Black pepper extract for enhancing bioavailability -
In those studies carried out in animals as well as human volunteers, it was noted that the active component is piperine. Piperine, or mixtures containing piperine, have been shown to increase the efficacy, blood levels, and bioavailability of a number of drugs including ingredients of vasaka leaves Bose, K.
et al. Piperine has also been added in multi-drug formulations for the treatment of tuberculosis and leprosy. A formulation containing rifampicin, pyrazinamide and isoniazid has been tested in human volunteers Indian Patent No.
For most drugs, the comparative levels and peak concentration of the drugs in the presence of piperine were higher. The applicability of these results to the development of anti-tuberculosis and anti-leprosy formulations, which are presently cost prohibitive in developing countries, is apparent.
Bioavailability enhancement helps to lower dosage levels and shorten the treatment course. The effect of piperine on the bioavailability of propranolol has also been studied.
The chronic oral administration of the anti-hypertensive agent propranolol is frequently rendered difficult due to the fact that steady therapeutic levels of this drug are not achieved or maintained.
In addition, large doses are needed to be administered for efficacy and this frequently causes side-effects. Piperine has been shown to enhance the bioavailability of this drug. Propranolol administered with piperine shows a significant increase in plasma levels of the drug, presumably due to decrease in metabolism by the liver.
Similar results have been obtained with piperine and vasicine, theophylline, and phenytoin. In summary, all of these examples clearly illustrate the role of piperine as a drug bioavailability enhancer.
The combination of piperine with tested drugs is effective primarily due to higher plasma concentration and a longer stay of the drugs in the body. The reduced dose of highly toxic drugs and their enhanced efficacy is obviously desirable.
As noted above, the exact mechanism of drug bioavailability enhancement by piperine is unknown. Several studies indicate that piperine may act primarily by non-specifically inhibiting the mixed function oxidases systems. This slows down the process of metabolic biodegradation of the drug and enhances the bioavailability of the drug.
In a detailed study of the interaction of piperine with enzymatic drug biotransforming reactions in jejunal epithelial cells and liver hepatocytes in vitro and in vivo, piperine appears to be a non-specific inhibitor of drug metabolism.
Such results led the authors to speculate that piperine may find useful applications in successful drug therapy, and represent an important addition to the chemotherapists armory for the quantitative enhancement of drug bioavailability Atal et al.
The principle of the present invention is to provide a mechanism which allows the extraction of additional nutritional value from less and fewer foods, by enhancing systemic bioavailability of the essential nutrients. The metabolic pathways for a nutrient and drug are different in that a nutrient sustains basic metabolism, and physiological functions of the organism, while a drug is utilized as an adjunct to basic metabolism, to restore homeostasis to the physiological functions.
This distinction allows one to understand the different mechanism of bioavailability of the present invention. One mechanism, as described by the prior art, is applicable primarily to sustain therapeutic levels of a drug in the organism.
The other, as discussed by the present inventors, is applicable to increase absorption of nutrients and increase their metabolic utilization. The invention has been intended primarily, but not exclusively, to increase the gastrointestinal absorption of nutrients and botanical compounds.
This invention is intended in general to enhance the crossing-over of nutrients and botanical compounds through biological barriers such as, but not limited to, gastrointestinal epithelium, respiratory lining, genitourinary lining, blood brain barrier and skin.
Although not wishing to be limited to any mechanism of action, it is believed that the basic mechanism of the invention is two-fold: by affecting various active and passive transport mechanisms as described in detail below; and by causing the increase for the substrate demand due to enhanced metabolism at the cellular level.
This latter mechanism is triggered when the compositions and method of the invention affect thermoregulation of the body, acting directly or indirectly through activation of thermoreceptors, which results in increased thermogenesis, or metabolic heat energy production and release.
By affecting thermoreceptors, particularly in the skin and mucosa, the invention prevents thermal and non-thermal nociceptive stimuli being carried to spinal dorsal horn cells, and acts as a local and general anesthetic, by increasing threshold for the nociceptive stimuli.
The present invention is directed to preparations and methods of using such preparations to improve the bioavailability of certain nutritional compounds. The compositions and methods of the present invention increase gastrointestinal absorption, improve crossing over through certain biological barriers such as respiratory lining, urinary lining, blood brain barrier and skin, and systemic utilization of certain nutrients and biological compounds.
The compositions of the invention also act by increasing thermogenesis. Secretion of catecholamines can also be mediated by ATP via a P2-type purinergic receptors, and through a direct or indirect stimulation by the compositions of the invention of dopaminergic and serotinergic systems.
It is known that stimulation of beta-3 adrenoceptors results in increased thermogenesis, decrease in the amount of white adipose tissue without food intake being affected, increased levels of insulin receptors, and decreased levels of serum insulin and blood glucose.
The invention may possess anti-obesity and anti-diabetic effects, which by themselves contribute to the mechanism of thermogenesis and the increase in lean body mass.
The anti-obesity and anti-diabetic effects of the present invention can be potentiated by using the compositions of the invention in combination with vanadium, in the form of vanadium organic and inorganic salts, both synthetic and naturally occurring.
The thermogenic effect of the invention may also be mediated by an increase in the activity of thyroid peroxidase, an important enzyme in thyroid hormone synthesis, an increase in the plasma levels of triiodothyronine T3 and thyroxine T4 with simultaneous increase in tissue oxygen uptake and increase in thermogenesis.
The thyrogenic and thermogenic effects of the present invention can be potentiated by using the compositions of the invention in combination with L-selenomethionine.
Alternatively, the compositions may be prepared from an extract of the fruit of piper longum. Compositions of the present invention may also contain extract from roots of zingiber officinale, with active ingredients 6-gingerol and 6-shogoal.
The compositions may be formulated with the extract from fruit of piper nigrum, extract from fruit of piper longum, and extract from roots of zingiber officinale combined in any weight ratio. Preferred weight ratios include , , , and When used in a preparation for oral administration, the piperine is used at a daily dose of 0.
When used as a preparation for topical or parenteral use to improve crossing over through a biological barrier, the compositions of the present invention contain, as an essential ingredient, 0. The compositions of the present invention may also be used to affect thermoreceptors and prevent thermal and non-thermal noxious stimuli from being carried to the dorsal horn cells, which exerts local and general analgesic affects.
The potentiation of analgesic affects is believed to be caused by increasing the absorption of the analgesic with which it is administered, and additionally, providing a synergistic or additive mechanism of analgesic action.
The compositions of the present invention improve gastrointestinal absorption and systemic utilization of the nutrients and nutritional supplements. The preparations of the present invention for improving gastrointestinal absorption and systemic utilization, may be made with any nutrient, biological compound, or nutritional supplement.
Particularly preferred biological compounds include boswellin, curcumin, capsaicin, ashwagandha, ginkgo biloba, and aconitine. The compositions of the present invention to improve gastrointestinal absorption and systemic utilization may also include water soluble vitamins and fat soluble vitamins.
Preferred water soluble vitamins include vitamin B1, vitamin B2, niacinamide, B6, B12, folic acid, and vitamin C. The absorption of water soluble vitamins is believed to work by preventing denaturing agents present in food from altering the proteintetramer hydrophilic channels which facilitate gastrointestinal absorption of water soluble vitamins.
In addition, the ability of piperine to enhance gastrointestinal absorption of vitamin B12 is believed to occur by stimulating synthesis and secretion of an intrinsic factor, a glycoprotein secreted by gastric parietal cells, which facilitates transport of vitamin B12 across the cellular membrane.
The preparations of the present invention used to improve gastrointestinal absorption may also contain fat soluble vitamins. Preferred fat soluble vitamins are vitamins A, vitamin D, vitamin E, and vitamin K.
In addition, carotenes such as alpha-carotene, beta-carotene and transbeta-carotene are believed to be subject to enhanced absorption due to a cholagogous mechanism which increases duodenal bile salts to emulsify fat soluble vitamins, and facilitate intracellular absorption via the mixed micelle system.
The compositions of the invention may also include amino acids, particularly the essential amino acids lysine, isoleucine, leucine, threonine, valine, tryptophan, phenylalanine, and methionine.
The amino acids are believed to be subject to enhanced gastrointestinal absorption by increasing the gamma-glutamyl cycle which facilitates transmembrane transport of amino acids.
As noted earlier, the nutritional status of older Americans is particularly problematic. Many antibiotics decrease the absorption of certain metallic and non-metallic minerals. To offset such losses, the compositions of the present invention may include essential minerals such as iodine, calcium, iron, zinc, copper, magnesium and potassium.
Other metals such as vanadium, chromium, selenium and manganese may also be included in compositions of the present invention. It appears that the compositions of the present invention facilitate gastrointestinal absorption of these metallic compounds mainly by enhancing the active transport of these compounds across the membrane.
In addition, the compositions of the present invention may prevent gastrointestinal absorption of certain dangerous heavy metals such as lead, mercury, and cadmium, and prevent systemic interference of the heavy metals with enzymatic functions.
The compositions of the invention can form insoluble salts with mercury chloride, lead chloride and cadmium chloride and also protect sulfhydryl groups of enzymes from reacting with heavy metals. The compounds of the present invention may also include antioxidants. The enhancement of antioxidant activity is believed to occur through enhanced systemic availability of antioxidant compounds through inhibition of lipid peroxidation and free radical formation.
Preferred compositions of the present invention may include a variety of any of the above ingredients, which are particularly needed in a particular population.
Many of the nutrients, biological compounds and nutritional supplements which may be included in the compositions of the present invention are available commercially. Particularly, vitamin, mineral, amino acid and antioxidants are available commercially.
The herbal compounds are generally used in powder form which is a dried ethanol extract of a particular plant. For example, Boswellic acid is from an ethanol extract of Boswellia serrata roots.
Ginsenosides are from an ethanol extract of Ginseng roots. Withanaloids are from an ethanol extract of Whitania somnifera plant. Gingko flavinoids are from an ethanol extract of Gingko biloba plant. Curcuminoids are from ethanol extract of Cucuma longa plant.
Pycnogenol is from an ethanol extract of Pinus pinaseter bark. Proanthocyanidins are from an ethanol extract of pine bark. Some of the herbal compounds are also available commercially from a variety of sources.
The piperine in the invention may be produced by the new method of isolation of piperine. The compound obtained in this manner has the trademark name of Bioperine®. Alternatively, piperine may be provided by the prior art methods.
The following examples are not intended to be limiting in any way, but demonstrate some of the preferred embodiments of the present invention. The above formulations and ingredients are examples, and are not intended to limit the invention in any way. Results of this study demonstrate that the average baseline serum β-carotene, and retinol values of volunteers from the two formulation groups were not significantly different prior to the β-carotene supplementation period.
Analysis of covariance was used to determine if the mean area under the serum β-carotene curve from baseline through day 14 of supplementation or the mean absolute changes in β-carotene values from baseline to day 14 of supplementation were affected by changes in retinol values from baseline to day These analyses determined that changes in β-carotene values in groups A and B from day 0 to day 14 were not affected by serum retinol changes during this period.
When mean absolute change from baseline level was used for comparison, group B also was found to produce significantly greater absolute changes than group A controls. Commercially available Black pepper oleoresin or Long pepper oleoresin is used as the source of piperine.
Ground up Black pepper or Long pepper can also be used. To a mixture of butanol and hexane 35 liters , 35 kg Black pepper oleoresin is added and heated to 40° C. The mixture is then cooled and filtered. The crude piperine is dissolved in methanol at 60° C.
and treated with alumina and charcoal by stirring. It is then filtered and concentrated under vacuum to obtain a powder. Material thus prepared has the following specifications: Color: Pale yellow crystalline powder. We claim: 1.
The composition of claim 1 wherein the piperine is extracted from the fruit of piper nigrum or black pepper. The composition of claim 1 wherein the piperine is extracted from the fruit of piper longum. The composition of claim 1, which contains additionally an extract from the root zingiber officinale.
The composition of claim 1 wherein the nutritional materials comprise one or more members selected from the group consisting of herbal extracts, water soluble vitamins, fat soluble vitamins, amino acids, minerals, anti-oxidants, and combinations containing two or more of the above nutritional materials.
The composition of claim 5 wherein the herbal extracts comprise one or more members selected from the group consisting of curcumin, boswellin, ashwagandha, ginkgo biloba, capsaicin, and aconitine. The maximum blood concentration of the drug increased two fold with piperine.
Importantly, despite dramatically improving the bioavailability of propranolol, piperine, as used in a 3 mg dose, did not affect the elimination rate of the drug. In an experimental design distinct from previous studies, the anti-asthmatic drug theophylline and the anti-epileptic drug phenytoin were tested Ban, C.
The study was done on six healthy volunteers. The participants were pretreated with 20 mg of piperine daily for seven days before receiving mg of theophylline or mg of phenytoin. The maximum concentration of theophylline was 1.
Importantly, the elimination rate of the drug was significantly slowed down with piperine pretreatment. Phenytoin blood concentration rose more rapidly in the group pretreated with piperine than in the group receiving the drug alone.
The pretreated group attained maximum concentration of the drug in shorter time and in significantly higher concentrations. The pretreatment with piperine resulted in significantly slower elimination of the drug. The prior art discussed above clearly illustrates the role of piperine as a bioavailability enhancer, and the importance of its effective dose on the overall mechanism of enhanced bioavailability.
In the case of propranolol, the co-administration with only 3 mg of piperine resulted in doubling its blood levels, but without slowing down the drug elimination rate.
Thus, it may be inferred that, in a small dose, piperine may not inhibit the biotransforming enzymes or affect the elimination rate of a drug. Rather, it may operate through enhancement of gastrointestinal events leading to rapid absorption mechanisms.
The present invention is directed to preparations and methods of using such preparations to improve the bioavailability of nutritional compounds. The compositions and methods of the present invention increase gastrointestinal absorption, improve crossing over through certain biological barriers such as respiratory lining, urinary lining, blood brain barrier and skin, and systemic utilization of certain nutrients and biological compounds.
The compositions and methods of the present invention contain, as an essential ingredient, piperine. Alternatively, the compositions may be prepared from an extract of the fruit of piper longum.
Piperine made synthetically may also be used in the present invention. Compositions of the present invention may also contain extract from roots of zingiber officinale, with the active ingredients 6-gingerol and 6-shogoal.
The compositions may be formulated with the extract from fruit of piper nigrum, extract from fruit of piper longum, and extract from fruits of zingiber officinale combined in any weight ratio.
Preferred weight ratios include , , , and As a daily supplement taken with a nutrient or is nutrients by an average healthy adult, piperine is effective and safe in a broad dose range.
A preferred effective dose range of piperine for oral use to enhance nutrient bioavailability is 0. When used as a preparation for topical or parenteral use to improve crossing over through a biological barrier, the compositions of the present invention contain, as an essential ingredient, 0.
The nutritional materials are used in nutritionally effective amounts. The present invention is directed to preparations and methods of using such preparations to improve the bioavailability of various nutritional compounds.
The compositions of the invention also act by increasing thermogenesis. Secretion of catecholamines can also be mediated by ATP via a P2-type purinergic receptors, and through a direct or indirect stimulation by the compositions of the invention of dopaminergic and serotinergic systems.
It is known that stimulation of beta-3 adrenoceptors results in increased thermogenesis, decrease in the amount of white adipose tissue without food intake being affected, increased levels of insulin receptors, and decreased levels of serum insulin and blood glucose.
The present invention may possess anti-obesity and anti-diabetic effects, which by themselves contribute to the mechanism of thermogenesis and the increase in lean body mass. The anti-obesity and anti-diabetic effects of the present invention can be potentiated by using the compositions of the invention in combination with vanadium, in the form of vanadium organic and inorganic salts, both synthetic and naturally occurring.
The thermogenic effect of the invention may also be mediated by an increase in the activity of thyroid peroxidase, an important enzyme in thyroid hormone synthesis, an increase in the plasma levels of triiodothyronine T3 and thyroxine T4 with simultaneous increase in tissue oxygen uptake and increase in thermogenesis.
The thyrogenic and thermogenic effects of the present invention can be potentiated by using the compositions of the invention in combination with L-selenomethionine and iodine supplementation. The metabolic pathways for a nutrient and drug are different in that a nutrient sustains basic metabolism, and physiological functions of the organism, while a drug is utilized as an adjunct to basic metabolism, to restore homeostasis to the physiological functions.
This distinction allows one to understand the different mechanism of bioavailability of the present invention. One mechanism, as described by the prior art, is applicable primarily to sustain therapeutic levels of a drug in the organism.
The other, as discussed by the present inventors, is applicable to increase absorption of nutrients and increase their metabolic utilization. The invention is intended primarily, but not exclusively, to increase the gastrointestinal absorption of nutrients and botanical compounds.
This, in general, enhances the crossing-over of nutrients and botanical compounds through biological barriers such as, but not limited to, gastrointestinal epithelium, respiratory lining, genitourinary lining, blood brain barrier and skin.
Although not wishing to be limited to any mechanism of action, it is believed that the basic mechanism of the invention is two-fold: by affecting various active and passive transport mechanisms as described in detail below; and by causing the increase for the substrate demand due to enhanced metabolism at the cellular level.
This latter mechanism is triggered when the compositions and method of the invention affect thermoregulation of the body, acting directly or indirectly through activation of thermoreceptors, which results in increased thermogenesis, or metabolic heat energy production and release.
By affecting thermoreceptors, particularly in the skin and mucosa, the invention prevents thermal and non-thermal nociceptive stimuli being carried to spinal dorsal horn cells, and acts as a local and general anesthetic, by increasing threshold for the nociceptive stimuli.
The compositions of the present invention may also be used to affect thermoreceptors and prevent thermal and non-thermal noxious stimuli from being carried to the dorsal horn cells, which exerts local and general analgesic affects. In addition, piperine may potentiation the analgesic affects is believed to be caused by increasing the absorption of the analgesic with which it is administered, and additionally, providing a synergistic or additive mechanism of analgesic action.
The compositions of the present invention improve gastrointestinal absorption and systemic utilization of the nutrients and nutritional supplements. The preparations of the present invention for improving gastrointestinal absorption and systemic utilization, may be made with any nutrient, biological compound, or nutritional supplement.
Particularly preferred biological compounds include boswellin, curcumin, capsaicin, ashwagandha, ginkgo biloba, and aconitine.
The compositions of the present invention to improve gastrointestinal absorption and systemic utilization may also include water soluble vitamins and fat soluble vitamins. Preferred water soluble vitamins include vitamin B1, vitamin B2, niacinamide, B6, B12, folic acid, and vitamin C.
The absorption of water soluble vitamins is believed to work by preventing denaturing agents present in food from altering the proteintetramer hydrophilic channels which facilitate gastrointestinal absorption of water soluble vitamins. In addition, the ability of piperine to enhance gastrointestinal absorption of vitamin B12 is believed to occur by stimulating synthesis and secretion of an intrinsic factor, a glycoprotein secreted by gastric parietal cells, which facilitates transport of vitamin B12 across the cellular membrane.
The preparations of the present invention used to improve gastrointestinal absorption may also contain fat soluble vitamins.
Preferred fat soluble vitamins are vitamins A, vitamin D, vitamin E, and vitamin K. In addition, carotenes such as alpha-carotene, beta-carotene and transbeta-carotene are believed to be subject to enhanced absorption due to a cholagogous mechanism which increases duodenal bile salts to emulsify fat soluble vitamins, and facilitate intracellular absorption via the mixed micelle system.
The compositions of the invention may also include amino acids, particularly the essential amino acids lysine, isoleucine, leucine, threonine, valine, tryptophan, phenylalanine, and methionine. The amino acids are believed to be subject to enhanced gastrointestinal absorption by increasing the gamma-glutamyl cycle which facilitates transmembrane transport of amino acids.
Many antibiotics decrease the absorption of certain metallic and non-metallic minerals. To offset such losses, the compositions of the present invention may include essential minerals such as iodine, calcium, iron, zinc, copper, magnesium and potassium.
Other metals such as vanadium, chromium, selenium and manganese may also be included in compositions of the present invention. It appears that the compositions of the present invention facilitate gastrointestinal absorption of these metallic compounds mainly by enhancing the active transport of these compounds across the membrane.
In addition, the compositions of the present invention may prevent gastrointestinal absorption of certain dangerous heavy metals such as lead, mercury, and cadmium, and prevent systemic interference of the heavy metals with enzymatic functions.
The compositions of the invention can form insoluble salts with mercury chloride, lead chloride and cadmium chloride and also protect sulfhydryl groups of enzymes from reacting with heavy metals. The compositions of the present invention may also include antioxidants. The enhancement of antioxidant activity is believed to occur through enhanced systemic availability of antioxidant compounds through inhibition of lipid peroxidation and free radical formation.
Preferred compositions of the present invention may include a variety of any of the above ingredients, which are particularly needed in a particular population.
Many of the nutrients, biological compounds and nutritional supplements which may be included in the compositions of the present invention are available commercially.
Particularly, vitamin, mineral, amino acid and antioxidants are available commercially. The herbal compounds are generally used in powder form which is a dried ethanol extract of a particular plant.
For example, Boswellic acid is from an ethanol extract of Boswellia serrata roots. Ginsenosides are from an ethanol extract of Ginseng roots.
Withanaloids are from an ethanol extract of Whitania somnifera plant. Gingko flavinoids are from an ethanol extract of Gingko biloba plant. Curcuminoids are from ethanol extract of Cucuma longa plant.
Pycnogenol is from an ethanol extract of Pinus pinaseter bark. Proanthocyanidins are from an ethanol extract of pine bark. Some of the herbal compounds are also available commercially from a variety of sources. The piperine in the invention may be produced by the new method of isolation of piperine shown in Example 14, below.
The compound obtained in this manner has the trademark name of Bioperine®. Alternatively, piperine may be provided by the prior art methods or made synthetically.
The following examples are not intended to be limiting in any way, but demonstrate some of the preferred embodiments of the present invention.
The above formulations and ingredients are examples, and are not intended to limit the invention in any way. The following is an example of the utilization of piperine in nutrient absorption.
The objective of the study was to compare the beta-carotene, in human volunteers receiving the formula with and without Bioperine®. Twelve healthy male volunteers, non-smokers, abstaining from alcohol, not taking nutritional supplements or prescription drugs during the period of cross-over study, received beta-carotene supplementation with and without Bioperine® for a period of 14 days.
Results of this study demonstrate that after 14 days of supplementation, volunteers from the control group, receiving formulation A, were found to have significantly smaller increase in blood levels of beta-carotene than those from the group receiving formulation B with Bioperine®.
The group receiving Bioperine® had almost a two fold increase in blood beta-carotene levels as compared to the group receiving beta-carotenes only.
The probable mechanism of piperine's effect on the bioavailability of beta-carotene is its effect on gastrointestinal events that lead to increased absorption of this nutrient and most probably other nutrients as well.
A dose of 5 mg of piperine, and up to 15 mg, would most likely not interfere with the metabolism of a majority of drugs as previously discussed. In fact, this dose as used with beta-carotene does not affect the metabolic pathways of this nutrient in the body, as measured by the blood levels of retinol which remained unchanged throughout the experiment see below.
It is an important finding that piperine does not elevate the conversion of beta-carotene to vitamin A, since toxic effects due to an overdose of vitamin A are well known. The benefit of increased blood levels of beta-carotene without danger of vitamin A toxicity translates into the safe and effective enhancement of anti-oxidant protection provided by beta-carotene.
Additional evidence from the experiment with 14 day supplementation of beta-carotene to 12 healthy volunteers show that piperine does not affect absorption, metabolism and elimination of nutrients that are not supplemented, but otherwise consumed with a daily food.
For example, the blood levels of water soluble vitamin C and lipid soluble vitamin E, which were not supplemented, were not affected as assessed before the study and after completion of 14 day supplementation of beta-carotene with piperine. The apparent lack of any inhibitory effect from piperine on human metabolism at low doses is an important observation.
This is particularly so because many of those who may require piperine co-administered with a nutrient like certain vitamins, may also be on a drug regimen which can not be altered.
Based on the available literature, a dose of piperine below 20 mg per day per person should not affect the metabolism of most if not all xenobiotics such as the drugs discussed above. This amount of crude pepper translates to According to other sources daily human consumption of black pepper constitutes 0.
Chandrasekhara, N. Food Safety, 7; pp. This particular diet with pepper and its components did not affect food intake, growth pattern of fed animals, the organ weights, and produced no clinical symptoms. Comparison of the blood chemistry tests results of the treated and untreated animals showed no alterations in RBC, WBC, the differential count, levels of hemoglobin, total serum proteins, albumins, globulins, glucose, cholesterol and levels of serum aminotransferases and phosphatases.
Acute, subacute and chronic toxicity studies of piperine in laboratory animals indicate that piperine used in broad range of doses, does not cause any abnormality in the general growth pattern, body to organ weight ratio, clinical symptomatology and blood chemistry data Johri, R.
The dose of piperine considered as bioenhancing absorption of nutrients is considered 0. The LD 50 data indicate a relatively high therapeutic index for piperine, which means high degree of safety in nutritional use of piperine.
Piper species have been traditionally used to induce abortion. The reported antifertility property of piperine was investigated in laboratory animals Plyachaturawat, P.
Piperine inhibited significantly pregnancy in mice when given by either intraperitoneal or oral route of administration at a dose of Piperine was effective at both pre- and post-implantation periods.
The dose of piperine that significantly inhibited pregnancy in mice did not interfere with the estrogen cycle, did not show uterotropic effect, and did not produce clinically noticeable toxicity.
The mechanism of anti-fertility action of piperine is not known at present, but it does not operate through a hormonal mechanism or uterotonic activity. Black pepper extracts have been shown to possess tumor inhibitory activity Loder, J. et al , "Black pepper: Evidence of carcinogencitiy", Nutrition and Cancer, 1; pp.
In this study an ethanol extract of black pepper at a dose calculated as to times higher than the pharmacologically effective dose of piperine, has been applied topically to mice for three months.
This treatment resulted in the significant increase in tumor occurrence in mice. The authors of this report discuss several chemicals that are known components in black pepper extracts as possible culprits.
Safarole, tanins and terpenoids like d-limonene, 1-pinene, linalool and phellandrene are specifically mentioned as potential carcinogens, cocarcinogens, or tumor promoters.
Piperine has not been implicated directly by the report as a possible tumorigenic compound, but because it contains the methylendioxybenzene structure in common with safarole, chavicine, piperittine and myristicine may be problematic.
However, experiments dealing with piperine and safarole metabolism have shown that despite chemical likeness, piperine and safarole are metabolized differently, giving rise to different types of products Ionnoids, C.
Piperine and safarole interact differently with rat liver microsomes, and those differences may be attributed to the structural dissimilarities in the side chain of these two compounds Wrba, H. In a separate experiment, preweaned mice injected with safarole, tannic acid or methylcholantrene, a reference carcinogen, developed tumors.
Safarole and tannic acid have been shown to be weak carcinogens when compared with methylcholantrene. Feeding of d-limonene to the mice which were injected with any of the above three substances reduced their carcinogenic activity.
Feeding piperine to the mice receiving the three compounds did not modify their carcinogenic activity Wrba, H. Owing to its interaction with xenobiotic-metabolizing enzymes, piperine may potentially inhibit detoxification of some toxic compounds. To investigate this possibility the in vitro influence of piperine on various enzymes that are closely related to the metabolism and detoxification system of a toxic compound such as benzo a pyrene has been studied Chu, C.
This study showed that piperine significantly enhanced benzo a pyrene cytotoxicity in vitro. The results of this study are contradicted, however, by another report indicating that piperine can in fact inhibit benzo a pyrene activation, by lowering benzo a pyrene-oxide production, thus decreasing benzo a pyrene cytotoxicity Atal, C.
Alteration of hepatic mixed function oxidases may potentially lead to hepatotoxic effect. Piperine was evaluated for potential hepatotoxicity in rats Dalvi, R.
Drug Interact, 9 1 ; pp. None of the treatment regiments altered significantly the following liver enzymes indicative of liver damage: serum sorbitol dehydrogenase SDH , alanine aminotransferase ALT , aspartate aminotransferase AST and isocitrate dehydrogenase ICD.
In a separate study piperine was found to have a hepatoprotective action in mice treated with potent hepatotoxins tetra-hydroperoxide and carbon tetrachloride Koul, I. This protective effect, demonstrated by both in vivo and in vitro experiments, was explained by piperine mediated decrease in lipid peroxidation, and reduction in hepatocellular damage as measured by reduced enzymatic leakage of glutamate pyruvate transaminase and alkaline phosphatase.
Piperine also prevented depletion of reduced glutathione and total thiols in the liver. The reduced glutathione is one of the most important biomolecules in protection against chemically induced cytotoxicity, and can eliminate toxic compounds by conjugation.
The effect of piperine on lipid peroxidation and liver enzymes was confirmed in other studies, which show piperine inhibiting lipid peroxide formation and leveling off increased levels of acid phosphatase in rats injected with carageenin--a compound which is known to stimulate liver peroxide formation Dhuley, J.
Liver peroxide output is increased as a result of damage of lysosomes probably elicited indirectly by inflammatory action of carageenin, with subsequent increased levels of liver lipid peroxidation and acid phosphatase.
The nitrosation reaction of piperine is of concern, as endogenous nitrosation could take place in the human stomach from ingested piperine and nitrites Wakabayashi, K.
This combination may lead to potentially mutagenic products. Nitrites can be ingested by consuming cured foods, such as meat and, in particular, bacon. Nonetheless, research data indicate a remote possibility of any potential nitrosation reaction of piperine, for the following reasons:.
Thus, nitro compounds formation with piperine, if any, would be a multifactorial and competitive event;. The doses of piperine, recommended for bioavailability enhancement are relatively low when compared to the toxic doses, and translate to a dose of pure piperine in a range of 2.
That dose equals to an average daily dose of 0. Commercially available Black pepper oleoresin or Long pepper oleoresin is used as the source of piperine. Ground up Black pepper or Long pepper can also be used.
To a mixture of butanol and hexane 35 liters , 35 kg Black pepper oleoresin is added and heated to 40° C. The mixture is then cooled and filtered. The crude piperine is dissolved in methanol at 60° C. and treated with alumina and charcoal by stirring. It is then filtered and concentrated under vacuum to obtain a powder.
Material thus prepared has the following specifications: Color: Pale yellow crystalline powder. We claim: 1. The composition of claim 1 wherein the piperine is obtained from an extract of fruits of the family Piperaceae. The composition of claim 1 wherein the piperine is extracted from the fruit of piper nigrum or black pepper.
The composition of claim 1 wherein the piperine is extracted from the fruit of piper longum. The composition of claim 1, which contains additionally an extract from the root zingiber officinale.
The composition of claim 1 wherein the nutritional materials comprise one or more members selected from the group consisting of herbal extracts, water soluble vitamins, fat soluble vitamins, amino acids, minerals, anti-oxidants, and combinations containing at least two of the nutritional materials.
The composition of claim 6 wherein the herbal extracts comprise one or more members selected from the group consisting of curcumin, boswellin, ashwagandha, ginkgo biloba, capsaicin, and aconitine.
The composition of claim 6 wherein the water soluble vitamins comprise one or more members selected from the group consisting of B1, B2, niacinamide, B6, B12, folic acid, and vitamin C.
Black pepper Self-care education for diabetes nigrum is a widely used spice bioavailabipity has been used for centuries Panax ginseng benefits traditional medicine. Enhacning not only a common ingredient in cooking booavailability also has medicinal Black pepper extract for enhancing bioavailability known for centuries. Caffeine and energy drinks of the key bioactive compounds in black pepper is piperine, which is responsible for its characteristic pungent taste and aroma. Black pepper is known for its potential to help enhance the bioavailability of certain supplements, including magnesium and turmeric. This is because of the presence of piperine, which is a natural bioavailability enhancer. Bioavailability refers to the amount of a nutrient that is absorbed and available for use by the body. Piperine is an alkaloid peoper black pepper Piper nigrum giving Body shape progression that pungent nioavailability. It is produced using extrct ethanol, including the oleoresinic part undoubtedly Black pepper extract for enhancing bioavailability enhancihg Caffeine and energy drinks rich in piperine extract. liposoluble vitamins, curcuminoids, etc Extraxt was declared not novel foods in March by the Belgium authorities. As an activity of "nutrient enhancer," it is not subject to the EFSA authorizations since improving bioavailability may not be a claim the claims are linked to the nutrient itself. It is produced using only ethanol, including the oleoresinic part undoubtedly the only currently-rich extract piperine. Its use is oral, 5mg per dose, and patented - including Europe use of piperine as a gastrointestinal absorbation enhancer.
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