss albino rats. The study showed that epithelization and wound contraction was faster in wounds treated with these compounds than the untreated wounds. The tensile strength of the scar significantly increased. The results were similar to the wounds treated with Nitrofurazone. [183]
Actions of Piperidine on the Breast
Naturally occurring piperidine, synthetic piperidine and synthetic derivatives of piperidine were screened for their activity against breast cancer. The results showed that they were effective in controlling ER-positive and ER-negative breast cancer. This effect is attributed to their potent antioxidant and oxygen-free-radical scavenging activities. [184]
Actions of Piperidine on Hematopoetic system
Naturally occurring piperidine, synthetic piperidine and its synthetic derivatives showed myelo-stimulatory activity. [185]
Actions of Piperidine on Eyes
When injected intravenously piperidine caused contraction of the nictitating membrane in cats and dogs. [186] 
Actions of Piperidine on Endocrine System
In two series of experiments, piperidine produced pressor action by liberation of adrenaline or another pressor compound from the adrenal glands. [187]
Actions of Piperidine onMusculoskeletal System
Piperidine displays antidegenerative activity. Its antioxidant, anti-inflammatory and analgesic properties can be useful for the treatment of arthritis.
Actions of Piperidine on Nervous System
Larger doses of tetraethyl ammonium chloride i. e. 20 and 30mg/kg body weight reversed the responses to piperidine.
In cats under chlorarose anesthesia, sympathectomy reduced the pressor response to piperidine.
Cocaine administered prior to sympathectomy slightly increased the responses to piperidine.
Piperidine and its derivatives display analgesic effects. [188]
Alzheimer’s disease is associated with decrease in the activity of the cholinergic system in the cerebral cortex and other areas of the brain. It is caused by reduced synthesis of acetylcholine by cholinesterase. A study shows that piperidine inhibits cholinesterase and stabilizes the levels of acetylcholine in the brain. Thus piperidine can be useful for the prevention and treatment of Alzheimer’s disease. [189]
Actions of Piperidine on Cardiovascular System  
In experiments on cats, piperidine was found to stimulate the liberation of acetylcholine from the perfused superior cervical ganglion. Intravenous injection of 5mg of piperidine hydrochloride to cats was found to release acetylcholine and reduce blood pressure.
In study on dogs, 10 mg of piperidine reduced elevated blood pressure. Tetraethyl ammonium bromide did not abolish the depressor responses to piperidine. [190]
Actions of Piperidine on Respiratory System
Piperidine exerts stimulant action on respiration. [191] 
Actions of Piperidine on Gastrointestinal System
Piperidine hydrochloride at the dose of 0.5 mg stimulated the contractions of rabbit’s intestine. This effect was very similar to that of nicotine and was not abolished by atropine. [192]  
Actions of Piperidine on Female Reproductive System
In three experiments piperidine caused increase in tone in the horns of guinea pig uterus. In non-pregnant cat uterus piperidine caused increase in tone which was ineffective in the presence of atropine sulphate. [193]
Antitumor activity of Piperidine
Piperidine and its derivatives display anti-tumor activity against drug-resistant tumors. [194]
Interactions of Piperidine
A study on mice demonstrated that simultaneous administration of nitrite and piperidine led to marked increase in the incidence of the cancer of urinary bladder [195]
Toxicity of Piperidine
·       Contact with piperidine can severely irritate and burn the skin and eyes with possible eye damage.
·       Breathing piperidine can cause irritation of nose, throat, trachea and lungs causing sneezing, coughing and wheezing.
·       Exposure to piperidine can cause dizziness, headache, irritability, depression, fatigue and muscle weakness.
·       Exposure to piperidine can cause salivation, nausea, vomiting and griping pain in abdomen.
·       Piperidine can cause liver and kidney damage. [196]   
Dose of Piperidine
By intra venous (IV) route:  0.06mg/kg body weight
By subcutaneous route: 0.1mg/kg body weight [197]

Chavicine
Molecular formula: C17H19NO3
Structural formula:


Chavicine is an alkaloid found in Mareecham-Black pepper (Piper nigrum). It is one of the four geometric isomers of piperine. [198]
Chavicine was believed to cause the peculiar taste of pepper.
On storage chavicine is slowly transformed into piperine.
Actions of Chavicine on Nervous System
Aluminum, especially Aluminum Chloride (AlCl3) is neurotoxic agent. It causes oxidative stress that leads to accumulation of amyloid-plaques in the brain. Chavicine protects the brain from aluminum induced neurotoxicity. Chavicine also acts as memory enhancer. [199]
Many pharmaceutical activities of Chavicine are similar to Piperine and Piperidine.
  
Dipiperamide D                   
Molecular formula: C36H40N2O6
Structural formula:



Dipiparamide D an alkaloid from Mareecham-Black pepper (Piper nigrum) belongs to the class of organic compounds known as benzodioxoles. These are compounds containing a benzene ring fused to either isomers of dioxoles. Dioxole is a five-membered unsaturated ring of two oxygen atoms and three carbon atoms. [200]

Two new bisalkaloids, dipiperamides D and E were isolated as inhibitors of a drug metabolizing enzyme cytochrome P450 (CYP) 3A4 from the white pepper, Piper nigrum. Their structures were elucidated by spectroscopic methods. Dipiperamides D and E showed potent CYP3A4 inhibition with IC50 values of 0.79 and 0.12 uM, respectively, and other metabolites from the pepper were moderately active or inactive. [201]

Dipiperamide E  

Molecular formula: C34H38N2O6
Structural formula:



         [202]
Pharmacological properties of Dipiperemide D and Dipiperamide E are similar to those of Piperine and Piperidine.

Some Testimonials from Modern Research

Pharmacokinetics of Piper nigrum
Mareecham-Black pepper (piper nigrum) is a bioenhancer par excellance so it should be used regularly in clinical arena. Mareecham-Black pepper (Piper nigrum) should be used in combination with drugs acting on nervous system, GI system, respiratory system, cardiovascular system etc, especially with antibiotics and anticancer drugs. [203], [204]
Anti-inflammatory and analgesic activities of Piper nigrum
In a study anti-inflammatory activity of hexane extract of Mareecham-Black pepper (Piper nigrum) was evaluated against carrageenan-induced paw inflammation in rats, analgesic activity was determined by tail immersion method. The study showed that Mareecham-Black pepper (Piper nigrum) displayed anti-inflammatory and analgesic activities. [205]
Antipyretic activity of Piper nigrum
To evaluate antipyretic activity of alcoholic extract of Mareecham-Black pepper (Piper nigrum) in Wistar albino rats, pyrexia was induced in rats by injecting 15% w/v Brewer’s yeast suspension. Administration of 100, 250 and 500mg/kg body weight of the extract showed antipyretic activity. [206]
Antioxidant activity of Piper nigrum
Methanolic extract of Maricham-Black pepper (Piper nigrum) L fruits display a potent antioxidant activity by inhibiting lipid peroxidation, lipoxygenase and arresting hydroxyl and superoxide free radicals. [207]
When there is imbalance between free radical generation and antioxidant activity, oxidative stress is generated which is harmful to our body, causing simple health problems to genesis of cancers. Different kinds of free radicals can attack cell membrane, alter membrane permeability, damage cell membrane, cause oxidation of lipids, cause loss of enzymatic activities and ultimately disrupt cell function and body physiology which may cause cancer. Plants are a potent source of antioxidant activity that protects body systems. Maricham-Black paper (Piper nigrum) is one such antioxidant that protects body by antagonizing oxidative stress at various levels. [208], [209]   
Immuunomodulatory activity of Piper nigrum
The aqueous extracts of Mareecham-Black pepper (Piper nigrum) significantly enhance splenocyte proliferation in a dose-dependent fashion. The extracts enhance T helper (Th) 1 cytokine release by splenocytes. Experimental evidence suggests that Maricham-Black pepper (Piper nigrum) displays a potent immunomodulatory activity. [210]
Antibacterial activity of Piper nigrum  
Qualitative analysis of methanol and chloroform extracts of Maricham-Black pepper (Piper nigrum) showed the presence of alkaloids, tannins, flavonoids and cardiac glycosides. The presence of phytochemicals in the extracts showed antibacterial activity against Staphylococcus aureus, Salmonella typhi, Escherechia coli and Proteus species. [211]
In another study Maricham-Black pepper (Piper nigrum) showed antibacterial activity against Streptococcus mutans isolated from tooth decay and inflammation of the teeth and Eschericiia coli from patients with diarrhea. [212]    
A group of researchers isolated phytochemicals (1) 2E.4E, 8Z-N-isobutyleicosatrienamide (2) pellitorine (3) tracheone (4) pergumidiene and (5) isopiperolein B from the berries of Maricham-Black pepper (Piper nigrum). All the phytochemicals were active against Bacillus subtilis, Bacillus sphaericus and Staphylococcus aureus, Gram positive bacteria; and Chromobacterium violaceum and Klebciella aerogenes, Gram negative bacterial strains. [213]
In another study the researchers found that Maricham-Black pepper (Piper nigrum) altered the membrane permeability of the cells there by acting as antibacterial agent against Staphylococcus aureus, Bacillus cereus, Streptococcus faecalis, Pseudomonas aeruginosa, Salmonella typhi and Escherichia coli.[214] 
The chloroform extract of Maricham-Black pepper (Piper nigrum) when incubated with Escherichia coli and Staphylococcus aureus inhibited the bacterial growth. The extract enhanced permeability of bacterial cell membrane, affected the metabolic rate of glycolysis, disrupted the normal metabolism of bacteria and disrupted the bacterial respiration. [215]
Recently by using nanotechnology, silver nanoparticles of leaf and stem extracts of Maricham-Black pepper (Piper nigrum) have been synthesized. They show antibacterial activity against Gram positive and Gram negative bacteria. [216] 
Antifungal activity of Piper nigrum
At concentration of 25 mg/mL methanol and petroleum ether extracts of Maricham-Black pepper (Piper nigrum) displayed antifungal activity against Candida albicans while at concentrations of 12.5 mg/mL the methanol extract of the leaf of Maricham-Black pepper (Piper nigrum) displayed antifungal activity against Aspergillus species. [217]
In another study, cold water, hot water extracts and pepper soup of the leaf of Maricham-Black pepper (Piper nigrum) displayed antifungal activity against Candida albicans. This activity was attributed to the presence of tannins, flavonoids and alkaloids in the leaf of the plant. [218]  
A group of researchers screened ethanolic extract of Maricham-Black pepper (Piper nigrum) for antifungal activity against Candida albicans by disc diffusion method. They found that at concentrations 500, 1000 and 2000μg the extract displayed antifungal activity against Candida albicans. [219]
Antiprotozoal activity of Piper nigrum
Visceral leishmaniasis is a life-threatening disease. Ethanolic and Hexane extracts of seeds of Mareecham-Black pepper (Piper nigrum) showed profound leishmanicidal activity against Leishmania donovani promastigoates and amastogoates via apoptosis. [220]  
Anthelmintic activity of Piper nigrum
In experimental phytopharmacology the anthelmintic activity of a phytochemical is evaluated against earthworm instead of round worm.
The alcoholic extract of the dried fruits of Mareecham-Black pepper (Piper nigrum) was found to kill earthworm (Pheritima prosthuma). The anthelmintic activity was comparable to that of Albendazole. Hence researchers concluded that Mareecham-Black pepper (Piper nigrum) had anthelmintic activity against round worms (Ascaris lumbricoides). [221]

Actions of Piper nigrum on Nervous system
Day by day the incidence of anxiety-depression and Alzheimer’s disease is increasing. Modern drugs used for their treatment have many untoward side effects. Hence search is on for safer herbal drugs to treat these neurological disorders.
A study shows that methanolic extract of fruit of Mareecham-Black pepper (Piper nigrum) significantly exhibits anxiolytic and antidepressant activities by attenuating oxidative stress. Further the extracts improve the clinical picture of Alzheimer’s disease. [222]
Another study was done in corticosteroid induced depression model of mice. After administration of Mareecham-Black pepper (Piper nigrum)/Piperine the depression and behavioral changes significantly improved. [223]
A study showed that Mareecham-Black pepper (Piper nigrum) significantly improved the memory in aluminum trichloride (AlCl3) induced neurotoxicity mouse model. These effects were attributed to the phytochemical chavicine present in Mareecham-Black pepper (Piper nigrum). [224]
Actions of Piper nigrum on Cardio Vascular System
In another experimental study on rats, Maricham-Black pepper (Piper nigrum) was administered to the animals in 250mg/kg and 500 mg/kg body weight for 10 weeks. The lipid profile showed a significant reduction in total cholesterol, phospholipids, free fatty acids and triglycerides thus preventing the risk of atherosclerosis. [225]
    
Actions of Piper nigrum on Respiratory System
Mareecham-Black pepper (Piper nigrum) shows antitussive and bronchodilator properties. The addition of little amounts of powdered Mareecham-Black pepper (Piper nigrum) in green tea significantly reduces bronchial asthma. [226], [227]
Actions of Piper nigrum on Gastrointestinal Systen
Mareecham-Black pepper (Piper nigrum) increases the production of saliva, activates salivary amylase, promotes gastric secretion and decreases gastric transit time. [228]
Oral administration of 1.5 G of Mareecham-Black pepper (Piper nigrum) to healthy volunteers significantly increased pepsin and parietal cell secretion, gastric cell exfoliation and potassium (K+) loss. [229]
Oral administration of aqueous extract of Mareecham-Black pepper (Piper nigrum) at doses of 75, 150 and 300 mg/kg body weight displayed antimotility, antisecretory and antidiarrheal effects. The effect was dependent on dose administered. The authors concluded that this effect was due to alkaloids present in Mareecham-Black pepper (Piper nigrum). [230]
Further some researchers had showed antibacterial activity of Mareecham-Black pepper (Piper nigrum) causing diarrhea. [231]
Actions of Piper nigrum on Liver
Oral administration of the methanol extract of fruit of Mareecham-Black pepper (Piper nigrum) at 100 and 200 mg/kg body weight for 15 days decreased the hepatotoxicity induced by ethanol and carbon tetrachloride (CCl4) in Wistar rats. Administration of Mareecham-Black pepper (Piper nigrum) significantly decreased the elevated levels of Triglycerides (TG), Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) and Bilirubin. [232]
In another study liver toxicity was induced with D-galactosamine. Administration of Mareecham-Black pepper (Piper nigrum) protected the liver from major liver damage. [233]
Actions of Piper nigrum on Metabolism
In anti-adipogenesis study Mareecham-Black pepper (Piper nigrum) extract inhibited the adipocyte differentiation without affecting normal cells. [234]
Actions of Piper nigrum against Diabetes
Mareecham-Black pepper (Piper nigrum) lowers elevated levels of serum glucose due to its antioxidant property. [235]


Actions of Piper nigrum on Male Reproductive System
Administration of 25 and 100 mg/kg body weight of fruit powder of Mareecham-Black pepper (Piper nigrum) for 20 and 90 days to male mice showed spermicidal activity. The histopathological study of testis showed non-uniform degenerative changes in the seminiferous tubules. The seminiferous tubules showed intraepithelial vacuolation, loosening of germinal epithelium, occurrence of giant cells and mixing of spermatids of different stages of spermatogenesis; in severe cases, the tubules were lined by mainly a layer of Sertoli cell. These changes were dose and duration dependent. The treatment for 20 days did not cause appreciable alterations in histological appearance of epididymis, while the treatment for 90 days caused detectable alterations in the duct. Fifty six days after cessation of treatment the organs and their functions returned to normal. [236]
Antitumor activity of Piper nigrum
In many experimental studies, Mareecham-Black pepper (Piper nigrum) has been reported to display anticancer activity. It inhibits formation of tumor at various stages of tumoergenesis. This activity was attributed to antioxidant and immunomodulatory property of the herb. [237]
Further research showed that phytochemicals, especially piperine present in Mareecham-Black pepper (Piper nigrum), arrests proliferation and G1/S transition of tumor cells causing their death without harming normal cells. This is due to inhibition of angiogenesis. [238]
Mareecham-Black pepper (Piper nigrum) displayed anticancer activity against androgen dependent and nondependent prostate cancer.
Mareecham-Black pepper (Piper nigrum) also exhibited anticancer activity against lung cancer and breast cancer. Further it was to be useful in arresting metastasis of these cancers. This activity was attributed to anti-inflammatory, anti-oxidant, free radical scavenging and immunomodualting properties of the plant. [239], [240] 


Toxicity and adverse effects of Piper nigrum

The ethanol extract of the plant was not toxic to rats up to 5000mg/kg body weight. This suggests that these levels could be safe for human consumption. Mareecham-Black pepper (Piper nigrum) was devoid of toxicity up to 2000 mg/kg body weight in experimental mice. [241]

Traditional and Ayurvedic Uses of Mareecham-Black pepper (Piper nigrum)
Traditionally, as household medicine and in Ayurveda; Mareecham-Black pepper (Piper nigrum) is used----  
·        as appetizer
·        as digestant
·        to relieve hyperacidity and heartburn
·        as antiflatulent and carminative agent
·        as antidiarrheal agent
·        to relieve constipation
·        as detoxicating agent
·        as health stimulant
·        as spice
·        for respiratory disorders as decongestant
·        as anthelmintic
·        for weight loss
·        as antidiabetic agent
·        to reduce fever
·        to treat rheumatism and arthritis
·        for skin care especially in vitiligo
Uses in Modern Medicine
In modern medicine, Mareecham-Black pepper (Piper nigrum) is used----
·        as a bioenhancer
·        as anti-inflammatory, antioxidant and immunomodulatory agent
·        to improve absorption of food and drugs
·        as memory enhancer
·        as antipsychotic and antidepressant
·        as an adjunct to many groups of drugs such as antibiotics, anticancer drugs
·        to lower lipid levels
·        as anti-obesity drug
·        to treat diabetes
·        for contraception in males
Formulations and doses:
Trikatu: Equal parts of Shunthi (Zingiber officinale), Mareecham (Piper nigrum) and Pippali (Piper longum)
Dose: Adults: 500 mg to 3 grams per day to be divided in 3-4 doses up to 7 days  
   Children: One to two pinchful 3-4 times a day up to 7 days

Marichi Choorna (Powder of Black pepper):
Marichyadi Vati:
Marichi Taila, Mareechyadi Taila: For skin care alopecia, vitiligo, psoriasis

References:
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