Herbal Antibiotics: Natural Alternatives for Treating Drug-Resistant Bacteria (39 page)

The synergistic actions of black pepper and piperine are primarily generated by three things: 1) the circulatory actions of the plant or its isolated constituent; 2) their effects on P-gp and CYP3A4; 3) their impacts on efflux pumps in bacteria.

Pepper and piperine expand blood vessel diameter and increase circulation. Piperine is strongly present in the blood (it binds to albumin for transport) and easily crosses internal organism barriers (organs and systems both: blood-brain barrier and so on). It reaches every part of the body.

Piperine and pepper have specific effects on blood constituents. In my opinion the actions of the plant and its constituent on red blood cells (reducing their fragility and increasing their oxygen uptake) play an important part in their synergistic actions. Pepper and piperine also appear to have specific actions on white blood cells. They do have some immune-stimulating actions, but more importantly they seem to be highly protective of white blood cells, being active against leishmanial and tryposomal parasites of the macrophages. They seem to produce the same effects on white blood cells as they do on red, that is, reducing their fragility and enhancing their normal actions. Although no one has tested for this, it seems as if piperine may play a particular role as a hematoprotector and hematoregenerator not only of red blood cells but also white, though differently than the other plants I have discussed so far.

A smaller role in the plant's synergism is played by the general medicinal actions of the plant—that is, it is to some extent antibacterial, which will give additive effects (at the least) to the antibacterial actions of the other herbs used with it; it is analgesic, helping with pain; it is anti-inflammatory; if you are treating inflammatory infections, its specific actions there will help immensely; and if you are treating CNS problems, it will, in addition to helping other herbs get to the affected area, add its own neuroprotective actions to the mix.

Black pepper and piperine also possess a number of efflux inhibition actions. Piperine inhibits the NorA efflux pump in
Staphylococcus aureus
. It also inhibits ethidium bromide efflux. Ethidium bromide is a substrate for all the efflux pumps in
Staphylococcus aureus
(except NorC). Ethidium bromide is also a substrate in a number of efflux pumps in some Gram-negative bacteria—those that possess the SMR efflux pumps, and in
Mycobacterium
spp. Specifically, piperine has been found to be an inhibitor of the RV1258c efflux pump in
Mycobacterium tuberculosis
.

But perhaps the major strength of the plant and its constituent piperine is the effects they have on permeability glycoprotein (P-glycoprotein or P-gp) and CYP3A4. Black pepper and piperine are potent inhibitors of both.

All living organisms have to deal with one primary survival reality: determining what is me and not me and then identifying whether or not
the “not-me” is going to be harmful to the “me.” There are a great many mechanisms that all organisms have to do this and they have a lot of options available for dealing with unsafe substances that “not-mes” can generate. Basically, they control access to their cells. In general, they all have four mechanisms for this: 1) assisted exclusion; 2) metabolic conversion; 3) solubilizer attachment; 4) reduction in assisted absorption. What this means in practical terms is this: When a substance is taken into the body and touches the GI tract membrane, an immediate identification process occurs. What is this thing? And is it safe? If the intestinal wall identifies it as harmful, then it can:

Exclude it; that is, use what is called an efflux pump or an efflux transporter to move the thing out, making sure it does not affect the cell/organism.

Metabolize it; that is, chemically turn it into something else that is not harmful, which is then either used or excreted from the cell/organism. The chemical substances that are thus created are called metabolites.

Attach it; that is, link the substance chemically to a highly water-soluble substance, often glucuronic acid. This creates a new compound that is unable to diffuse through cell membranes. It is then excreted in either urine or feces.

Reduce assisted absorption; that is, inhibit influx transporters. Assisted absorption involves the use of transporter proteins, a.k.a. influx transporters, in the lining of the intestinal wall. These proteins transfer useful substances into the cells of the intestinal wall and from there they are transported to the blood. Influx transporters are strongly active in moving such things as amino acids across the intestinal membrane. One of the most potent is gamma-glutamyltransferase (GGT). It is present in the cell membranes of the intestines, kidneys, bile duct, liver, spleen, heart, brain, and seminal vesicles.

All these responses make it harder for substances to get into the body and affect it. Many pharmaceuticals are considered to be foreign substances and, when these actions take place, up to 85 percent of a pharmaceutical may be inactivated, which is part of the reason doses are so high with some drugs.

Piperine affects all four of those mechanisms that control access to cells. It has particularly strong effects on efflux pumping, metabolization, glucuronic acid attachment, and GGT.

There are a number of efflux transporters. P-gp, or permeability glycoprotein, is one of the more prominent. P-gp is found mainly in the intestinal wall, kidneys, liver, brain, testes, adrenal gland, and uterus. It is also common in cancer cells and a few bacteria. You can visualize P-gp as a barrier lining the intestinal wall and choosing which substances to let into the body and, if so, how much (it also does this at the blood-brain barrier). Piperine significantly reduces the ability of P-gp to block incoming substances. As a result, if you take piperine or black pepper (or the traditional Ayurvedic blend trikatu), more of the medicinal will pass through the intestinal wall and into the bloodstream. Sometimes, the amount getting into the blood is substantially higher, up to 32 times its
levels without piperine. This is why particular care needs to be taken if you are using piperine and are also taking pharmaceuticals. It is also why you should never take piperine with severe infections of the intestinal wall such as
E. coli
and cholera. Piperine would allow the bacteria to more easily infiltrate the intestinal wall and get deeper into your system.

CYP3A4 is one of the more important metabolizers in the human body. It affects the broadest range of substances (or substrates as they are called) of any of the CYP family of enzymes, affecting thousands if not hundreds of thousands of substances. It is a main metabolizer in the intestinal wall and liver. Generally, it does one of two things: converts a substance to another that has lower biological activity or makes substances more water soluble, which reduces their ability to move into cells. Inhibition of CYP3A4 means that the substance is left in its original, highly bioactive form when it gets into the body. Piperine strongly inhibits CYP3A4. (It has also been found to inhibit CYP1A2, CYP1A1, and CYP2D6.)

Piperine/black pepper also inhibits AHH or aryl hydrocarbon hydroxylase, which metabolizes aromatic hydrocarbons. (This makes piperine useful for enhancing the impact of herbs like juniper berry, which is high in aromatic hydrocarbons, in the treatment of UTI.)

Piperine/black pepper also strongly inhibits UDP-glucuronyl-transferase (a.k.a. UGT). UGT is the enzyme that attaches glucuronic acid to xenobiotics to facilitate their removal from the body. This action by piperine increases the time that foreign substances, e.g., herbs or pharmaceuticals, remain in the body/bloodstream prior to elimination, from 2 to 4 hours longer.

Piperine/black pepper also significantly stimulates the activity of the influx transporter GGT, increasing the movement of substances across the intestinal membrane.

Piperine, and black pepper, thus increase the amount of any substance going into the body, keep it in its most potent form (unmetabolized), and keep it in the body longer. Piperine/black pepper also, for similar reasons, facilitates the movement of substances into the brain and CNS, uterus, testes, adrenals, kidneys, and liver. If any of those systems are being treated for disease, for example, bacterial meningitis or hepatitis C, piperine will increase the amount of herb getting to the meninges or the liver.

At the same time piperine/black pepper stimulates circulation and increases blood vessel size so that the substances are widely circulated throughout the body very rapidly.

A number of studies have looked at the actions of black pepper and piperine along these lines. Most studies have occurred with piperine. However, there has been some work with trikatu, the traditional Ayurvedic blend of the two peppers and gingerroot.

In vivo, goats, pharmaceuticals:
If trikatu was preadministered to mountain goats before their treatment with pefloxacin (a fluoroquinolone antibiotic used in India in veterinary practice), the drug levels in the body and its penetration into various parts of the body were substantially increased. Other studies have found
that trikatu increases the bioavail-ability of vasicine and indomethacin.

Human clinical study, pharmaceuticals:
Trikatu increased the concentrations of vasicine by over 200 percent and sparteine by over 100 percent in the blood plasma of human volunteers.

In vivo, mice/rats, pharmaceuticals:
Piperine increased the effects of pentobarbital-induced hypnosis in mice. Blood and brain pentobarbital levels were higher in treated animals; piperine also prolonged hexobarbital sleeping time and zoxazolamine paralysis; enhanced the bioavailability of aflatoxin B1; enhanced the bioavailability of etoposide; increased the bioavailability of nimesulide, thus allowing the use of reduced, and safer, doses; and delayed elimination of phenytoin.

In vivo, mice/rats, herbs:
Piperine increases the movement of radio-labeled L-leucine, L-isoleucine, and L-valine across the intestinal wall, enhancing uptake; increases the uptake of curcumin and its presence in serum; and increases plasma levels of epigallocatechin gallate from green tea.

Human clinical study/trial, pharmaceuticals:
A single oral dose of propranolol (40 mg) or theophylline (150 mg) alone or in combination with piperine (20 mg) was given each day for 7 days. Increased oral bioavailability was found in the piperine group. A single dose of piperine (20 mg) administered with phenytoin significantly increased the mean plasma concentration of phenytoin; a crossover, placebo-controlled study found that piperine increased the bioavailability of nevirapine, increased its mean plasma concentrations, and reduced its elimination from the body; another study found it increased the bioavailability of vasicine and sparteine.

Human clinical trial/study, herbs:
A crossover study with volunteers given 2 grams curcumin found that its serum levels were either undetectable or very low. When piperine was administered with the curcumin, serum levels were 2,000 percent higher. Piperine enhanced bioavailability, serum concentration, and extent of absorption; a double-blind study found that piperine (5 mg) increased plasma concentrations of CoQ10 by 30 percent.

The man is not sick because he has an illness; he has an illness because he is sick.

—Chinese proverb

A basic truism of antibiotic treatment is that it just will not work under most circumstances unless the body can mount its own attack against invading bacteria.

—Marc Lappé,
When Antibiotics Fail

No matter the virulence of a disease,
and this includes fierce diseases such as Ebola, some people remain healthy in spite of being exposed. In fact, medical studies have consistently shown the presence of virulent bacteria in most peoples' systems though they never become ill.

Countless studies have found that the healthier your immune system, the less likely you are to get a disease and the more likely you are, if you do get sick, to have a milder episode. This is especially true in diseases such as Lyme. Researchers have consistently noted that the higher certain immune markers are, the less likely that infection
will occur and, if it does, the disease will be less severe than if the immune markers are low.

Our immune system is in fact our first line of defense. Its job is to protect us from disease and, if disease occurs, to cure it. A healthy immune system is therefore the first and most important part of health and healing.

Some of the specific elements of our immune system are the thymus, spleen, liver, lymph system, lymph nodes, tonsils, appendix (basically a large lymph node), and bone marrow. The thymus coordinates immune activity, the spleen processes worn-out red blood cells and platelets and provides a location to engulf and destroy invading bacteria. The liver cleans toxins from the blood and produces most of the body's lymph. Lymph is the liquid that flows in the lymph system, somewhat similar to a city's sewer system. The lymph system runs parallel to the blood vessels and stores, filters, and circulates waste, especially dead bacteria and the massive numbers of white blood cells produced during active infections. Lymph nodes are large intersections of lymph channels and store or warehouse the waste products being processed through the lymph system. When the lymph nodes are processing a lot of waste they tend to swell, clog up, and become painful to the touch. When they do, the processing of waste slows down. Keeping the nodes clear helps the body process infections much more quickly. The lymph nodes also produce unique white blood cells called lymphocytes (as does the thymus gland) that are particularly strong elements of the immune system.