Guest guest Posted January 18, 2006 Report Share Posted January 18, 2006 At 04:54 PM 1/17/2006, vaeagle2@... wrote: Yes, I would too! Anything to keep the liver among other organs strong and healty... I want to learn... There's a rather lengthy review I'd written for DAAIR a few years ago, partially reproduced below. M. ** http://www.daair.org/DAAIR/dp.NSF/35c2de9c87f81b5f85256b850083b2be/7892be277722f38885256b850081dacc?OpenDocument Detoxification-Part I, Specific Strategies for Optimizing Long-Term Multidrug Use While Maintaining A Healthy Body: Detoxification Nota bene Much of the basic science and toxicological information in this paper, where not otherwise cited, was obtained from the excellent volume, Ioannides C, editor, Cytochromes P450: Metabolic and toxicological aspects, CRC Press, 1996. Additional information has been obtained from Goodman & Gilman's Pharmacological Basis of Therapeutics, Pergamon Press, Inc., 1990; and on's Principles of Internal Medicine, McGraw-Hill, 13th ed. New York:1994. Please note that the Internet version of this document will be periodically updated at a more frequent rate than the printed version. Overview Why should you review this section? Simply put, there is a strong chance you are or will have to use various pharmaceutical drugs if you have HIV. Understanding toxicity and how to prevent or offset it is critical to help to maximize the benefit of these drugs, to establish the most effective dose and to assure that you don't take other drugs that might cause problematic or even fatal interactions. The use of multiple drugs in various combinations is called polypharmacy. Never before in the short history of western medicine, have so many combinations of drugsmany with substantial long-term toxicitiesbeen required for such long periods of time. If you are on combination antiviral therapy with or without other prophylactic drugs, you're going to need the following explanation of detoxification, and you're going to need to implement any number of the strategies listed in the following pages in order to maximize the longest possible benefits from those drugs. Finally, understanding a bit about potential toxicities will alert you to signs and symptoms (or changes in blood work) that may require a change in your therapeutic regimeneither with alternative/complementary treatments in an attempt to lessen the toxicities, or completely changing pharmaceutical drugs. But DAAIR can not stress strongly enough that, wherever you are with this disease, you must start now. The longer you wait, the greater the deterioration, the more difficult it is to put Humpty Dumpty back together again. Do everything you can to delay the need for any drugs. And keep doing what you need to do should the time come that you need to use prophylaxis or antiretroviral therapy. Trying to offset toxicities after they have established a foothold is much more difficult to manage. But even then, you can give it 110%. DAAIR supports the notion that you must both improve the host response and fight the virus at the same time. The newest combinations of nucleoside analog drugs (such as AZT, ddI, ddC, 3TC and d4T or nukes) and their non-nucleoside reverse transcriptase inhibitor (NNRTI) cousins (delavirdine and nevirapine) along with the protease inhibitors (indinavir, ritonavir) herald a new era. However, there are many potential drawbacks with HAART: Highly Active AntiRetroviral Therapy. While longer and more sustained benefits are being seen than with nuke monotherapy (e.g., just taking AZT), failures have been noted (Gilden, 1996). Failure may occur due to HIV developing resistance to the drug resulting in the need to switch combinations. The toxicities may kick in, resulting in the need to drop a drugand/or switch to another regimen. Questions about when to start combination therapy are not always clear-cut. Which particular combinations are best is not fully understood, although there is ample evidence to suggest bad or worthless combinations of nucleoside analogs (e.g., taking ddI with ddC). This of course leads to a new acronym, defined as Failed Active AntiRetroviral Therapy: FAART. For years, possibly decades, people may have to keep rolling from combo to combo. It is not at all clear whether asymptomatic people with HIV infection will benefit or be hurt by the " hit-em-hard-hit-em-early " philosophy propounded by some since the July, 1996 International Conference on AIDS in Vancouver. In essence, this approach prescribes some combination of drugs to anyone who is HIV+ no matter the viral load or T-cell count. Beyond the initial incredulity this idea has been met with by many in the AIDS activist community, many questions arise that have not been addressed by the proponents of immediate therapy. Which drugs? Just nukes? What are the best doses? How long will they last? Will they affect viral load in lymph tissue? What about cells called macrophages where there is a reservoir of HIV? How will toxicities be dealt with? Will drugs be layered one on top of the other when the treatment begins to fail? Will people remain symptom-free for yearsas many doif long term, highly toxic chemotherapy is initiated? Will this ultimately be more detrimental than no treatment? The hit 'em hard philosophy seems dangerous as it implies the practice of sequential use of therapies or layering therapies. Sequentially prescribing these drugs one after the other or adding a protease inhibitor on top of a nuke regimen and the consequent increased likelihood of developing resistance is insane and should be a cause for malpractice suits in people who have not previously had retroviral therapy (treatment naïve). Clearly, however, some people do benefit from the combinations. Some evidence is accumulating suggesting that people on HAART just at or near seroconversion may substantially benefit by a short regimen as may those exposed to a needlestick injury. People with deteriorating immune functioning and increasing viral loads or those with frank AIDS benefit. PWAs who have avoided the nukes over the years get the best bang for the buck. This may constitute another argument against the " hit 'em hard " philosophy in that early use may wind up spoiling the real value of the drugs when they are needed most. (As a side note, such a strategy will likely be most successful when tissues can be cleared of HIV, meaning the need for a 6 to 8 log reduction in viral load in lymph tissue, a feat not yet accomplished by even the best of the current combinations.) Meaningful ways to address the toxicities that arise from such combinations must be developed. Such approaches help to detoxify the body and provide the body the building blocks it needs to aid the healing process. This allows the body to do its job fighting HIV while offsetting deleterious immune responses and enhancing those that effectively control HIV. Finally, drug efficacy may be prolonged by the toxicity-reducing methods discussed herein. Taking Drugs, Nutrients, Herbs What happens when you take a drug (or nutrients, herbs, etc.)? The science that answers this question is called pharmacokinetics. This science studies how much of a drug is absorbed into systemic circulation (bioavailability), where a drug goes in the body (distribution), how a drug is changed or transformed (biotransformation) and how a drug is removed or excreted (clearance). Pharmacodynamics is the study of the effects drugs have in living organisms. For example, clindamycin has been used to successfully treat numerous infections. Understanding the pharmacodynamics describes how it accomplishes this, as well as describing the deleterious effect it has wiping out the body's gut store of " friendly " bacteria. Aside from swallowing a pill, there are a number of ways to take drugs. Injections may be given into a vein (intravenous or IV), under the skin (subcutaneous or sub-q), into central nervous system fluid (intrathecal) or into a muscle (intramuscular or IM). Substances may be taken into the body by the rectum as a suppository or retention enema. In addition, therapies may be inhaled or applied to the skin surface topically. Absorption of a drug depends in part on the route of administration. Methods other than oral consumption will bypass the digestive processes (liver). IV drugs may have more serious side effects due to their instant, untransformed availability to tissues. This is because the blood is the body's communication highway (besides the lymphatic and nervous systems). Orally consumed drugs, in contrast, may be more liver toxic. In addition, absorption is affected by how much a drug will bind to proteins in the body. This can induce toxicities by exciting an immune response or by withdrawing a potentially vital protein from a cell's proper functioning. How is the dosage determined? Aside from the cynicaland sometimes accurateconcept of giving as much as tolerated for the patients' bank account, three principals are involved in arriving at a dose. These are clearance, volume of distribution (how much is in the plasma versus the tissues) and bioavailability. Each of these variables is different for any particular drug. For example, one drug may be quickly cleared from the body, possibly meaning a higher dose is necessary to achieve a therapeutic goal or endpoint. Another drug may be poorly absorbed, again, meaning most of the drug is excreted after ingestion even though the clearance time is longer. In addition to these concepts, how long the drug stays in the body must also be considered. When a drug is taken by injection, consumption, etc., a certain amount winds up in the plasma. Injected drugs, for example, will induce a spike in how much is seen in the blood. This eventually levels off to an equilibrium concentration that steadily declines. The length of time it takes for half the drug to disappear from the blood stream is called the half life. Knowing how much normally gets into blood and how much goes to tissues has an impact on what that half life is. Understanding how a therapy becomes distributed throughout the body is also important. If you know a disease directly affects the brain, but the drug can not cross the blood-brain barrier, the usefulness of the therapy is limited. In understanding toxicities, we begin to understand what happens if a drug accumulates in particular organs or tissues. The way a drug is transformed in the body also has a significant impact on toxicity. The compound itself may be damaging to cells. Or it might damage a specific organ (e.g., pancreatitis caused by ddI). In addition, the processes the body uses to modify therapies may also result in toxic byproducts (also know as toxic intermediates or toxic metabolites). The condition of the person taking the drug must also be considered. A healthy individual with an intact gastrointestinal tract may have no trouble absorbing therapeutic levels of a drug. Another individual with kidney impairment may have difficulty in adequately clearing the drug from the body. Thus, western medicine already embraces certain holistic principles which, if adhered to more stringently and broadened to include nutritional, psychological and other aspects, will lead to a more complete, more effective philosophy of healing. What Are Toxicities? What is a toxicity? Basically, it means you've been poisoned. When some individuals castigate all pharmaceutical therapies as " poisons " they are absolutely correct, if a bit extreme. In fact, almost anything you take or eat can be poisonous. If you ate nothing but sugar and LOTS of sugar all day long for weeks, this would poison you. In fact, everything we eat contains certain products for which the body has no use or that may pose a threat and which it must eliminate. The trick, in part, is the dose. How much of a drug or food you take is the first step in whether your body becomes poisoned. Some folks can consume bucketsful of drugs and suffer nothing; others can try it as aromatherapy and keel over. (Well, maybe that's exaggerating a bit). So first it is the dose that makes a substance a poison. At an ideal dose, therapies may have the benefit of eliminating a pathogen or improving bodily function in ways that far outweigh the risk the toxic side effects may pose. Second is the way your body responds. Your body is a big, very fancy chemistry set. Food or air goes in and is changed both in its substance and the energy it haseither providing energy or expending it. Energy is burned or stored. Molecules are modified. This process of chemical changes is known as metabolism. The building up of tissues is anabolism while their breakdown is catabolism. The transformed products of ingesting food or a drug are called metabolites. Because the make up of certain chemicals varies between people, the way one responds to drugs or toxic metabolites varies: some can take more of a drug for a longer period than others. In the process of transforming or metabolizing drugs, toxic, reactive intermediates are formed. These intermediates can be broken down into four main varieties: electrophilic compounds, free radicals, carbenes and nitrenes (unusual forms of carbon and nitrogen atoms) and activated oxygen species (free radicals like hydroxyl radicals, hydrogen peroxide, etc.) These are usually short lived and many may be formed and eliminated (or the transformation continued) and thus pose no problem. Some however may need to be removed from the body (Ioannides, 1996). Other terms are used to describe unwanted effects from drugs. A side effect is an effect other than the desired one from using a drug, like nausea, vomiting, headache, insomnia or a drug interaction. It may refer to euphoria, sleepiness or other effects, which may be pleasant or unpleasant, beneficial or detrimental effects but unintended effects of using a drug. An adverse event (or adverse reaction), in pharmacology and therapeutics, is the development of undesired side effects or toxicity caused by administration of a drug. Onset may be sudden or take days to develop. Early detection by using tests to monitor kidney, liver or other blood levels may help prevent the development of adverse events. These terms are often interchanged, however side effects are usually not deemed life threatening or requiring intervention. Those suffering side effects often dispute this dismissal. DAAIR refers to these as a negative effects believing the word " side effect " minimizes what's really going on. Generally, there are two ways to look at drug toxicity, referred to as Type A and Type B. Type A toxicity is well characterized based on the pharmacodynamics of a drug. If you take too much, trouble ensues. For example, too much of a hypertension drug can decrease blood pressure to the point of hypotension (too low), which can be dangerous. Too much of an anticoagulant may cause bleeding disorders. Type B toxicity is " idiosyncratic, " meaning that people's responses can be different. While all drug toxicity arises once a drug is metabolized (transformed), this is accomplished first by the cytochrome P450 enzyme system. From here, the drugs may be turned into something that is very toxic to the body. The glutathione S-transferase (or other) system kicks in to remove these toxic intermediates. If for some reason or another one of these systems isn't functioning properly, the consequences may range from irritating or annoying to life threatening or fatal. Type B reactions like anaphylaxis can kill rapidly. Anaphylaxis is an allergic hypersensitivity that may cause a person to go into shock, a state that may develop rapidly. The onset of anaphylactic shock is characterized by irritability, dyspnea (difficulty breathing), blue tinge to the fingernails (cyanosis), sometimes convulsion, unconsciousness and, if not immediately treated, possibly death. No physician or individual can know how a person will react to a particular drug. This type of reaction may develop fairly rapidly or may take months to develop in some individuals. Taking certain steps as outlined in this paper may help to tilt the balance of this wild card in your favor, preventing the development of the toxicity and allowing a safer, longer-term use of drugs when it is necessary to do so (for example, PCP prophylaxis). Comparison of Toxic and Allergic Drug Reactions. Differences may be indistinct. Shock from drug overdose may be no different from allergic shock.ToxicAllergicIncidenceMay occur with any drugOccurs infrequentlyDosageUsually highTherapeuticRection timeMay occur with first dose or may be due to cumulative effectUsually only upon re-exposure, but som edrugs cross-react with chemicals of similar structureSymptomsMay be similar to pharmacologic action of drugNot related to pharmacological action of drugAssociated disordersNoneAsthma, hay fever Abstracted from Taber's Cyclopedic Medical Dictionary, 16th ed., FA Company, 1989. Hypersensitivity: The Type B Response Allergy or hypersensitivity is one of many different ways toxicity may be expressed and one of the most common. It can manifest either immediately (a toxic response that may lead to anaphylaxis) or a delayed hypersensitivity. In the latter case, this is induced by the body's immune response, generating lymphokines as well as specific antibodies to a hapten or allergen. This is the type of thing that occurs in poison ivy or DNCB rashes. A hapten is that which induces an antibody or immune response (an antigen) but an incomplete or partial one. It fully becomes an antigen by binding to a bodily protein. An allergen is often something that is otherwise innocuous like pollen but which, upon repeated exposure, causes an allergic response. Allergens include anything that causes an acquired hypersensitivitybe it food, drug, fungi, chemical or metal contactants, etc.that does not normally cause such a reaction. Thus, such responses are idiosyncratic. For example, bee stings are generally just a painful irritant that quickly goes away. In others, however, it can cause anaphylaxis, a condition that if not immediately treated can be fatal. Another common example of an allergic reaction is the hives some people develop from overuse of penicillin. For people with HIV, perhaps the most common drug negative effect is the rash associated with using TMP/SMX (Bactrim, Septra as mentioned above in glutathione S-transferase) as prophylaxis or treatment for Pneumocystis carinii pneumonia (Carr, 1995-6). Many other drugs commonly used by PWHIV can cause hypersensitivity reactions including ampicillin, amoxicillin-clavulanic acid, atovaquone (Mepron), clindamycin, phenytoin, carbamazepine, isoniazid (and other mycobacterial meds), ciprofloxacin, rifampicin, thalidomide, pentamidine and sodium fusidate. The NNRTIs, nevirapine and (to a lesser extent?) delavirdine may also induce these types of hypersensitivity. In addition, AZT, ddI and ddC (and rsCD4) all can induce hypersensitivity reactions (Carr, 1995-6). It is important to realize that these responses can take time to develop. Hypersensitivity is distinguished in four ways, although some of the distinctions are a bit artificial. Type I is associated with an elevation of one type of antibody, IgE. This arises when IgE binds to a toxin and subsequently causes a cell type known as a mast cell to release its toxic contents. This type includes anaphylaxis (not hereditary) as well as hereditary conditions like asthma or hay fever as well as food or drug allergies. Type II hypersensitivity is related to the IgG or IgM antibodies which reacts to self tissues. It is associated primarily with newborn and autoimmune hemolytic anemias, transfusion reactions and graft rejection. Type III involves clumping of immune complexes which can circulate through the body, possibly clogging up the kidneys (and known as CICs: circulating immune complexes). The amount of CICs increases, jamming up the works of various organs. It includes Arthus reactions (caused by repeated injections of a non-irritating antigen like the protein albumin) and serum sickness (a drug or antisera response that may occur from 2-3 days to several weeks after administration). Finally, the type IV variety is an inflammatory response associated with a delayed (up to 48 hours in humans) reaction. T cells identify specific antigens which results in release of lymphokines and subsequent inflammatory activation of macrophages (Pirmohamed, 1996; Klein, 1990). Type IV delayed type hypersensitivity is subdivided further: tuberculin, -Mote, contact and granulomatous. The two most relevant are tuberculin and contact. Tuberculin is the kind currently used to test for exposure to TB. Koch of the Koch's postulates fame had originally thought this tuberculin antigen would serve as a vaccine but, to his embarrassment, this did not work out to be the case. In contrast, contact hypersensitivity is characterized by a skin reaction (eczema-like) and infiltration of the tissues by lymphocytes and monocytes. The skin reaction is characterized by redness (erythema) and swelling (edema). In some cases, it may result in the formation of blisters. They reach their peak within 24-48 hours of application and then subside. Among the common agents that induce this reaction are uroshiol (poison ivy), varnish, resins, nickel and dinitrochlorobenzene (DNCB) as well as dinitrofluorobenzene (DNFB) or trinitrophenol. When the chemical comes in contact with the skin, it reacts with self proteins (becoming a hapten-carrier conjugate). The self proteins are then transformed and processed by Langerhans cells (macrophages that have migrated into the skin). These present antigen to T cells which subsequently are stimulated to proliferate (Klein, 1990). Unfortunately, it would appear that this would be a generalized, clonal proliferation primarily attacking self antigens. To which proteins DNCB (or other) hapten binds with is not known. That any should help to identify HIV or infected cells seems unlikely. The only value DNCB appears to have is to damage local tissues at the site of application. HIV-specific transfer factor may well be a more potent and specific stimulator of CMI, however it remains embroiled in political limbo. Besides costing a lot, no clinical studies are likely, despite the evidence that cryptosporidium-specific transfer factor appears to be a worthwhile treatment for this devastating infection. Few studies have been conducted of DNCB for people with HIV. Despite the advocacy and strong promotion of this chemical by a vocal minority, the data from these studies are not convincing. It remains to be seen if the generalized stimulation of DTH by DNCB will have a salutary effect on clearing HIV or stimulating cell-mediated immunity (CMI), which is a specific and strong response to intracellular infections. The strength and specificity of that CMI enhancement by DNCB has not been established. Organs of Elimination Almost anything ingested can be harmful to the organism. The body has a remarkable way of dealing with food and fluids we consume and the stuff we breathe in. Many diseases occur due to faults or flaws in these well balanced and complex systems. Here, we describe the functions of some of the most important organs for eliminating unwanted toxins. Over thousands of years, many methods have been developed to help eliminate an excess build up of toxins. These methods are reviewed in the second part of this paper on Detoxification- Ridding the Body of Removable Toxins. The gastrointestinal (GI) tract: The GI tract consists of the stomach and intestines. In the stomach, material is broken down by powerful acids. It is then transferred to the intestine, the first part known as the duodenum. The environment shifts from acid to base, with the gall bladder excreting bile while the pancreas adds in various digestive enzymes. The larger molecules are first to be chopped up (like fats, carbohydrates and proteins). This process continue along the small intestine. The broken down material is absorbed along the small intestine. The leftover material arrives at the large intestine or colon where remaining solid material (mostly fibrous material) is excreted (i.e., shit). The smallest molecules have meantime gotten through. This is why the size of the drug makes a big difference in how well it is absorbed. The nukes are by and large smaller molecules that get through pretty much intact. The protease inhibitors may bind to proteins, which may prevent them from being properly absorbed. Even at this early stage, the body is identifying potential dangers and attempting to slow them down. Immune cells (a type of T cell called a gamma/delta and soluble immunoglobulin A) line the GI tract, alert for any dangerous (pathogenic) intruders. Glutathione S-transferase binds to (or conjugates) dangerous chemicals, preparing them for excretion (see below). For most orally taken drugs, the gastrointestinal (GI) tract can be damaged by some drugs. Glutamine is proving to be an extremely important addition for drug-associated diarrhea and in general as a promoter of healing of intestinal tissues (see TIP's Treatment Information Sheet on Glutamine). Even some drugs that are taken by IV or IM may, to a small degree, be recirculated into the intestinal tract via bile. In addition, maintaining appropriate levels of acid in the stomach and enzymes in the duodenum is important. Gut flora can be wiped out by antibiotic use; supplementation with Lactobacillus acidophilus, L. bulgaricus and Bifidobacterium bifidus may go a long way to regenerating this flora (De Simone, 1992; Harp, 1992). Liver: Some drugs and other small molecules pass through the digestive processes and are transported to the liver. Thus, most of the material that we take by mouth winds up being transformed in the liver. The liver, the largest internal organ is a primary detoxification organ. This is why the major toxicity of drugs is often damage to the liver known as hepatotoxicity. These transformations are primarily conducted by a different enzyme families, discussed below. A lot of the transformations seem deceptively simple. An electron is added or removed. A functional group is added or cleaved. Functional groups may consist of bonding an oxygen (epoxidation) or some combination of oxygen and hydrogen (esterification, hydroxylation, etc.) The molecule may be split (dealkylation). If you look at a picture of an original molecule and the form that causes toxicity, you may not be able to immediately spot the differencebut your body does! After material is digested, the nutrient rich blood from the intestines is sent to the liver for processing. Aside from converting glucose (a sugar) into various useful components, it functions as a site for detoxifying various dangerous substances. Detoxification in this context is also known as biotransformation. Kidneys: The kidneys, a pair of organs at the back on either side of the spinal column, act as a site of filtration of various fluids. Much of this winds up being sent to the bladder for excretion (i.e., peeing). Otherwise, they operate to help maintain a balance the amount of water and electrolytes as well as the acid-base content of the blood. This filtration system is vital for elimination of toxic metabolites and glutathione activities can be high here. When the works get seriously gummed up, renal failure (renal refers to the kidneys) may occur and this can be fatal. Skin/sweat glands: The skin and the sweat glands embedded in it are another important way for the body to excrete unwanted toxins and excesses. Working up a good sweat has long been deemed an important way to increase body temperature and thus help eliminate temperature-sensitive pathogens. This may be done in steam rooms, hot baths or hot rooms. Sweating induced by strenuous exercise has other benefits, as long as the exercise doesn't go on too long. See the second part of this Detoxification for best methods, more details and warnings specific to people with HIV regarding steam baths, etc. Lymphatic organs: The lymphatic organs include the vessels through which lymph flows and organs such as the thymus, the spleen, tonsils and lymph nodes. The lymphatic system has been referred to by some as the body's sewer. This vascular (tubes) system often parallels the blood-carrying veins and arteries. It is characterized by nodules which are collections of lymph vessels known as lymph nodes. When the body is exposed to an infection, very often the lymph system is a place where immune system cells cruise to identify the danger and seek it out to destroy it. This is particularly true of HIV infection, where the virus has been shown to cling to cells called follicular dendritic cells. As HIV disease progresses, the architecture of the lymph node deteriorates, as does the thymus gland. The lymph nodes sometimes swell during an infection, a condition known as lymphadenopathy, or " swollen lymph nodes " in common parlance. These are a common feature in many (but not all) people with HIV. Lymph fluid is derived either from the intestines (part of fat digestion and absorption) and travels upward; other lymph fluid is generated by the blood. Once the lymph has circulated through from the intestines or other areas, it eventually drains back into the blood stream from the thoracic duct. Lymph nodes are particularly important as filters, preventing bacteria from gaining entry to the bloodstream and possibly stopping cancer cells. Unfortunately, when they aren't working properly, they may become a site for transmission of pathogens or a site of metastasis (cancer spreading from one organ to another). Spleen, pancreas: Theseand some otherorgans also function in the process of detoxification. The function of the pancreas can be compromised by various drugs, including the nucleoside analog drug ddI (De Wit, 1993). Molybdenum can help prevent this. B12 absorption can be severely reduced (as evidenced by serum B12 levels) during cases of pancreatitis; intramuscular injections of 100 u/g daily for a week are helpful, followed by 100 micrograms twice a week. FROM COMPREHENSIVE GOALS (for citations, please refer back to the comprehensive goals): Acute or chronic pancreatitis sometimes occurs in people with HIV/AIDS, although it appears to be associated mostly with therapeutic drugs (like ddI) or, as is true generally, alcohol abuse. An enzyme called amylase is usually checked. Saliva levels versus amylase levels in plasma need to be assessed (the saliva level may be high but have nothing to do with pancreatitis); (Merino, 1994; Sweeney, 1992). Even more than HIV, pentamidine and ddI can play a significant role in damaging the pancreas. Other pancreas damaging influences include alcohol, non-Caucasian origin, MAI (Murthy, 1992) and TB (Brandao-Mello, 1992). In one study trypsin and, to a lesser extent, elastase were found to be elevated, increasing as CD4 counts declined; the authors suggested that this underscored that damage to the pancreas occurs in some even early on without direct evidence of pancreatitis (Pezzilli, 1992). The elevations in plasma probably indicate that the pancreas is damaged, leaking enzymes into the circulatory system instead of passing into the duodenum where they belong (underscoring the potential use of pancreatic enzyme supplementation.) Women suffer from hyperamylasemia more than men, and this condition worsens with reductions in CD4 count (Portilla, 1993). Subclinical pancreatitis is often present but asymptomatic, according to one group (Merino, 1994). For a good review, see the NIH's Pancreatitis Fact Sheet (Anonymous, NDDIC, 1995?)…. The spleen has areas ( " white patches " ) that have been found to be productively infected by HIV (Tsai, 1994). (partly due to this organ's unusually high number of monocytes/macrophages.) Its normal function of helping produce platelets and many other cells is thus compromised. Radiation and surgery should be the last resort; many other options should be explored first. Macrophages: These cells (not organsbut they're important) basically cruise around and gobble up extraneous material, dead cells and other stuff that doesn't belong in the body. They basically eat themselves to death. Thus, they are a first defense against unwanted intrusion. They are also, unfortunately, one of the first cells infected by HIV, before the CD4+ T cell is targeted. How Drugs Are Changed or Biotransformed in the Body Drugs can have deleterious effects in any of these detoxification organs if they are not working up to snuff. (And even when they arethis is described below). The way the body creates toxic metabolites depends in part on how a drug is metabolized by the liver and kidneys. This may take place in three phases: Phase I consists of the first pass of transformations made by the cytochrome P450 enzyme system. For those of you who are interested and who have access to the internet ( www.immunet.org/daair, the Detoxification papers), a more detailed explanation of CYP450 may be found. Phase I transformations include three distinct actions (or chemical reactions) that transform drugs into other forms: Reduction and oxidation are two sides of the same coin. They are part of an underlying chemistry that is very important and radically (pardon the pun) understudied. Reduction is the process of gaining an electron. Since electrons have a negative charge, this means a positive valence is reduced. Thus, an iron ion (Fe+++) that becomes reduced gains an electron and becomes Fe++. Oxidation is the process of losing an electron or becoming more negative. Hydrolysis is basically the removal of water (H2O) from a chemical compound. Phase II is the conjugation phase and includes the following three important elements. Conjugation here means that a chemical is slightly modified and another chemical (like glutathione) attaches to it. At any point, a toxic reactive intermediate that can cause damage may be formed. In the case of glutathione alone, it's primary function is to detoxify hydrogen peroxide that may be formed naturally or as a by-product of drug metabolism. (An intermediate means that the process has not been completedanother final form may arise that is either utilized by the body or excreted.) 1) Glutathione S-transferases: Glutathione (GSH) is a peptide made up of three amino acids: cysteine, glycine and glutamic acid. Glutathione is the substrate that binds with the S-transferase enzymes. This system identifies the toxin, latches onto it (or conjugates), and escorts it out of the body (, 1987). Further transformations may occur before the lot is excreted in the feces or urine. However, people with HIV very often have very low levels of glutathione (Buhl, 1989) and those with lower levels tend to progress faster (Herzenberg, 1996). Unfortunately the use of many pharmaceutical drugs further depletes already scarce stores of this critical compound. There is strong evidence that glutathione deficiency may play a central role in the development of hypersensitivity to sulfa drugs like TMP/SMX (Bactrim, Septra) (Mathelier-Fusade, 1993). Thus, supplying the body's cells with a sufficient supply of glutathione is absolutely critical, not only to help the body fight the disease but also to help maximize the effects of the drugs used to fight HIV or other infections. Unfortunately, these enzymes systems don't always work perfectly even under normal conditions. This is why smoking, exposure to asbestos or other toxic chemicals may cause cancer. The very drugs used to fight cancer (and often used in AIDS) can cause cancer (Raunio, 1995). Other problems may occur when the glutathione S-transferase conjugates with a toxic or other intermediate and, rather than being excreted, may stick around or be exported. And this conjugate may be toxic (Mantle, 1995). What does this mean? That repleting glutathione may be dangerous? We don't know but it is possible. The only way to determine this would be a drug-by-drug analysis to determine if the drugs taken would create toxic intermediates. Here is where a risk/benefit analysis must be made. What is the bigger risk? The potential of hypothetically creating carcinogenic conditions? Or the rather certain realization that NOT repleting glutathione will permit the advancement of immune dysregulation and enhanced drug toxicity? At the moment, all of the available evidence, in DAAIR's view, strongly supports the idea of helping the body attain a more natural homeostasis. To the extent that such a process will improve and lengthen lifespan, such strategies should be strongly considered. Simultaneously, any risk involved should be clinically assessed (Commandeur, 1996). (Please refer to the Information Sheets on NAC and Glutathione in the DAAIR TIP.) There are many potential ways to generate stores of glutathione inside cells, including whey proteins, glutamine, NAC, alpha lipoic acid and vitamin B6.These are reviewed in more detail in the Glutathione information sheet. 2) Glucuronidation: This is a variant of the simple sugar glucose. It performs important detoxifying roles by binding to various chemicals, usually in the liver. These eventually pass to the kidneys where they are excreted in the urine. Commonly detoxified chemicals through glucuronidation include AZT (Gallo, 1993), camphor, female sex hormones, phenol and benzoic acid. This pathway, too, is involved in the process of conjugating glucuronic acid with drug metabolites (as well as its natural function of binding to various steroid hormones) and allowing the body to excrete them in the urine. These conjugates are known as glucuronides. The highly refined product of licorice root, known as glycyrrhizin, is a potent anti-inflammatory and breaks down into glucuronic acid. It is actually the treatment of choice for drug hypersensitivity and allergy in Japan and China. DAAIR sells glycyrrhizin in several forms, including Jarrows' product known as GL Forte. 3) Acetylation: . Other pathways may acetylate the toxic metabolite, rendering it harmless (, 1987). This is a process where an acetyl group is added to a molecule. This process alters the pH and chemical structure of the molecule and is a common method of detoxification from a variety of chemicals, including caffeine, isoniazid (a drug commonly used to treat TB) and dapsone (sometimes used as PCP prophylaxis). The acetyl group comes from an important enzyme called acetyl coenzyme A. The parent compound, coenzyme A, is involved in a number of biological processes including the synthesis of sterols and fatty acids. People are differentiated as either slow or rapid acetylators. Slow acetylators may respond differently to drugs, for example, those who use hydralazine to control high blood pressure may be more likely to see a greater effect at the same doseand consequently a higher rate of a serious side effect, lupus erythematosus. Several tests can determine whether you are a slow or rapid acetylator. Phase III reactions involve enzymes from Phases I or II. The substrate being acted upon is a product of those first two phases. This phase of detoxification features reversible reactions (it goes back to its original constituents) or development of toxic intermediates. This is why it is very important for physicians to, ideally, address the way individuals utilize drugs so that appropriate dosing and drug selection can be undertaken. Cancers : Cancers come in a variety of forms. They may affect the blood, bones, tissue, skin, brainanywhere there are cells. This is because cells stop behaving the way they are supposed to. The genes of the cell that provide the instructions for cellular function become disrupted and the cell begins to transform. The next stage is proliferation: the cell begins to make more copies of itself, and the kids are all bad. This is when a tumor develops and it is known as malignant transformation. It begins to hijack the blood supply so that it can feed and sustain itself, actually forming new blood vessels in the region of the tumor in some types of cancer. In some cases, it will get bored with the 'hood and start traveling to other sites in the body. This is called metastasis and often bodes dire results. Many things can cause cancer; from inherited genes to cigarette smoke to occupational exposure to solvents or other hazardous chemicalsto various pharmaceutical drugs. Perhaps the most fearsome aspect to the use of certain drugs is reflected in terms like mutagenesis, teratogenicity and tumirogenesis. These drugs are oncogenic which is to say they can cause cancer. Drugs either may directly or through toxic intermediates cause DNA damage. Certainly, there is plenty of test tube and animal studies underscoring the cancer-causing (carcinogenic) effects of AZT. Mice developed vaginal squamous cell carcinomas when administered AZT at a fairly high dosage, however, anemia that necessitated stopping the drug was more like to occur first (PDR). Cells that line the vagina (epithelial cells) were shown to become cancerous in mice in the presence of high concentrations of AZT (Olivero, 1994). While doses in humans are declining as it becomes clear that lower doses are just as effective (even 300 mg/day vs. the standard 600 mg/day; which would halve Glaxo-Wellcome's AZT profits and not something they're likely to trumpet to physicians), it is not clear if long term use will cause a cumulative effect which may increase the risk of cancer. Specific cancers like lymphoma, multiple myelomas and others are particular concerns (Raunio, 1995). The combinations of drugs have other toxicities and side effects (which DAAIR intentionally refers to as " negative effects " since the term side effects often minimizes their seriousness). In addition, drugs may cause damage to the cells' powerhouse, the mitochondria. (These have their own store of DNA). The fear in AIDS stems largely from the long term use of drugs such as the nucleoside analog class of drugs (again: AZT, ddI, ddC, etc.) One type of muscle deterioration caused by AZT has been associated with damage to mitochondrial DNA (Sinnwell, 1995; Butori, 1995; Chen, 1991). And the studies above suggest that other nukes (like ddI, ddC, etc.) also can cause this damage, if to a somewhat lesser degree. ddC, for example, strongly interferes with mitochondrial DNA synthesis (s, 1996). This reality can have serious long-term, and often irreversible consequences. Part of this process is related to aberrant expression of free radicals. In cancer, the tumor protects itself in ingenious ways. First, it prevents cells from killing themselves via apoptosis. In addition, the tumor cell protects itself from degradation by expressing Cu/ZnSOD, catalase and other endogenous antioxidants. When this occurs, we need to do just the opposite as in AIDS, presuming the goal is to kill cancer cells. Thus, increased apoptosis and oxidative stress at the site of the tumor will help to eliminate it. Unfortunately, methods to do this are not so specific and such efforts may well result in increased HIV production. It's a bit of a Catch 22. In contrast, other methodologies may help to restore cancerous cells to normal functioning. This is a novel concept that has barely been explored. Traditional means have included adaptogenic herbs like astragalus. High tech methods include the recently announced attempt to restore the functioning of an important gene in cells that produces the p53 protein, a protein integrally involved in cell function and prevention of cancer from developing. This is why, however, it is critical to do everything possible to prevent cancer from developing. How can this be prevented? The important idea to understand here is that preventing this process from turning into cancer is the best thing to do. Once a cancer gets established, the following methods may have only limited benefit, if any. Thus, it is all the more critical to consider a comprehensive antioxidant protocol to prevent the damage to cellular DNA. Liver support is also critical. The metabolism of AZT and its glucuronidation occur in the microsomes of liver cells (Resetar, 1991) and may very well be improved with the use of the licorice extract glycyrrhizin. If enzymes (ALT, AST) become elevated, silymarin, alpha lipoic acid and glycyrrhizin all may help. Glycyrrhizin, by it's potent detoxification properties also has value in some PWHIV in improving liver as well as kidney function. Again, the body's ability to prevent cancers from becoming established depends on a strong system of detoxificationand here again, the observed depletion of glutathione may play a pivotal role in enhancing tumor development. This adds another layer to the importance of improving intracellular stores of glutathione. Finally, there are other specific toxicities related to the nukes that may enhance the growth of cancers. This specifically refers to the reduction in numbers of various cell types. Particularly worrisome are the leukopenia (white blood cell drop) and anemia (red blood cell drop). More specific types of white blood cells, like neutrophils, which are important in protecting the body against cancerous cells are frequently depleted, more severely in some people than others. Helping to restore their number and function is essential. Certain Chinese herbs may have efficacy here, including the dong quai, bai shao and chuan xiong among others. In addition, acupuncture may help build blood, specifically through points ST36, LI11, LI4 and SP10 (Fields, 1992). Role Of Antioxidants Antioxidants, mostly comprised of vitamins, minerals, coenzymes and certain amino acids (collectively, micronutrients), can help to dampen this aberrant, potentially cancer-causing chronic response. The level of many of these micronutrients declines, even early after initial infection and supplementation slows progression (Abrams, 1993; Eck, 1989; Tang, 1993). By dampening down the flames of battle with antioxidants, conditions for HIV growth become less favorable. Tissue damage to guts, liver, lungs and so forth may be minimized, resulting in viral load decreases. Abnormal increase of inflammatory cytokines (cell messengers) can be normalized. And it is likely the level of HIV in lymph nodes and blood will stabilize or decrease. But such a program of antioxidant use should not rely on any single antioxidant but a carefully crafted regimen. Several micronutrients play important roles in building and maintaining the body's detoxification systems. Perhaps the two most important organs for detoxification are the kidneys and the liver. B-vitamins, folic acid, alpha lipoic, vitamins C and E are extremely important in maintaining healthy function. Herbs like astragalus and ginseng may further serve in an " adaptogenic " role, helping the body to rebalance (bolster where there are deficiencies, normalize function when there is excess). Further research into these herbs will help to better characterize their value. The following is abstracted from the Statement of Fred Bingham, Executive Director, DAAIR. This testimony was given to a panel convened by the Office of AIDS Research of the National Institutes of Health. The panel, headed by Dr. Arnold Levine reviewed NIH AIDS research to identify gaps and overlaps in research. Fred and other activists identified several HUGE gaps which to this day have not been meaningfully addressed. For the complete testimony, see DAAIR's web site or contact the office. " It is important to remember that HIV's growth and dissemination does not occur in a vacuum, but depends on favorable conditions within both the macro and micro-environments of the bodywhat I and many clinicians and researchers call The Host Defense. NIH has generally taken an extremely limited view, focused almost exclusively on various viral dynamics, while ignoring host factorsall at great peril to those of us living with this disease. " So what are a few of these host factors, other than genetics, influencing both viral dynamics and disease progression? This panel should convene a separate group to assess the following and to make sound recommendation forat the very leastnesting various clinical interventions impinging on these factors within larger trials of standard anti-retroviral therapies, whether they be nucleosides, non-nucleoside reverse transcriptase inhibitors, proteases, integrases, etc., or any combination thereof. " Nutritional Deficiencies: Nutrition's role in maintaining an adequate immune response has been exhaustively documented. It has also been well-documented that in the hyper-metabolic and immune-activated state of HIV disease there exists dramatically increased energy expenditures. These conditions put well characterized nutritional stressors on the Host which can either suppress or dysregulate not only critical immune system responses, including cell-mediated immunity, but the Host's ability to maintain a sustained anabolic, as opposed to catabolic, state. Whether the deficiency be vitamins A and B6, minerals such as zinc and selenium and amino acids like methionine and cysteine or the extremely critical and substantial glutathione deficiency, these factors need to be addressed within nested larger trials of more standard agents. " Oxidative Stress: The most important component of the nutritional state is the well-documented loss of many antioxidants and the increased production of free radicals. Free radical by-products have been measured in numerous studies and found to be dramatically increased at all stages of HIV Disease. This " oxidative imbalance " , i.e. the presence of large quantities of highly reactive molecules, including free radicals, combined with severe deficiencies in protective antioxidants, has clearly been shown to be one of the numerous ways HIV alters the Host Defense in order to increase its own expression and dissemination. Several years ago, research by at Webb-Waring revealed that the HIV/tat gene strongly down-regulated the critical intracellular enzyme manganese SOD, one of the main regenerators of glutathione within the cell. This is certainly one of the major factors leading to a global and severe deficiency in this critical amino acid. With a pro-oxidative intracellular environment, it has been clearly shown that HIV uses the excess of free radicals to either activate or to increase its replication through the two NF-kB (nuclear factor kappa binding sites on its LTR (long terminal repeat). This intra- and extra-cellular oxidative imbalance also favors the over-expression of many cellular genes controlling the acute phase response, which brings me to another facet of The Host Defense Model. (It is an outright scandal that NIH has not begunyears agoa major trial of the possible therapeutic benefits of antioxidant administration in slowing disease progression, particularly for those in earlier stages of HIV Disease. Yet, like so many other unpatentable treatment modalities in wide use within the HIV community, this remains thoroughly unexplored.) " Many of nutrientsmainly antioxidants and bioflavonoidswork on human cellular components of viral replication as well as favorably altering the total environment of the body, which also slows viral growth. These human cellular component are parts of the human cell which HIV kidnaps and uses in order to replicate. Since these are human parts, and not unstable and quickly mutating viral parts, there is a very low chance of developing viral resistance to these compounds. Also, by inhibiting these human components of viral growth, an additional viral suppression is gained since the targets are different from more familiar pharmaceutical targets such as reverse transcriptase (nucleoside analogues) and proteases (protease inhibitors), both of which are more error prone viral components. L-Carnitine and acetylcarnitine are excellent examples of compounds which also have a proven ability to lower inflammatory immune messengers (cytokines) such as tumor necrosis factor (TNF). TNF has been added to laboratory viral culture and has completely negated the antiviral effects of AZT! These additional mechanisms of suppression can only help slow the development of resistance to standard pharmaceutical antiviral agents while reducing their known toxicities. Most importantly, by down regulating these human cellular components of viral growth you target latently infected cells and cells which produce chronic low levels of virus such as macrophages. By further inhibition of these two pools of virus, which can remain unaffected by either nucleoside analogues or proteases, you may substantially reduce opportunities for the gradual development of viral resistance. A broader and more in-depth discussion of this topic, with relevant citations can be found variously in the Comprehensive Goals, TIP's article on Oxidative Stress and AIDS and individual information sheets such as Glutathione, NAC and others. A General Protocol for Detoxification from Long-Term Prescribed Drug Use: For a ideas on how to offset specific toxicities associated with specific drugs, see the tables below as well. This protocol is for anyone using pharmaceutical drugs to offset toxicities and to aid the body in detoxification. Not only will it lessenor eliminatethe possibility of side effects, more importantly, it may allow you to take life-extending therapies for substantially longer periods of time. Please remember that it is far easier to protect against the development of drug toxicities using these suggested compounds, than it is to reverse toxicities once they have occurred! There are nine elements to the basic protocol followed by additional substances for people on specific drugs which are found in the tables following this section. People who inject heroin are often referred to drug " detox " programs. What this means in current scientific medical parlance is the substitution of one addictive drug (heroin) with another (methadone). This concept seems ludicrous to us, given the toxicities of methadone and underscores the bankrupt policies of a nation bent on criminalizing a health issue. In any event, this is absolutely NOT what we mean by detoxification. In fact, just the opposite. The protocols designed here are intended to either a) re-supply the body with building blocks it needs that drugs may deplete; help the body to remove toxins that may form from using drugs; c) re-establish a balance by modifying immune function (e.g., increasing neutrophils depleted by a drug like AZT) and/or d) to minimize negative effects of drugs. This special protocol, abstracted from the Personal Protocols, does not include other basic elements to your nutrient protocols such as a multi-vitamin, etc. Please read the DAAIR MOP Personal Protocols section. The following briefly summarizes some of the roles these individual constituents may play in offsetting toxicities. For more detail and citations, please refer to the individual Information Sheets in TIP. CoEnzyme Q10: Coenzyme Q10 is part of the cell's powerhouse, the mitochondria. It is specifically involved in the electron transport chain and is critical for cellular functioning. If there isn't enough of this chemical around, the chain may be broken and aberrant free radical generation can damage the mitochondria. Specific studies on the drug doxorubicin, which can damage the heart, have underscored the role for CoQ10 as a cardioprotectant. Many other drugs widely used in HIV management damage cellular mitochondria and CoQ10 can help to offset this destruction. N-Acetyl-L-Cysteine (NAC): NAC performs a variety of important detoxifying functions. It is recognized as an antidote for overdose of acetaminophen (Tylenol). In addition, it is an important precursor to the formation of glutathione. The sulfur atom found in NAC acts as a critical antioxidant and detoxicant. Glutathione, one of the major detoxifiers, is critically low in most PWHIVs. Glycyrrhizinate (GL) Forte: GL is a highly refined extract of licorice root which is a widely used treatment in Asia for drug toxicity and allergic reactions. It breaks down into the potent detoxifier glucuronic acid. Vitamin C, Ascorbic: This vitamin provides a great deal of different functions, starting with improving cartilage health. It is also a regenerator of several antioxidants. Alpha lipoic (Thioctic) acid: This liver protecting coenzyme also has a variety of functions as an antioxidant and in other roles. In addition, evidence points to its ability to improve intracellular glutathione. It has a proven track record for lowering liver enzyme levels in persons sensitive to pharmaceutical drugs. Vitamin E and natural tocopherols: At least one study suggests that vitamin E may be as good a way to offset AZT associated anemia as the hideously expensive drug erythropoietin (EPO). It has been shown to increase AZT's ability to penetrate virally infected cells and to lessen bone marrow toxicity in laboratory conditions. Barley: It contains water-soluble fiber (good for digestive processes), has a high selenium content. Some stuff about detoxifying herbicides by vacuolar uptake and detoxifying with GSHbut what's that got to do with eating and digesting the stuff? Kyogreen researchers assert that the leaves are full of other vitamins (esp. B vitamins), chlorophyll, calcium, magnesium and potassium. One study of barley oil showed a decrease in LDL as did barley bran flour, but the flour also reduced HDL levels. HIV Mix Lysine/Glycine/Methionine: These are amino acids (which make up proteins). Glycine is needed for glutathione production. Methionine can also be converted to cysteine in the body and may improve GSH levels in the liver. Lysine performs its best action as an anti-herpes amino acid. B100-Complex: B vitamins, B6 and B12 in particular, have been found to be depleted at all stages of HIV infection. B6 plays particularly important roles in reducing HIV infection as well as converting methionine to cysteine. B12 is important to protect the myelin (sheaths around nerves). A balance of B vitamins is eminently sensible and lends support to the bodies ability to metabolize drugs and eliminate toxins. Herbs to Aid the Body In Detoxification/Off-setting Toxicities Philosophies that favor only one approach to healing to the exclusion of all others do so at the peril of one's life. For some infections, for example, antibiotics and other medicines can be essential components in a holistic healing protocol. Certain herbs may have beneficial effects at restoring bodily function or fighting disease. Nutrient interventions may further restore bodily functions while offsetting drug toxicities by maintaining or increasing detoxification pathways. Any of these approaches misused, however, may result in toxicities. As has been mentioned, various Chinese herbs such as dong quai, bai shao and chuan xiong are blood tonifying and may help to offset the immunosuppressive effects of drugs like TMP/SMX (Bactrim) and AZT (Field, 1992). Please don't forget to review the TIP Information Sheets on Astragalus, Ginseng and the general review of adaptogenic herbs. Codonopsis has been suggested by Misha Cohen of the Quan Yin healing arts center as a important in improving red blood cell numbers. DAAIR sells one useful Chinese combination which contains many of the above herbs called Marrow Plus. Other herbs are known as adaptogenic. This refers to a generally characterized impact on normalizing function. If there is too much activity, it is toned down while deficiency is augmented. Studies have been performed on just what this might mean for Siberian ginseng and astragalus. The loose Russian studies of Siberian ginseng suggest a tonic effect. These studies suggest that it may improve fatigue (a side effect of some drugs) and may help people in handling physical stresses. Siberian ginseng needs to be more carefully studied. Astragalus also is used to modify immune function but again, there are few studies. One study of people with cancer showed that moderate doses improved T cell function in test tube. Rats treated with cyclophosphamide had enhanced immune response when also using astragalus (Majchrowicz, 1994). (Please see the Ginseng, Astragalus and Adaptogens Information Sheets in TIP). Glycyrrhizin is a potent extract of licorice. It can increase blood pressure and deplete bodily stores of potassium, so these must be carefully monitored. However, it is indicated for a variety of conditions in Japan, including minimizing the side effects, allergy or poisoning of a number of drugs including penicillin, streptomycin, PAS, isoniazid, pyrazinamide, thiacetazone, ethionamide, chlorpromazine, sulfanilamide, aminopyrine, arsenobenzol, oxophenarsine and others. In additions , it has been used to treat people after radiation therapy or treatment with the chemotherapy drug, mitomycin C. Corticosteroid treatment also has potentially serious side effects which glycyrrhizin may ameliorate. In addition, it may reduce the eczema while offsetting leucocytopenia (low white blood cells) and low platelets (thrombocytopenia). A more general plan for colon detoxification includes products produced by Yerba Prima. The elements of this protocol include use of an herbal formula called Kalenite, a daily fiber formula and application of an olive oil cream. The logic of the latter escapes us so we will focus on the herbs used. In the Kalenite formula, the herbs include acacia gum used to soothe mucous membranes, yellow dock root for blood purification and as a mild laxative also good for liver function, plantain leaves to loose stagnant, impacted waste and as a mild diuretic, blessed thistle to moderate the cleansing action of other herbs and blood circulation, cloves to counteract flatulence and soothe the digestive tract, red clover blossoms to help eliminate toxins, corn silk extract as a diuretic and aid elimination through the kidneys and butternut bark as an active blood purifier, mild laxative and bowel regulator. The fiber product contains psyllium husks, guar gum, oat bran, pectin and barley fiber (Berry, 1985). What Are Ways To Offset Specific Toxicities? This depends on the toxicity! First off, let us be clear. Offsetting toxicities once a drug is started is not easy. Keeping toxicities from developing in the first place is the desired approach. To the extent one can avoid taking these drugs by remaining stable through other means, this is the best way to avoid drug toxicities. But even the most valiant efforts do not guarantee that progression will not occur. When it does and you feel it is time to do the drugs, we hope that your understanding of their risks will help you to avoid serious complications, maximize benefits by selecting the most optimal combinations at the best dosages. Avoiding serious complications may mean stopping or switching therapies. We also provide a brief paragraph on interventions that may help to minimize toxicities and prevent them from arising. Where clinical data exist, we cite it, however, more data are clearly needed. The next important thing to recognize is to balance the risk of toxicities against the risks involved with AIDS. Does the benefit outweigh the risks of AIDS? Are the toxicities common? Life-threatening? Some definitely are as well as the potentially fatal cross reactions that may occur. However, the clinical studies strongly suggest that people with AIDS benefit in many ways from some of these drugs in combination. Some of the toxicities are tolerable, if unpleasant. But too often physicians will ignore them at their patients' peril. Informing yourself of these dangers can help you to possibly identify them when they arise, do what you can to offset them and help you decide when is the best time for you to take these drugs. One compound that might help for antibiotic sensitivities is a sulfur compound given the fancy name, methylsulfonylmethane or MSM for short. (For the aficionados, yes, DMSO is similar and can chemically convert into MSM). Sulfur is used in a variety of ways by the body. Proteins sustain their 3-dimensional shape by disulfide bridges. Importantly for detoxification and as has been noted, the sulfur moiety is central to removing xenobiotics (foreign material like pathogens or toxic drugs). A review paper reported on studies suggesting that 250-750 mg/day of oral MSM moderated allergic responses to drugs, some antibiotics and exerted an antiparasitic action against Giardia (, 1983). For treating allergy or other problems, a dose of 1000-2000 mg per day for a week to 21 days or more has been suggested by the manufacturer. There are no apparent toxicities. There are a number of potential interventions which are highlighted by " symptom " in the first table following this list of toxicities. The second table briefly reviews, by drug, some of the possible negative effects and interventions to ameliorate them. One must ALWAYS be careful to assure one's self of the etiology (or origin) of a symptom. That is, is that diarrhea caused by the drug? Or is it an infection? Or is it HIV kicking up its heels and having a nasty party in your guts? If the symptom occurred within hours to a week or two of starting a drug, it may be the drug. Often, one might stop the drug and see if this causes the symptoms to cease. However, this may not be advisable with the protease inhibitors, since even stopping briefly may allow the development of resistant HIV. Nucleoside analogs: These drugs, commonly known as " nukes " for a variety of reasons, are seriously toxic. Lower doses clearly are an important way to reduce toxicities without losing much benefit. For example, AZT at 300 mg per day is not only as effective as the standard 600 mg per day dose, resistance is slower to develop (Hosein, 1996). This reduces costs as well as limiting side effects. Such studies have shown similar results with other nukes but if you cut the dose in half, so go half the profits! This, of course, is not pleasing to the money grubbing executives of the pharmaceutical companies that own the drug. However, these drugs may also cause cancer (, 1994). Will years long use increase this risk? How can it be offset? Clearly, this is an area that must be guarded against with great vigilance. A complete and well crafted regimen of antioxidant supplementation may go a long way toward preventing cancer from developing. AZT (zidovudine, Retrovir, Aztec, azidothymidine): This drug, of all therapies used for the chronic management of HIV infection, is the most problematic. How any sane person can consider this extremely toxic substance a long-term therapy for any condition is beyond our comprehension. Ask any doctor how long he thinks someone can continue to take AZT without significant life-debilitating negative effects and an honest response should be " perhaps 16-18 months " . In particular, AZT targets the bone marrow as well as the cells' energy factories called mitochondria. One type of muscle deterioration caused by AZT has been associated with damage to mitochondrial DNA (Sinnwell, 1995; Butori, 1995; Chen, 1991). The body's cells contain a nucleus where the DNA is found. This DNA produces all the proteins essentially for life. However, there is another organelle in cells called the mitochondria. These are the powerhouses of cells, producing lots of the energy-providing chemical adenosine triphosphate (ATP). And, as noted above, mitochondria have their own DNA. Unfortunately, it is not as well protected as the DNA found in the nucleus. Drugs like AZT and the other nukes get into the mitochondria and can cause significant damage. Some do it worse than others. For example, the drug fialuridine was used to treat people with chronic active hepatitis B and the unfortunate result was a number of deaths and several people with permanent, crippling neuropathy. AZT specifically damages mitochondria in muscle cells resulting in a myopathy which features ragged red appearance (Dalakas, 1994). Minimizing these toxicities is essential to maximizing their benefit. Dose reductions have clearly shown to be as effective and even delay resistance. Carnitine may also help offset damage to mitochondria (De Simone, 1993; De Simone, 1992). Astragalus and carnitine (or acetyl-carnitine) are all particularly protective in both these structures and are strongly suggested for anyone using AZT for any length of time. Also, vitamin E has been shown to increase AZT's ability to penetrate virally infected cells and to lessen bone marrow toxicity in laboratory conditions. Please review the Information Sheets on these and Adaptogenic Herbs in TIP. If you are beginning AZT chronic therapy with already low blood cell counts, you may want to think about using the Chinese herbal combination called Marrow Plus. For more information on this product please refer to the DAAIR Catalogue. A significant percentage can not tolerate AZT at all under any circumstances. The primary toxicities associated with AZT are anemia (red blood cell declines), bone marrow suppression resulting in neutropenia (reduced white cell count) and myopathy (muscle wasting). The most frequent adverse events and abnormal laboratory values are granulocytopenia (loss of immune cells called granulocytes) and anemia (low red blood cells). Anemia is the result of impaired red blood cell maturation. Nausea, severe headache, insomnia and myalgia were reported in at least 5 percent of patients. Two rare but potentially fatal clinical syndromes have been reported in people with HIV on AZT. These two syndromes, lactic acidosis (lactic acid in the bloodstream due to breakdown of muscle) and severe hepatomegaly with steatosis (fatty, enlarged liver), which may be disproportionately prevalent in obese women. These syndromes have occurred both separately and together in patients; thus, it is possible that these two syndromes are related (PDR 1993; Burroughs-Wellcome Co: Retrovir Adverse Effects Warning. Aug 1993; S. Kent, MD, Vice Pres Medical Affairs). AZT is contraindicated for patients who have potentially life-threatening allergic reactions to any of the components of the drug formulation of Retrovir capsules (PDR 1993). ddI (didanosine, Videx): The primary toxicities are pancreatitis (inflammation of the pancreas in about 10% of users in one clinical study; Grady, 1992) and neuropathy. Oxidative stress clearly appears to be involved in the development of ddI-related pancreatitis. Doctors at Manchester Royal Infirmary tried out a regimen on people with alcohol-induced pancreatitis and obtained significant reduction in relapse rates. The regimen included 600 mcg selenium, 9000 IU beta carotene, 540 mg vitamin C, 270 IU of vitamin E and 2 grams of methionine. Anecdotally, this seems to improve symptoms (-on, 1995). Clearly, a DAAIR protocol will provide significant protection against this toxicity. Neuropathy (pains in the feet and legs) occurred in about 34% and indicates one should stop using didanosine (ddI); the neuropathy should clear up within 1 to 2 weeks. Other effects include increased amylase levels, increases in uric acid levels (hyperuricemia), rashes, elevations in liver function tests, liver failure, seizures, central nervous system (CNS) toxoplasmosis, and retinal depigmentation in pediatric patients. Adult tolerance to ddI at doses of less than 1.5 g/day has generally been good. Clinical experience suggests that treatment with ddI may cause leukopenia (low white blood cells), anemia (low red blood cells), neutropenia (decreases in neutrophils), thrombocytopenia (low platelets which help blood coagulate), gastrointestinal disturbances, reproductive organ toxicities, neurologic disturbances (convulsions, seizures, coma, death), skin rashes, tachycardia (abnormally rapid heart beat), hypotensive responses (lowered blood pressure), and emesis (vomiting) (PDR 1993; N Engl J Med 1990;332; NIAID ACTG 064). Should not be used by pregnant or lactating women or by patients with a history of seizure disorders or heart disease (NIAID ACTG 064). ddC (dideoxycytidine, zalcitabine, HIVID): The primary toxicity is neuropathy. Other dose-related adverse effects are rashes and oral ulcers. ddC may also cause pharyngitis (inflammation of the pharynx in 5% of patients) and coughing, dyspnea (trouble breathing), cyanosis (bluish tinge to skin or fingernails: a serious toxicity), fever and flu-like manifestations (less than 1% of patients) have been reported. Rare occurrences of lactic acidosis (lactic acid in the blood due to muscle breakdown and lack of oxygen) in the absence of hypoxemia (insufficient blood oxygenation) and severe hepatomegaly with steatosis (enlarged fatty liver) have been reported and are potentially fatal. Rare cases of liver failure and death considered possibly related to underlying hepatitis B also have been reported. (PDR 1995; AHFS Drug Information 1995). Discontinue on signs of numbness, tingling, burning or pain of extremities; use with caution in patients with history of pancreatitis, elevated serum amylase concentration, renal impairment, baseline cardiomyopathy or congestive heart failure. Should be used during pregnancy only the potential benefits justify possible risks to the fetus. (AHFS Drug Information 1995). d4T (stavudine, Zerit): Dose-associated adverse events include sensory peripheral neuropathy, hepatotoxicity (liver toxicities), some develop anemia requiring a transfusion (in these reported cases discontinuation of drug was not necessary). [J Infect Dis. 1993 Jan;167(1)]. Should not be used by pregnant or nursing women. (ACTG 089). 3TC (lamivudine): The primary toxicities, relative mild in contrast to other nukes, can still be unpleasant. Hair falling out is one. In clinical trials, 3TC was relatively well-tolerated with few side effects. Nausea and vomiting were reported in 15% to 26% of volunteers in clinical trials, but people given placebos had similar rates of side effects. Similarly, headache was reported in 9% of participants in the two 3TC+AZT studies (2 studies were mentioned earlier in the article). At higher doses (20 mg per kg of body weight per day, which is approximately 1,400 mg/day for a 150lb person), 3TC has caused serious deficiencies in white blood cells called neutrophils (neutropenia), which can cause increased risk of infection. Peripheral neuropathy-nerve damage characterized by numbness, pain, or tingling in the extremities-occurs in roughly 10% to 15% of people taking 3TC. Protease Inhibitors: Many test tube studies suggest that most of the protease inhibitors are specific for the HIV protease. Our body, of course, plays host to a number of proteases that are important for protein digestion. These include cathepsins D and E, pepsin, renin, gastricsin and others. (In addition, your body uses its own protease inhibitors like pepstatin A). Now, while it is encouraging that the protease inhibitors are, by industry studies, so specific, the negative effects being seen (particularly with ritonavir and nelfinavir) suggest that other activity is occurring. Indeed, it seems obvious that a fairly high concentration of the orally ingested protease inhibitor is passing through the gut. Why does the diarrhea occur? Is it due to a lack of complete digestion? Which natural protease enzymes are the drugs inhibiting? How much of these drugs is in the GI tract causing inhibition of cathepsins or other endogenous proteases? Different proteases are identified by where they cut a protein. Thus, there are aspartic proteases (aspartic acid is an amino acid) and serine proteases. Many of the body's proteases are serine proteases (thrombin, chymotrypsin, plasmin, etc.) while the HIV protease is an aspartic (or aspartate) protease. Other important bodily aspartic proteases include renin, pepsin and cathepsin D, among others. Cathepsins are enzymes that are involved in the metabolism (cutting up) of proteins. Cathepsin B is found inside cells of vertebrates (animals with a spine); C is also known as dipeptidyl peptidase-I while cathepsin D (or E) is a proteinase active in an acid environment, somewhat similar to pepsin A. The inhibitors target HIV specifically and are part of rational drug design. Knowing the exact shape and structure of HIV's protease, novel compound are created that specifically bind to it, disrupting its function. To the extent it does so without interfering with other bodily functions can be tested in vitro. A first general question might be, is there an effect nonetheless on aspartic proteases? One study suggests they may have reversible effects (Reboud-Ravaux, 1996). One type of protease inhibitors was found to have weak activity against renin and stronger activity against cathepsin D (Grobelny, 1990), although we're not sure if this bears any resemblance to the protease inhibitors currently being used. DMP 323 was shown in the test tube to inhibit various cathepsins, however not to a great degree and only at concentrations much higher than are needed to inhibit HIV's protease; what this means to people taking it of course is unknown (kson-Viitanen, 1994). Whether this holds true for drugs like ritonavir is not at all clear! The data to date suggest its activity may be against cathepsins D and E. Indinavir (Crixivan): The two primary toxicities are a generally temporary increase in bilirubin (liver function) and, more troublesome, the eventual development of painful kidney stones. Other effects include abdominal pain (20%), asthenia/fatigue (31%), diarrhea (36%), dry skin (24%), headache (46%), insomnia (16%), lymphadenopathy (24%), nausea (34%), rash (37%) and taste abnormalities (16%). Blood abnormalities that may occur include decreased hemoglobin (5%), hematocrit (red cell count, 6%), neutrophils (white cell count, 9%), platelets (20%). Ritonavir (Norvir): diarrhea, increased triglycerides and cholesterol, increased liver enzymes (transaminases) are the most problematic. Taste perversion, weakness and nausea are also very common. One child saw serious (grade 3) increases in transaminases (liver enzymes) in a study of 9 kids. Reports of elevations beyond 5 times normal have been reported using ritonavir alone or with other drugs; people with hepatitis B or C or other liver inflammation should probably avoid using ritonavir at all. People with hemophilia may need to increase factor VIII use since increased bleeding and skin hematomas (a swelling filled with blood from a blood vessel break) and hemarthrosis (blood in a cavity or joint) has been noted. Increased blood sugar (hyperglycemia) has also been reported: diabetics beware. Because it blocks a cytochrome P450 enzyme important for many other drugs, see the notes on cross-reactions with other drugs below. In addition, allergic responses have been reported in some users that include rashes, hives, bronchospasm (nothing to do with OJ, but rather a (muscles in the lung spasm, causing a constriction of the bronchi which are main airways), angioedema (swelling, itching and hives; can involve skin or tissues lining organs), and rare reports of anaphylaxis and s- syndrome (Abbott letter dated November, 1996). Saquinavir (Invirase): diarrhea. Nausea and vomiting may also be a problem. Don't take with rifampin (will kill saquinavir effect). Possibly taking with grapefruit juice will increase bioavailability but some feel it will be just enough to not do any good but develop resistance quickly according to Delaney at PI. Saquinavir has largely been abandoned by those at the cutting edge (activists and physicians) except possibly as a combination with ritonavir. This combination has not yet been adequately explored. Nelfinavir (VIRACEPT): diarrhea. 1 of 12 patients had to drop the drug due to a grade 3 elevation in creatine kinase, an enzyme in skeletal and heart muscle and found in the brain. Watch for liver toxicity. From DAAIR's Nutritional Protocols… Many PWHIV using protease inhibitors either have, or want to prevent from developing, numerous gastrointestinal (GI) complaints including gastritis, generalized inflammation, bloating, cramping, gas and pain, and various degrees of diarrhea. The following protocols have proven to be remarkably effective at either reducing or eliminating many of these negative effects. Proteases inhibit the HIV enzyme aspartate protease. Unfortunately, the human body also uses aspartate protease for many different functions. Some cells which use aspartate protease are neutrophils, erythrocytes, digestive enzymes, pepsin and gastricsin and kidney enzymes, renin and cathepsins D and E. Cathepsin E is also present on epithelial cells (surface cells coating most tissues like a plastic bag), in the stomach and intestines, and overlying the lymph nodes in the small intestines. Judging from the frequent community reports of various gastrointestinal negative effects, protease inhibitors appear to be interfering with numerous human functions as well. There was also a consensus from Vancouver that proteases are, to varying degrees, interfering with macrophage functions which use inhibited enzymes cathepsins D and E. It is unclear what, if any clinical relevance this reality may have for persons with HIV. These enzymes do play an important role in the macrophage function of chewing up and destroying harmful bacteria damaged cells and other 'non-self' substances in the body. This underscores the role for frequent detoxification techniques while on these drugs. If you are experiencing persistent low grade infection(s) while on a protease, you might want to try the beta, 1-3 glucan known as NSC-24, which has been shown to upregulate macrophage function. Aside from the first five to seven items mentioned in the protocol above, PWHIV have also found the following below to be helpful with the outlined reactions. If your GI problems are severe, you should address them first before starting any additional nutrients. Description Daily Dose If GI tract problems are severe use for 6 weeks then decrease doses: L-Glutamine bulk powder x 1 kilogram30-40 grams1kt=4grams 10 kt-ES/d (3B, 3L, 4D) (kt shd be rounded) Innerfresh Liquid Chlorophyll x 16oz6 kt-ES/d (2B, 2L, 2D) mix in 4 oz water N-acetyl-glucosamine 750mg x 1203/d (1B, 1L, 1D) If GI tract problems are not severe or for prophylaxis: L-Glutamine bulk powder x 170grams3 KT-ES/d (1B, 1L, 1D) (or tablets 4-6 grams) Innerfresh Pro Liquid Chlorophyll3 kt-ES/d (1B, 1L, 1D) N-acetyl-glucosamine 750 mg x 1203/d (1B, 1L, 1D) If on indinavir (Crixivan) with mild to moderate allergic reactions add: Cell Strength 600 mg x 1204-6/d (2+B, 2+D) If experiencing persistent low grade infections, slow healing: NSC-24 2.5 mg x 601/d (on empty stomach for three-four days) Non-nucleoside reverse transcriptase inhibitors: Nevirapine (Viramune): 20% dropped out of study due to toxicities. Test tube studies show that it suppresses young cells that eventually grow and differentiate into other cells (specifically, blast forming units). Rash has been observed at higher doses of nevirapine (400 mg/day and above). Fourteen of 32 patients who received initial therapy with nevirapine 400 mg/day experienced side effects; 11/14 permanently discontinued treatment as a result (8 rash, one thrombocytopenia, and two fever). Protocols studying higher doses of nevirapine currently use a two-week " lead in " regimen of 200 mg/day, which appears to improve tolerance of higher doses. One patient who received nevirapine 600 mg/day had a severe reaction including facial edema and inability to swallow. Delavirdine (Rescriptor): If used with protease inhibitors, may result in serious liver toxicity. Care should be taken if using with saquinavir; dose of saquinavir may need to be lowered since use with delavirdine increases plasma concentrations of saquinavir; ditto with indinavir. No interactions noted (at this time) with ritonavir. What Can I Do for Unavoidable Negative effects? Review the section above on toxicities which also provides some background information on offsetting toxicities. The table below is for informational purposes. Please remember that the symptoms listed below are very general. Be sure to work vigorously with your healthcare provider to identify the cause(s) of any persistent symptoms. Do NOT rely on the interventions alone to treat these conditions, but if a drug is identified as a possible culprit, consider the interventions. If they do not work for you or become too severe, you may have to stop the drug (e.g., pancreatitis or neuropathy). Remember that the number of people who actually experience the listed negative effects is often fairly small in some cases. The information provided is by no means exhaustive. (See the list of abbreviations at the end of the table). Potential Drug Side Effects and Interventions to Offset Them: [please click on link at beginning of document for the rest of this document] Quote Link to comment Share on other sites More sharing options...
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