Cholestyramine As A Binder
What Is Cholestyramine
Quick answer: Cholestyramine is a non-absorbed medication that has largely been used in the past to lower elevated levels of cholesterol. We are using it to lower mycotoxin levels. Myctoxins need to be altered, and removed from the body in one manner or another. Cholestyramine is both a sequester or bile acids and has been shown to bind directly to some mycotoxins to remove them from the body.
Once you are removed from moldy environments you need to remove the mycotoxins from your body. This is best done with a mix of binders and support of the biotransformation/detox system. Cholestyramine is a prescription drug that is used as one type of a binder. There are other possible alternatives that I have collected data on and some of them I have used. Other lay people and practitioners are using them also. All of the binders have variable responses which makes sense as some of them are more or less hydrophillic/hydrophobic and the mycotoxns are more or less polar. Please see data on binders to understand how most of them work.
Detailed answer: Cholestyramine is a bile acid sequestrant, like colestipol and colesevelam. These molecules are positively charged non-digestible resins that bind to bile acids in the intestine to form an insoluble complex, which is excreted in the feces. They are used mainly for the treatment of high cholesterol levels, in patients not responding to dietary treatment as well as a second line-treatment for itching associated with cholestatic disease, in patients with incomplete biliary obstruction. Several data indicate that modulation of bile acid homeostasis has a good clinical effect in managing diabetes mellitus and the diarrhea from bile acid malabsorption. Cholestyramine is an anion binding resin that has a quaternary ammonium side chain that creates a localized, net positive charge. (Clay generally has a negative charge.) The functional group of the anion exchange resin is a quaternary ammonium group attached to an inert styrene-divinylbenzene copolymer.
Reasons Cholestyramine May Be Used Other Than As A Binder
- Promote gallbladder health through emptying of the gallbladder and preventing stones
- Itching associated with liver failure or cholestasis
- Stops diarrhea
- Reduces blood glucose
- May help hyperthryoidism
- Treatment for Digoxin intoxication
- Decrease colon inflammation
Associated Side Effects of Cholestyrmaine
- Can decrease absorption of medications
- Can decrease absorption of nutrients in food
- Can decrease absorption of supplemenets/vitamins/minerals/herbs etc.
- Can lower thyroid hormones
- Gastrointestinal irritation or pain
- Occasional calcified material has been observed in the biliary tree, including calcification of the gallbladder, in patients to whom QUESTRAN has been given. However, this may be a manifestation of the liver disease and not drug related.
When is Cholestyramine used by Practitioners?
In the past it was used to treat high cholesterol levels. In this regard, Cholestyramine has largely been replaced by statins. It is still used in people who feel a need to lower their cholesterol but can not or do not want to take statins.
Additionally, it is used to treat itchy skin that occurs during liver failure or partial biliary obstruction. It is also used to treat diarrhea due to bile acid malabsorption.
One use that is becoming more common-place is its use to adsorb toxins A and B produced by Clostridium difficile biotoxins.
It is used in a “wash out” procedure in patients taking leflunomide or teriflunomide to aid drug elimination when the drug needs to be discontinued due to severe side effects.
The use of Cholestyramine for Chronic Inflammatory Response Syndrome or Biotoxin Illness is an “off label” use. This means that it has not been studied for its use for CIRS. However, the FDA in 1999 did rule that there was not reason to expect an increased risk to a person’s health from use of Cholestyramine in patients who have biotoxin illness such as from ciguatera, mold, pfiesteria, or post-lyme syndrome compared to people who do not have these illnesses. Practitioners can prescribe Cholestyrmine under this FDA exemption.
What To Expect From Cholestyramine
Cholestyramine is used to assist in removal of some types of toxins/biotoxins such as mycotoxins that individuals with mold related illness due to water-damaged buildings have trouble removing from their body.
People with mycotoxin related illness are often unable to remove the mold toxins from their body due to HLA genetic varients and/or other biotransformational/detox varients. The immune system of the CIRS (Chronic inflammatory related syndrome) due to water-damaged building individual is unable to remove these toxins and is in fact the instigator of an inflammatory response. Cholestyramine can bind to some types of mycotoxins, or other biotoxins that cause CIRS, allowing them to be eliminated via the feces. This only works for toxins that are in the food, go through the enterohepatic circulation and show up in the intestine or are excreted by the gut, and additionally these toxins need to be capable of binding to the cholestyramine or to bile acids. These biotoxins must be removed from the body of the person with CIRS or they often to not get well. Once they are removed the inflammatory process that started in their body also needs to be addressed. You can read more about binders here.
Alternatives To Using Cholestyramine
Why use Cholestyramine for CIRS Or Mold Related Illness
People with CIRS are often unable to remove the mold toxins from their body due to a genetic varient. The immune system of the CIRS patient is unable to remove these toxins and is the instigator of an inflammatory response. If the toxins are not removed, the individual continues reacting to them. Cholestyramine binds to biotoxins that cause CIRS allowing them to be eliminated via the feces. These biotoxins must be removed from the body of the person with CIRS or they will never get well. Once they are removed, the inflammatory process that they started also needs to be addressed. The use of Cholestyramine is considered “off-label.” It is legal to give medications off label and most physicians give medications off label. You need to know that your prescription is being used off-label.
How does Cholestyramine work?
Cholestyramine is not absorbed. It is taken in a precise manner so as to bind to bile salts, cholesterol and biotoxins in the small intestine. They are not able to be absorbed and are excreted with the cholestyramine in the stool. Overtime the biotoxins are removed from the bodies tissues as long as there is no re-exposure. Cholestyramine only removes the biotoxins from the body. It does not necessarily correct inflammatory problems or other cascading events that those biotoxins created. Additional work usually needs to be done to correct these issues.
Details on How Cholestyramine Works:
It is used as a bile acid sequestrant although it can also bind directly to some toxins. Since it is a strong ion exchange resin, it can exchange it’s choloride anions with anionic bile acids in the gastrointestinal tract and bind them strongly in the resin matrix. It removes bile acids from the body by forming insoluble complexes with the bile acids. The whole thing is then removed in the feces. Usually, the bile and things attached to the bile acids would be picked back up from the intestines as part of the enterohepatic circulation. This is a continual recycling of bile and any biotoxins in the bile. However, when the bile acids are bound to Cholestyramine, the Cholestyramine and the bound bile acids/biotoxins are removed via the feces.
Besides binding the bile acids, cholestyramine has been shown to also bind some free mycotoxins. For instance it binds a significant amount of Ochratoxin A when given as a contaminant to rats in their diet. The cholestyramine showed a greater affinity for the ochratoxin than the bile salts taurodeoxycholate and taurocholate. (Bile salts are bile acids that are conjugated to usually taurine or glycine amino acids.)
How the enterohepatic circulation is involved in circulating biotoxins.
Bile acids are made in the liver cells, from cholesterol. CYP7A1 regulates the rate-limiting step in the bile biosyntheitc pathway. The bile acids are secreted into the gallbladder via the bile acid exporter pump (BSEP)(for storage and concentration). During normal digestion, bile, with the bile acids included, is secreted from the liver and gall bladder into the intestines. Most of the bile acids are usually re-absorbed in the part of the intestines called the terminal ileum, via the apical sodium-dependent bile acid transporter (ASBT). They are transported back to the liver in the portal blood to be re-excreted into the bile again. The movement of the bile from the liver into the intestines and its return back to the liver is called the enterohepatic circulation. Biotoxins bound to the bile acids in the bile are re-circulated back to the liver with the bile acids. If the bile acid/biotoxin mix becomes bound by a bile acid sequestrant such as Cholestyramine while still in the intestines, the mix is not able to be reabsorbed by the intestines.
You might wonder why can’t the mycotoxin/bile acid/cholestyramine mix be re-absorbed. Cholestyramine is not able to be absorbed by the intestines, so anything attached to cholestyramine is not going to be absorbed, even if the bile acid/toxin compound would usually get re-absorbed. Since Cholestyramine is strongly bound to the the bile acids and they are bound to the mycotoxins, the whole lot is lost in the feces.
What Else Has Been Used To Bind Biotoxins?
Welchol is less effective compared to Cholestyramine. According to Dr. Ritchie Shoemaker, the pioneer in CIRS treatment it is 25% less effective. Dr. Shoemaker uses this as an alternative to Cholestyramine if his patients can not tolerate Cholestyramine. However, treatment takes much longer.
Although Dr. Shoemaker claims other agents are not able to provide similar clinical results in his 10,000 patients he has treated for CIRS due to water-damaged buildings, I am listing a link to them below so you can get additional details on them. The fact is that some of them are used by individuals with great success and some of them have research to support them. However, the research shows that some of them are only affective for certain mycotoxins.
Other Types of Toxin/Mycotoxin Binders
There are many of them. For the list of other binders/transformers that may be beneficial in binding or transforming mycotoxins, go to this link.
Protocol Outline for taking cholestyramine for biotoxin illness
- Take on an empty stomach. Take 4 grams of pure cholestyramine or 9 grams of Questran, or as prescribed.
- Mix with 6 oz of water or apple juice and drink. Follow with another 6 oz of water or more.
- Wait 30-60 minutes and then eat your meal. To decrease binding of important nutrients in meals, wait the full 60 minutes.
- Take Medications 30 minutes before cholestyramine or 2 hours after.
- If you forget the cholestyramine and eat, wait for 1 hour before taking the next dose of cholestyramine.
- Take 3-4 doses of cholestyramine per day
- If you have indigestion, reflux, or constipation see information below.
Deatils of How to Take Cholestyramine, Safety, Detoxification Reactions, Contraindications & Adverse Reactions
How is Cholestyramine used?
To bind biotoxins, 4 grams of Cholestyramine is taken 4 times per day. (Dosing for children or people under 120# needs to be altered accordingly.) Cholestyrmine products on the market usually mix Cholestyramine with other ingredients to make it taste better and mix into water better or look more appealing to the user. These products are often in 9 gram doses (4 grams of cholestyramine and 5 grams of additives.) However, some folks with biotoxin illness are unable to take Cholestyramine with these additives and their practitioner has a compounding pharmacist provide Cholestyramine without these extra ingredients since a pure cholestyramine is unavailable on the open market.
It is taken 30-60 minutes prior to a meal. Make sure the meal has at least 1 teaspoon oil/fat in it. Could be one egg or a pat of butter/coconut oil etc. This will get the bile going at the correct time to meet up with the Cholestyramine. Take it 30 minutes before breakfast, lunch and dinner and then at bed. Drink a minimum of 12 oz of water with it, but better to drink more if you are able. This helps decrease constipation from the Cholestyramine. For people who are concerned about constipation or having a reaction from pulling out the biotoxins, start slow at 1 gram (1/4 dose) 2 times per day on day one. If no problems increase to 2 grams (1/2 dose) the next day for two times that day, then 3 grams or ¾ dose day 3 for two doses that day and the full dose on day 4 but still only two times. Then on day 5 go to using the full dose of 4 grams Cholestyramine 3 times per day, 30 minutes before meals and on the 6th day 4 times, with the last dose before bed. Four doses each day is best, but for some people due to drug regimens or other reasons they can only take it three times per day.
If you eat first, wait at least 1 hour before taking your next dose of Cholestyramine.
When Can I take other medications
Take all medications one hour prior to taking the Cholestyramine or two hours after taking cholestyramine. Do not take any food with them unless necessary for the medicine and then only what is necessary and try to stay away from eating fatty foods if possible.
How Long is it used?
It is usually used until a person’s Visual Contrast Sensitivity Testnormalizes. It is generally prescribed for one month. This allows the body to dump most of the biotoxins out of the body via the bile. Usually, people report feeling better the first week. However, generally they need to use it for the full month to get the full effect. Additionally, if the person is re-exposed to biotoxins again (see list of biotoxins) they will once again need to remove these biotoxins with a bile acid sequestrant or binder such as Cholestyramine.
The length of time it is to be taken depends on each individual and your practitioner will need to decide if it is to be used very short term due to concern of side effects or to be used on a longer basis.
Is it Safe?
It has been used for more than forty years and many patients have taken it for long periods of time. The FDA ruled in 1999 that there was no reason to expect an increased risk from giving Cholestyramine to patients with biotoxin illnesses, such as mold, Lyme, cuguatera, pfiesteria and blue green algae syndromes compared to those who do not have biotoxin illnesses.
Detox Reactions (Also see Contraindications & Adverse Reactions)
Some people report a detox reaction. Sometimes this can be lessened by using anti-inflammatory supplements/diet/lifestyle. Omega-3-fatty acids and a low inflammatory diet with supplements specific to that individual for a week prior to starting the cholestyramine or other binder can be beneficial.
Dr. Ritchie Shoemaker (CIRS due to water-damaged buildings pioneer and leader in field) has noted that reactions to cholestyramine treatment may be specific to CIRS causes and are often associated with various illnesses or lab makers. For instance the person with a significantly elevated MMP-9, a history of ciguatera, Lymes or MARCoNs may have a worsening of symptoms with taking Cholestyramine. True intensification or worsening of clinical presentation, will result in a fall in VCS scores in row E by day 3 (after Cholestyramine treatment begins) followed by a fall in row D. MMP-9 will rise from baseline. (If this happens Lymes should be ruled out as well as MARCoNs.)
What is thought to be happening when detox reactions occur?
This usually happens around dose 6-10. Some practitioners feel it is more common in post Lyme patients than others. It is thought that the reaction is tied to a dissociation constant of toxins to receptors. If the binding is tight, like ciguatera the intensification never occurs. If the toxins are internalized into dendritic cells such as in mold and cyanobacteria toxins, there is no intensification. When the Cholestyramine binds the toxins and they are removed with it in the stool, this pushes the dissociation to the right to release more toxin from everywhere in the body. Before the newly released toxins go into the bile and are removed by the Cholestyramine they cause an intense release of cytokines in the body. This in turn causes the inflammation that leads to the various detox symptoms. Personally, I feel this can happen with things other than binders. Taking glutathione or alpha lipoic acid which both help to remove biotoxins can also cause a similar reaction as binders.
How long until I feel better?
Generally people notice improvement the first week. Most people feel much better after a month. Treatment is faster for the young and slower for the elderly. The sicker can take longer to get well. Other reasons it may take longer are poor compliance with Cholestyramine or another binder, or the person may still be exposed to toxins (Did they remove themselves from all water-damaged buildings or remediate their home appropriately?) They also may have a MARCoNs infection or heavy metal poisoning or other pathogens in their body complicating their progression.
Digestion Reactions That May Occur
Common reactions early on in treatment are reflux of stomach acid (heart burn), bloating, belching and general indigestion, as well as constipation. Some people will dissolve the Cholestyramine in apple juice to help reduce the heartburn. This really does help. Some people also find dissolving it in luke-warm water and then adding ice will help reduce heartburn.
Dealing With The Constipation
The simplest thing is that patients are helped by drinking more water. 16 oz with each dose is best. 12 oz is necessary at minimum. Drinking more water thru the day is also necessary. Fruits such as plums and cherries are helpful. Some people use water soluble fiber such as psyllium seed. Research has shown psyllium mixed with cholestyramine works better to lower cholesterol than cholestyramine by itself. It may be that it will work similar with biotoxins although there is not research on using the two of them together for biotoxins. If using the water soluble fiber, drink plenty of water with it. Some patients find using vitamin C to bowel tolerance can be helpful, while others use magnesium for constipation. Those using Vitamin C, usually take it 1 hour prior to taking their Cholestyramine dose or they take it with their meals. Most patients are taking 1 -2 grams 4 times per day. They back off the dose if they get loose bowels. Magnesium is taken with meals usually in 100-200 mg doses per meal. While magnesium glycinate is a good form to absorb, magnesium citrate or chloride is a better form if you want to induce bowel evacuation. However, all magnesium will cause an evacuation if you take enough. The vitamin C and magnesium is only used as a solution to constipation if water, fruit and water soluble fiber is not helping enough.
5- Hydroxytryptophan (5-HTP), a supplement that people take at night to help them sleep, also helps move the intestines to promote evacuation of bowel contents. People sometimes take this at night before bed to help them sleep and have a bowl movement in the AM. Vitamin C, magnesium and 5-HTP should not be substituted for drinking lots of water.
Some patients with chronic biotoxin illness have diarrhea or softer, frequent stools. For these people the cholestyramine is usually beneficial as it helps to solidify their stool.
Contraindications & Adverse Reactions For Cholestyramine
- Research has shown that Choleystyramine is not absorbed, but entirely removed in the feces.
- Problems that arise therefore are usually related to its action in the gut.
- It is not given to kids under 3 years old.
- It is not indicated for oral consumption if there is complete biliary obstruction where bile is not secreted into the intestine.
- It is also not indicated in individuals who have shown hypersensitivity to it or any of it’s components.
- Choleystramine binds bile acids, so it may therefore interfere with normal fat digestion and absorption and thus may prevent absorption of fat-soluble vitamins such as A,D,E and K.
- When Cholestyramine is given for long periods of time, concomitant supplementation with water-miscible or parenteral(shots) forms of fat-soluble vitamins should be considered.
- The adverse reactions are largely due to Cholestyramine binding bile acids and causing fat soluble vitamin deficiencies or binding of drugs.
- Cholestyramine also lowers cholesterol. Many people find this to be a plus, however some may have low cholesterol and this could be a problem.
- Can decrease absorption of medications
- Can decrease absorption of nutrients in food
- Can decrease absorption of supplmenets/vitamins/minerals/herbs etc.
- Can lower thyroid hormones
- The most common adverse reaction is constipation
- Gastrointestinal irritation or pain
- Possible liver issues: Occasional calcified material has been observed in the biliary tree, including calcification of the gallbladder, in patients to whom QUESTRAN has been given. However, this may be a manifestation of the liver disease and not drug related.
- Is expensive on your wallet
Less Common Adverse Reactions
Please go to this link for an extensive list of less common adverse reactions: http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=63274
Where do people get Cholestyramine?
- A prescription is necessary in the United States.
- If you want pure Cholestyramine without additives you need to get it from a compounding pharmacist.
- In the United States we have a couple products that are common on the market.
The following list of ingredients in the products available are from this link: http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=63274
QUESTRAN® (Cholestyramine for Oral Suspension, USP), the chloride salt of a basic anion exchange resin, a cholesterol lowering agent, is intended for oral administration. Cholestyramine resin is quite hydrophilic, but insoluble in water. The cholestyramine resin in QUESTRAN is not absorbed from the digestive tract. Four grams of anhydrous cholestyramine resin is contained in 9 grams of QUESTRAN POWDER. QUESTRAN POWDER contains the following inactive ingredients: acacia, citric acid, D&C Yellow No. 10, FD&C Yellow No. 6, flavor (natural and artificial), polysorbate 80, propylene glycol alginate, and sucrose (421 mg/g powder).
Four grams of anhydrous cholestyramine resin is contained in 6.4 grams of QUESTRAN LIGHT. QUESTRAN LIGHT (Orange Vanilla) contains the following inactive ingredients: aspartame, citric acid USP anhydrous, D&C Yellow No. 10, FD&C Yellow No. 6, flavors (natural and artificial Orange, natural and artificial Vanilla Cream), maltodextrin, magnesium sulfate USP heptahydrate, propylene glycol alginate, colloidal silicon dioxide, and xanthan gum.
If you do not want these additives in your Cholestyramine, you will need to have your practitioner order it from a compounding pharmacist.
Please note that Questran Light contains aspartame which should never be consumed by people with the genetic condition knows as phenylketonuria or PKU. Additionally, there are other people who react to aspartame too.
I do want to point out one interesting research article:
Research with a cholestyramine product called Coestipol showed if you mixed it 50% (2.5 g of psyllium and 2.5 g colestipol) with Psyllium seed was able to reduce cholesterol more significantly than colestipol alone or psyllium alone. It also reduced gastrointestinal irritation from the cholestyramine.
This leads me to believe that we might be able to use psyllium or other water soluble fibers to mix 50/50 with cholestyramine for biotoxin removal. However, I do not know how much of this action is due to an increased synthesis of bile acids from cholesterol lowering cholesterol levels. What do I mean? Well, here are the mechanisms of action of cholestyramine and how it effects cholesterol:
Mechanism of Action:
Bile acids are synthesized by the liver by oxidation from cholesterol.
These sequestering/binding drugs bind to bile acids in the intestinal lumen & prevent their normal reabsorption. The resin itself (cholestryamine) is not absorbed from the GI tract.
The fecal loss of bile acids results in an increased hepatic synthesis of bile acids from cholesterol, resulting in a reduction in hepatic cholesterol content.
The fall in hepatic cholesterol content results in an up-regulation of LDL receptors.
The upregulation of hepatic LDL receptors increases the removal of LDL and intermediate-density lipoprotein cholesterol (IDL) from plasma.
Research on Use of Cholestyramine as bile sequestrant
In vitro and in vivo studies to assess the effectiveness of cholestyramine as a binding agent for fumonisins.
Solfrizzo M, Visconti A, Avantaggiato G, Torres A, Chulze S.
Several adsorbent materials were tested at I mg/ml for their in vitro capacity to adsorb fumonisin B1(FB1) from aqueous solutions. Cholestyramine showed the best adsorption capacity (85% from a solution containing 200 microg/ml FB1) followed by activated carbon (62% FB1). Bentonite adsorbed only 12% of the toxin from a solution containing 13 microg/ml FB1, while celite was not effective even at the lowest tested FB1 concentration (3.2 microg/ml).
Now animal and human bodies are different than a test for adsorbancy in solution. So, they went forward with the research and tested in vivo. Cholestyramine was tested in vivo to evaluate its capacity to reduce the bioavailability of fumonisins (FBs) in rats fed diet contaminated with toxigenic Fusarium verticillioides culture material. Rats were exposed for one week to FBs-free diet, FBs-contaminated diet containing 6 or 20 microg/g FB1 + FB2 and the same FBs-contaminated diet added of 20 mg/g cholestyramine. The increase of sphinganine/sphingosine (SA/SO) ratio in urine and kidney of treated rats was used as specific and sensitive biomarker of fumonisin exposure. The addition of cholestyramine to the FBs-contaminated diets consistently reduced the effect of FBs by reducing significantly (P < 0.05) both urinary and renal SA/SO ratios.
J Food Prot. 1999 Dec;62(12):1461-5.
Cholestyramine protection against ochratoxin A toxicity: role of ochratoxin A sorption by the resin and bile acid enterohepatic circulation.
Kerkadi A1, Barriault C, Marquardt RR, Frohlich AA, Yousef IM, Zhu XX, Tuchweber B.
We have shown that the addition of cholestyramine (CHA, a resin known to bind bile salts in the gastrointestinal tract) to ochratoxin A (OTA)-contaminated rat diets reduced plasma levels of the toxin and prevented OTA-induced nephrotoxicity. To elucidate the mechanism of action of CHA, we carried out in vitro experiments to determine whether the resin may bind the toxin. For comparative purposes, binding of bile salts to the resin was also examined. Results showed that CHA binds both OTA and bile salts (taurodeoxycholate [TDC] and taurocholate [TCA]). Also, CHA showed greater affinity for OTA and TDC than for TCA. At 1 mM concentration, 96% of OTA and 80% of TDC were bound to the resin, while for TCA binding was only 50%. However, saturation of the resin was reached at higher levels with bile acids compared to OTA (3.67 mmol/g resin for TCA and 3.71 mmol/g resin for TDC versus 2.85 mmol/g resin for OTA). To characterize the nature of the binding of the toxin to CHA, NaCl (0 to 200 mM) was added to a fixed amount of OTA or bile acids. As expected, TCA absorption was decreased by the addition of NaCl (<50 mM), indicating electrostatic binding. However, OTA and TDC sorption was decreased only at high concentrations of NaCl (>150 mM), suggesting a stronger binding to the resin than that shown with TCA. Sequential competitive studies demonstrated that CHA binds more OTA than TCA. The results of the in vivo study show the role of bile salts in OTA absorption. The toxin's plasma levels at 1 and 3 h after a single oral dose of OTA were significantly decreased in bile salt-depleted rats compared to the control. Thus, the alteration of the bile salt biliary pool and OTA enterohepatic circulation may be an additional mechanism of action of the resin against mycotoxin toxicity.
PMID: 10606152 [PubMed - indexed for MEDLINE]
Food Addit Contam. 2005 Apr;22(4):379-88.
Recent advances on the use of adsorbent materials for detoxification of Fusarium mycotoxins.
Avantaggiato G1, Solfrizzo M, Visconti A.
The extensive use of adsorbents in the livestock industry has led to the introduction of a wide range of new products on the market, most of them claiming high in vitro mycotoxin adsorption capacity. However, adsorbents that may appear effective in vitro do not necessarily retain their efficacy when tested in vivo. Studies performed in our laboratory during the past few years aiming to evaluate the efficacy of various adsorbent materials in binding Fusarium mycotoxins are reported. Adsorption experiments were performed in in vitro screening tests for Fusarium mycotoxins at different pHs; by in vivo tests using the increase of the sphinganine to sphingosine ratio in rat urine and tissues as a biomarker of fumonisin exposure; and by a dynamic, computer-controlled, gastrointestinal model simulating the gastrointestinal tract of healthy pigs. Most of the commercially available mycotoxin-binders failed in sequestering in vitro Fusarium mycotoxins. Only for a small number of adsorbent materials was the ability to bind more than one mycotoxin demonstrated. Cholestyramine was proven to be an effective binder for fumonisins and zearalenone in vitro, which was confirmed for zearalenone in experiments using a dynamic gastrointestinal model and for fumonisins in in vivo experiments. No adsorbent materials, with the exception of activated carbon, showed relevant ability in binding deoxynivalenol and nivalenol. The in vitro efficacy of activated carbon toward fumonisins was not confirmed in vivo by the biomarker assay. The dynamic gastrointestinal model was a reliable tool to study the effectiveness of adsorbent materials in reducing the bioaccessibility of Fusarium mycotoxins, as an alternative to the more difficult and time-consuming studies with domestic livestock.
PMID: 16019808 [PubMed - indexed for MEDLINEless common adverse reaction
1: Neurotoxicol Teratol. 2006 Sep-Oct;28(5):573-88. Epub 2006 Aug 7.
Sick building syndrome (SBS) and exposure to water-damaged buildings: time series study, clinical trial and mechanisms.
Chronic Fatigue Center, 500 Market Street, Suite 103, Pocomoke City, MD 21851, USA. email@example.com
Occupants of water-damaged buildings (WDBs) with evidence of microbial amplification often describe a syndrome involving multiple organ systems, commonly referred to as "sick building syndrome" (SBS), following chronic exposure to the indoor air. Studies have demonstrated that the indoor air of WDBs often contains a complex mixture of fungi, mycotoxins, bacteria, endotoxins, antigens, lipopolysaccharides, and biologically produced volatile compounds. A case-series study with medical assessments at five time points was conducted to characterize the syndrome after a double-blinded, placebo-controlled clinical trial conducted among a group of study participants investigated the efficacy of cholestyramine (CSM) therapy. The general hypothesis of the time series study was that chronic exposure to the indoor air of WDBs is associated with SBS. Consecutive clinical patients were screened for diagnosis of SBS using criteria of exposure potential, symptoms involving at least five organ systems, and the absence of confounding factors. Twenty-eight cases signed voluntary consent forms for participation in the time-series study and provided samples of microbial contaminants from water-damaged areas in the buildings they occupied. Twenty-six participants with a group-mean duration of illness of 11 months completed examinations at all five study time points. Thirteen of those participants also agreed to complete a double-blinded, placebo-controlled clinical trial. Data from Time Point 1 indicated a group-mean of 23 out of 37 symptoms evaluated; and visual contrast sensitivity (VCS), an indicator of neurological function, was abnormally low in all participants. Measurements of matrix metalloproteinase 9 (MMP9), leptin, alpha melanocyte stimulating hormone (MSH), vascular endothelial growth factor (VEGF), immunoglobulin E (IgE), and pulmonary function were abnormal in 22, 13, 25, 14, 1, and 7 participants, respectively. Following 2 weeks of CSM therapy to enhance toxin elimination rates, measurements at Time Point 2 indicated group-means of 4 symptoms with 65% improvement in VCS at mid-spatial frequency-both statistically significant improvements relative to Time Point 1. Moderate improvements were seen in MMP9, leptin, and VEGF serum levels. The improvements in health status were maintained at Time Point 3 following a 2-week period during which CSM therapy was suspended and the participants avoid re-exposure to the WDBs. Participants reoccupied the respective WDBs for 3 days without CSM therapy, and all participants reported relapse at Time Point 4. The group-mean number of symptoms increased from 4 at Time Point 2 to 15 and VCS at mid-spatial frequency declined by 42%, both statistically significant differences relative to Time Point 2. Statistically significant differences in the group-mean levels of MMP9 and leptin relative to Time Point 2 were also observed. CSM therapy was reinstated for 2 weeks prior to assessments at Time Point 5. Measurements at Time Point 5 indicated group-means of 3 symptoms and a 69% increase in VCS, both results statistically different from those at Time Points 1 and 4. Optically corrected Snellen Distance Equivalent visual acuity scores did not vary significantly over the course of the study. Group-mean levels of MMP9 and leptin showed statistically significant improvement at Time Point 5 relative to Time Points 1 and 4, and the proportion of participants with abnormal VEGF levels was significantly lower at Time Point 5 than at Time Point 1. The number of participants at Time Point 5 with abnormal levels of MMP9, leptin, VEGF, and pulmonary function were 10, 10, 9, and 7, respectively. The level of IgE was not re-measured because of the low incidence of abnormality at Time Point 1, and MSH was not re-measured because previously published data indicated a long time course for MSH improvement. The results from the time series study supported the general study hypothesis that exposure to the indoor air of WDBs is associated with SBS. High levels of MMP9 indicated that exposure to the complex mixture of substances in the indoor air of the WDBs triggered a pro-inflammatory cytokine response. A model describing modes of action along a pathway leading to biotoxin-associated illness is presented to organize current knowledge into testable hypotheses. The model links an inflammatory response with tissue hypoxia, as indicated by abnormal levels of VEGF, and disruption of the proopiomelanocortin pathway in the hypothalamus, as evidenced by abnormalities in leptin and MSH levels. Results from the clinical trial on CSM efficacy indicated highly significant improvement in group-mean number of symptoms and VCS scores relative to baseline in the 7 participants randomly assigned to receive 2 weeks of CSM therapy, but no improvement in the 6 participants assigned placebo therapy during that time interval. However, those 6 participants also showed a highly significant improvement in group-mean number of symptoms and VCS scores relative to baseline following a subsequent 2-week period of CSM therapy. Because the only known benefit of CSM therapy is to enhance the elimination rates of substances that accumulate in bile by preventing re-absorption during enterohepatic re-circulation, results from the clinical trial also supported the general study hypothesis that SBS is associated with exposure to WDBs because the only relevant function of CSM is to bind and remove toxigenic compounds. Only research that focuses on the signs, symptoms, and biochemical markers of patients with persistent illness following acute and/or chronic exposure to WDBs can further the development of the model describing modes of action in the biotoxin-associated pathway and guide the development of innovative and efficacious therapeutic interventions.
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