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Cholestyramine versus Other Toxin Binders
Presently these are over 30 substances used or promoted as binding "toxins" such as those found in indoor mold, Lyme and possibly Bartonella. Often we are not given any information as to whether these are binding gas toxins, heavy metal toxins, plastic toxins, petroleum based toxins or simply help in removing drugs and keeping the liver healthy. If they specifiy that a biotoxin is being removed, we often do not know if they are talking about a bacterial biotoxin, a bee biotoxin, a snake biotoxin or dozens of possible indoor mold biotoxins.
Here is a sample of research showing that while other agents can remove some select biotoxins, that cholestyramine, in our experience, seems to be the best global biotoxin binder.
- 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.
Shoemaker RC, House DE.
Chronic Fatigue Center, 500 Market Street, Suite 103, Pocomoke City, MD 21851, USA. ritchieshoemaker@msn.com <ritchieshoemaker@msn.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.
Publication Types:
PMID: 17010568 [PubMed - indexed for MEDLINE]
- 2: Age Ageing. 2006 Jan;35(1):85-6. Epub 2005 Nov 22.
Intravenous immunoglobulin for resistant Clostridium difficile infection.
Murphy C, Vernon M, Cullen M.
Department of Geriatric Medicine, Wythenshawe Hospital, Manchester, UK. drclmurphy@aol.com
Clostridium difficile (CD)-associated diarrhoea and colitis may relapse in up to 20% of treated patients. We present a patient who failed to respond over a 6-month period to treatment either singly or in combination with metronidazole, vancomycin, rifampicin, cholestyramine and probiotics. Her diarrhoea rapidly resolved after a 3-day course of intravenous immunoglobulin. This treatment may compensate for a failed immune response to CD toxin and should be considered for relapsing CD-associated diarrhoea where there is no response to conventional treatment strategies.
Publication Types:
PMID: 16303776 [PubMed - indexed for MEDLINE]
- 3: Can J Gastroenterol. 2005 Aug;19(8):497-501.
Clostridium difficile-associated diarrhea in 200 Canadian children.
Morinville V, McDonald J.
Division of Pediatric Gastroenterology and Nutrition, McGill University Health Center, Montreal, Canada.
OBJECTIVE: Clostridium difficile-associated diarrhea is a major problem in adults. The present study was conducted to assess risk factors and outcomes in children with C difficile-associated diarrhea. METHODS: Laboratory records at a university-affiliated pediatric hospital were reviewed for all C difficile toxin-positive stools (cell culture cytotoxin assay) between 2000 and 2003. Charts on identified patients were reviewed. RESULTS: Two hundred patients with a diagnosis of C difficile-associated diarrhea were identified between February 2000 and November 2003. There were 107 males and 93 females (mean age 5.4 years; median age 2.6 years). Underlying factors were identified in 19% (12 patients underwent chemotherapy; seven patients had Crohn's disease; six were transplantation recipients; seven an immunodeficiency; four with Hirschsprung disease; two diagnoses of 'other'). Of the 200 identified patients, 149 (74.5%) had documentation of antibiotics in the previous two months (32 penicillins; 38 cephalosporins; three clindamycin, nine other single-agent, 59 multiple; eight not specified), and 111 (55.5%) had been hospitalized in the previous month. The symptoms of C difficile-associated diarrhea included bloody stools in 12.5% and frequent watery stools in 79%. Hospitalization was required in 27 of 116 outpatients; stay was prolonged in seven of the 84 patients already hospitalized. Fifty-five per cent received metronidazole, 34% were not treated, and treatment data were not available for the remainder. Recurrence occurred in 31% of those treated and retreatment consisted of vancomycin (15%), probiotics (15%) and cholestyramine (6%). No colectomies were required but two deaths occurred. CONCLUSIONS: The majority of pediatric patients developing symptomatic C difficile-associated diarrhea had antibiotic exposure or hospitalization within the previous one to two months. This is higher than previously reported. One-third had spontaneous symptom resolution. For those treated, recurrence rates were high. Mortality was significantly lower than described in adults, in agreement with prior literature.
Publication Types:
PMID: 16107901 [PubMed - indexed for MEDLINE]
- 4: Neurotoxicol Teratol. 2005 Sep-Oct;27(5):733-43. Epub 2005 Aug 15.
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Chronic biotoxin-associated illness: multiple-system symptoms, a vision deficit, and effective treatment.
Hudnell HK.
U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Neurotoxicology Division, MD:B105-05, Research Triangle Park, NC 27711, USA. hundell.ken@epa.gov
Blooms of toxigenic organisms have increased in spatial and temporal extent due to human activities and natural forces that alter ecologic habitats and pollute the environment. In aquatic environments, harmful algal blooms pose a risk for human health, the viability of organisms, and the sustainability of ecosystems. The estuarine dinoflagellate, Pfiesteria piscicida, was discovered in the late 1980s at North Carolina State University as a contaminant in fish cultures. P. piscicida was associated with fish death in laboratory aquaria, and illness among laboratory workers who inhaled the mist above aquaria. Both the fish and humans exhibited signs of toxicity. During the 1990s, large-scale mortality among fish and other aquatic organisms was associated with high concentrations of Pfiesteria sp. in estuaries on the eastern seaboard of North America from New York to Texas. Illness among humans was associated with direct exposure to estuaries and exposures to estuarine aerosols around the time of Pfiesteria-related fish kills. This review of the scientific literature on associations between Pfiesteria and human illness identified some of the possible mechanisms of action by which putative Pfiesteria toxins may have caused morbidity. Particular attention was given to the Pfiesteria-associated, human-illness syndrome known as Possible Estuary Associated Syndrome (PEAS). PEAS was characterized by multiple-system symptoms, deficits in neuropsychological tests of cognitive function, and rapid and severe decrements in visual contrast sensitivity (VCS), an indicator of neurologic function in the visual system. PEAS was diagnosed in acute and chronic illness cases, and was reacquired during re-exposure. Rapid normalization of PEAS signs and symptoms was achieved through the use of cholestyramine therapy. Cholestyramine, a non-absorbable polymer, has been used by humans to lower cholesterol levels since it was approved for that use by the U.S. Food and Drug Administration in 1958. When dissolved in water or juice and taken orally, cholestyramine binds with cholesterol, bile acids, and salts in the intestines, causing them to be eliminated rather than reabsorbed with bile during enterohepatic recirculation. Cholestyramine also has been reported to bind and eliminate a variety of toxic substances. The efficacy of cholestyramine therapy in treatment of PEAS supported the hypothesis that PEAS is a biotoxin-associated illness.
Publication Types:
PMID: 16102938 [PubMed - indexed for MEDLINE]
- 5: Food Addit Contam. 2005 Apr;22(4):379-88.
Recent advances on the use of adsorbent materials for detoxification of Fusarium mycotoxins.
Avantaggiato G, Solfrizzo M, Visconti A.
Institute of Sciences of Food Production, National Research Council, Bari, Italy. giuseppina.avantaggiato@ispa.cnr.it
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.
Publication Types:
PMID: 16019808 [PubMed - indexed for MEDLINE]
- 6: Neurotoxicol Teratol. 2005 Jan-Feb;27(1):29-46.
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A time-series study of sick building syndrome: chronic, biotoxin-associated illness from exposure to water-damaged buildings.
Shoemaker RC, House DE.
Chronic Fatigue Center, 500 Market Street, Suite 103, Pocomoke City, MD 21851, United States.
The human health risk for chronic illnesses involving multiple body systems following inhalation exposure to the indoor environments of water-damaged buildings (WDBs) has remained poorly characterized and the subject of intense controversy. The current study assessed the hypothesis that exposure to the indoor environments of WDBs with visible microbial colonization was associated with illness. The study used a cross-sectional design with assessments at five time points, and the interventions of cholestyramine (CSM) therapy, exposure avoidance following therapy, and reexposure to the buildings after illness resolution. The methodological approach included oral administration of questionnaires, medical examinations, laboratory analyses, pulmonary function testing, and measurements of visual function. Of the 21 study volunteers, 19 completed assessment at each of the five time points. Data at Time Point 1 indicated multiple symptoms involving at least four organ systems in all study participants, a restrictive respiratory condition in four participants, and abnormally low visual contrast sensitivity (VCS) in 18 participants. Serum leptin levels were abnormally high and alpha melanocyte stimulating hormone (MSH) levels were abnormally low. Assessments at Time Point 2, following 2 weeks of CSM therapy, indicated a highly significant improvement in health status. Improvement was maintained at Time Point 3, which followed exposure avoidance without therapy. Reexposure to the WDBs resulted in illness reacquisition in all participants within 1 to 7 days. Following another round of CSM therapy, assessments at Time Point 5 indicated a highly significant improvement in health status. The group-mean number of symptoms decreased from 14.9+/-0.8 S.E.M. at Time Point 1 to 1.2+/-0.3 S.E.M., and the VCS deficit of approximately 50% at Time Point 1 was fully resolved. Leptin and MSH levels showed statistically significant improvement. The results indicated that CSM was an effective therapeutic agent, that VCS was a sensitive and specific indicator of neurologic function, and that illness involved systemic and hypothalamic processes. Although the results supported the general hypothesis that illness was associated with exposure to the WDBs, this conclusion was tempered by several study limitations. Exposure to specific agents was not demonstrated, study participants were not randomly selected, and double-blinding procedures were not used. Additional human and animal studies are needed to confirm this conclusion, investigate the role of complex mixtures of bacteria, fungi, mycotoxins, endotoxins, and antigens in illness causation, and characterize modes of action. Such data will improve the assessment of human health risk from chronic exposure to WDBs.
Publication Types:
PMID: 15681119 [PubMed - indexed for MEDLINE]
- 7: Arch Anim Nutr. 2004 Aug;58(4):311-24.
In vitro studies on the evaluation of mycotoxin detoxifying agents for their efficacy on deoxynivalenol and zearalenone.
Dšll S, DŠnicke S, Valenta H, Flachowsky G.
Institute of Animal Nutrition, Federal Agricultural Research Centre (FAL), Braunschweig, Germany. susanne.doell@fal.de
A simple in vitro system was developed to study the efficacy of commercially available mycotoxin detoxifying agents and adsorbing substances as feed additives to detoxify deoxynivalenol (DON) and zearalenone (ZON) in situ. The in vitro model simulates the conditions (pH, temperature and transit time) of the porcine gastrointestinal tract, as pigs react most sensitively to these mycotoxins. The commercially available products were not effective in detoxifying DON and ZON under the applied conditions, while activated carbon was able to bind both toxins and cholestyramine, and a modified aluminosilicate showed good adsorption abilities for ZON. Data obtained in dose dependency studies showed an estimated adsorption capacity of cholestyramine and the modified aluminosilicate of 11.7 and 5.7 g ZON/kg detoxifying agent. The in vitro system deployed in the present study was demonstrated to be a simple, helpful tool in screening substances for their ability to detoxify DON and ZON under the simulated conditions of the porcine gastrointestinal tract. Nonetheless in vivo experiments are indispensable to proof the efficacy.
Publication Types:
PMID: 15570745 [PubMed - indexed for MEDLINE]
- 8: Curr Treat Options Neurol. 2004 Mar;6(2):115-123.
Marine Neurotoxins: Envenomations and Contact Toxins.
Watters MR, Stommel EW.
Department of Medicine, Division of Neurology, University of Hawaii, 1356 Lusitana Street, 7th Floor, Honolulu, HI 96813, USA. mwatters@hawaii.edu
Familiarity with the appearance and habitat of venomous sea creatures, the location of their stinging apparatus, and surveillance of population concentrations within recreational waters are essential in avoiding envenomations. Compared with the thermo-stable low molecular weighted ingestible seafood toxins, venomous toxins are often large molecular weight proteins and many are heat labile, which provides opportunity for therapeutic intervention. Heat therapy may denature the toxins, and provide immediate relief of pain in coelenterate and venomous fish envenomations. Injections of local anesthetic agents may also be used. First aid measures at the seashore may limit the spread of venom, and include immobilization of the affected sites, compression bandaging, and venous-lymphatic occlusive bandages. Measures to limit continued envenomation by attached stinging cells include topical vinegar for jellyfish tentacles and irrigation with debridment for spines of venomous fish. Antivenins are of limited availability and may be used for envenomations with sea snakes, Chironex box jellyfish, and some venomous fish. Sea snakes bites may be treated with antivenin from land snakes or with hemodialysis when antivenin is not available. Neuromuscular paralysis occurs with bites by sea snakes, cone snails, blue octopuses, and some jellyfish. Supportive treatment includes attention to cardiopulmonary resuscitation and intubation. Exposure to Pfeisteria may result in cognitive and behavioral abnormalities. Treatment with cholestyramine may be helpful in binding the toxin and improve recovery.
PMID: 14759344 [PubMed - as supplied by publisher]
- 9: Food Chem Toxicol. 2003 Oct;41(10):1283-90.
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Assessing the zearalenone-binding activity of adsorbent materials during passage through a dynamic in vitro gastrointestinal model.
Avantaggiato G, Havenaar R, Visconti A.
CNR Institute of Sciences of Food Production, I-70125 Bari, Italy. giuseppina.avantaggiato@ispa.cnr.it
A novel approach is presented herein to study the intestinal absorption of mycotoxins by using a laboratory model that mimics the metabolic processes of the gastrointestinal (GI) tract of healthy pigs. This model was used to evaluate the small-intestinal absorption of zearalenone from contaminated wheat (4.1 mg/kg) and the effectiveness of activated carbon and cholestyramine at four inclusion levels (0.25, 0.5, 1 and 2%) in reducing toxin absorption. Approximately 32% of ZEA intake (247 microg) was released from the food matrix during 6 h of digestion and was rapidly absorbed at intestinal level. A significant reduction of intestinal absorption of ZEA was found after inclusion of activated carbon or cholestyramine, even at the lowest dose of adsorbents, with a more pronounced effect exhibited by activated carbon. In particular, when 2% of activated carbon or cholestyramine was added to the meal the ZEA intestinal absorption was lowered from 32% of ZEA intake to 5 and 16%, respectively. The sequestering effect of both adsorbents took place already during the first 2 h of digestion and persisted during the rest of the experiment. The GI-model is a rapid and physiologically relevant method to test the efficacy of adsorbent materials in binding mycotoxins and can be used to pre-screen mycotoxin/adsorbent combinations as an alternative to animal experiments.
Publication Types:
PMID: 12909260 [PubMed - indexed for MEDLINE]
- 10: Mycopathologia. 2001;151(3):147-53.
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.
Istituto Tossine e Micotossine da Parassiti Vegetali, CNR, Bari, Italy. itmpms12@area.area.ba.cnr.it
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). 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.
Publication Types:
PMID: 11678589 [PubMed - indexed for MEDLINE]
- 11: Environ Health Perspect. 2001 Oct;109 Suppl 5:791-6.
Residential and recreational acquisition of possible estuary-associated syndrome: a new approach to successful diagnosis and treatment.
Shoemaker RC.
McCready Outpatient Services Center, Pocomoke City, Maryland 21851, USA. ritchieshoemaker@msn.com
Evidence suggests that the estuarine dinoflagellates, Pfiesteria piscicida Steidinger & Burkholder and P. shumwayae Glasgow & Burkholder, members of the toxic Pfiesteria complex (TPC), may release one or more toxins that kill fish and adversely affect human health. In the current study we investigated the potential for undiagnosed cases of possible estuary-associated syndrome (PEAS), as termed by the Centers for Disease Control and Prevention (CDC), in a population that had residential and/or recreational exposure to TPC-affected estuaries, but that did not have direct contact with fish kills or lesioned fish. Age-adjusted visual contrast sensitivity (VCS) was significantly lower and the presence of PEAS-associated symptoms was much higher in the estuary cohort (n = 77) than in combined-control cohorts (n = 87), one without exposure to bodies of water (n = 53) and one with exposure to marine waters (n = 34). In the estuary cohort, 37 individuals met the CDC case definition for PEAS and had significantly lower VCS than non-PEAS cases. The VCS improved and symptoms abated after 2 weeks of treatment with cholestyramine. Cholestyramine, the original drug approved for treatment of hypercholesterolemia, has previously been reported to enhance the elimination rates of a variety of toxins, presumably by interruption of enterohepatic recirculation through toxin entrapment in its polymeric structure and/or anion-exchange process. Control studies showed that repeated VCS testing alone did not improve VCS scores and that cholestyramine treatment did not affect VCS in patients with elevated cholesterol levels. These results suggested that a) susceptible individuals may acquire PEAS through residential and/or recreational contact with TPC-affected estuaries in the absence of an active fish kill; b) VCS is a useful indicator in PEAS diagnosis and treatment monitoring; and c) PEAS can be effectively treated with cholestyramine. Because the study did not use population sampling techniques, the results do not indicate PEAS prevalence. Furthermore, definitive diagnosis of PEAS and association with TPC toxin(s) must await identification of, and a serologic test for, the putative TPC toxin(s).
PMID: 11677191 [PubMed - indexed for MEDLINE]
- 12: Antimicrob Agents Chemother. 2001 Aug;45(8):2340-7.
GT160-246, a toxin binding polymer for treatment of Clostridium difficile colitis.
Kurtz CB, Cannon EP, Brezzani A, Pitruzzello M, Dinardo C, Rinard E, Acheson DW, Fitzpatrick R, Kelly P, Shackett K, Papoulis AT, Goddard PJ, Barker RH Jr, Palace GP, Klinger JD.
GelTex Pharmaceuticals, Inc., Waltham, Massachusetts 02451, USA. ckurtz@geltex.com
GT160-246, a high-molecular-weight soluble anionic polymer, was tested in vitro and in vivo for neutralization of Clostridium difficile toxin A and B activities. Five milligrams of GT160-246 per ml neutralized toxin-mediated inhibition of protein synthesis in Vero cells induced by 5 ng of toxin A per ml or 1.25 ng of toxin B per ml. In ligated rat ileal loops, 1 mg of GT160-246 neutralized fluid accumulation caused by 5 microg of toxin A. At doses as high as 80 mg/loop, cholestyramine provided incomplete neutralization of fluid accumulation caused by 5 microg of toxin A. GT160-246 protected 80% of the hamsters from mortality caused by infection with C. difficile, whereas cholestyramine protected only 10% of animals. Treatment of C. difficile-infected hamsters with metronidazole initially protected 100% of the hamsters from mortality, but upon removal of treatment, 80% of the hamsters had relapses and died. In contrast, removal of GT160-246 treatment did not result in disease relapse in the hamsters. GT160-246 showed no antimicrobial activity in tests with a panel of 16 aerobic bacteria and yeast and 22 anaerobic bacteria and did not interfere with the in vitro activities of most antibiotics. GT160-246 offers a novel, nonantimicrobial treatment of C. difficile disease in humans.
Publication Types:
PMID: 11451694 [PubMed - indexed for MEDLINE]
- 13: Environ Health Perspect. 2001 May;109(5):539-45.
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Comment in:
Possible estuary-associated syndrome: symptoms, vision, and treatment.
Shoemaker RC, Hudnell HK.
McCready Outpatient Services Center, Pocomoke City, Maryland, USA.
The human illness designated as possible estuarine-associated syndrome (PEAS) by the Centers for Disease Control and Prevention (CDC) has been associated with exposure to estuaries inhabited by toxin-forming dinoflagellates, including members of the fish-killing toxic Pfiesteria complex (TPC), Pfiesteria piscicida and Pfiesteria shumwayae. Humans may be exposed through direct contact with estuarine water or by inhalation of aerosolized or volatilized toxin(s). The five cases reported here demonstrate the full spectrum of symptoms experienced during acute and chronic stages of this suspected neurotoxin-mediated illness. The nonspecific symptoms most commonly reported are cough, secretory diarrhea, headache, fatigue, memory impairment, rash, difficulty in concentrating, light sensitivity, burning skin upon water contact, muscle ache, and abdominal pain. Less frequently encountered symptoms are upper airway obstruction, shortness of breath, confusion, red or tearing eyes, weakness, and vertigo. Some patients experience as few as four of these symptoms. The discovery that an indicator of visual pattern-detection ability, visual contrast sensitivity (VCS), is sharply reduced in affected individuals has provided an objective indicator that is useful in diagnosing and monitoring PEAS. VCS deficits are present in both acute and chronic PEAS, and VCS recovers during cholestyramine treatment coincident with symptom abatement. Although PEAS cannot yet be definitively associated with TPC exposure, resolution with cholestyramine treatment suggests a neurotoxin-mediated illness.
Publication Types:
PMID: 11401768 [PubMed - indexed for MEDLINE]
- 14: Biochim Biophys Acta. 2001 Mar 9;1546(1):171-84.
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Analysis of the physicochemical interactions between Clostridium difficile toxins and cholestyramine using liquid chromatography with post-column derivatization.
Palace GP, Lazari P, Norton K.
Analytical Chemistry Department, GelTex Pharmaceuticals, Inc., 153 Second Avenue, Waltham, MA 02451, USA. gpalace@geltex.com
A potential therapy for antibiotic-associated pseudomembranous colitis is to bind Clostridium difficile toxins A and B using cholestyramine, a hydrophobic anion exchange medium. Frontal analysis in isotonic phosphate buffer was studied using post-column derivatization with o-phthalaldehyde, which gave a highly sensitive (> or =30 ng) flow-through analysis. Following load (1.5-3.0 microg toxin/3.6 mg), toxin A was bound at a slightly higher capacity than B, due to slower kinetics. A salt gradient eluted roughly 20% of bound toxin A with 0.6 M NaCl and toxin B with 1.1 M NaCl, hence toxin A showed weaker electrostatic affinity. The remainder of toxin A (65%) and some of toxin B (10% out of 50%) were eluted using a subsequent gradient to 60% acetonitrile in normal saline, which measured predominantly hydrophobic binding. Low and high affinity populations of both toxins were observed. Glycocholic acid or amino acids were competitive binders, although these components had little effect on the toxin A population bound primarily through ionic interactions. Competitive protein constituents in hamster cecal contents were also profiled. These results help to explain the variable clinical response in using cholestyramine to treat colitis. Using quaternary amine-polyhydroxymethacrylate (PHM) ion exchange chromatography, a trend for increased binding at higher pH was observed, especially for toxin A. Binding to strong cation exchange resins (sulfonate-PHM) was not observed. A range of reversed phase media retained both toxins, although recovery was very poor relative to protein standards. Size exclusion chromatography with light scattering detection showed that toxin B exists in different aggregation states, while toxin A remains monomeric.
Publication Types:
PMID: 11257520 [PubMed - indexed for MEDLINE]
- 15: 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 A, Barriault C, Marquardt RR, Frohlich AA, Yousef IM, Zhu XX, Tuchweber B.
Department of Nutrition, UniversitŽ de MontrŽal, QuŽbec, Canada.
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.
Publication Types:
PMID: 10606152 [PubMed - indexed for MEDLINE]
- 16: Hepatogastroenterology. 1999 Jan-Feb;46(25):343-8.
The diagnosis and treatment of Clostridium difficile in antibiotic-associated diarrhea.
Gorenek L, Dizer U, Besirbellioglu B, Eyigun CP, Hacibektasoglu A, Van Thiel DH.
Department of Infectious Diseases, Gulhane Military Medical Academy, Ankara, Turkey.
BACKGROUND/AIMS: This study was initiated to evaluate the role of C. difficile in diarrhea associated with the use of antibiotics, to determine which antibiotics are most often responsible, to characterize the response to several different treatment regimens, and to define the relapse rate as seen in a large teaching hospital in Turkey. METHODOLOGY: Three different patient groups were studied. The first group consisted of 154 individuals with antibiotic-associated diarrhea. The stools of all 154 cases were cultured on cycloserine-cefoxitin-fructose agar (CCFA). If any bacteria grew out, they were identified specifically as C. difficile using a commercially available latex agglutination kit specific for bacterial antigens of C. difficile (MicroScreen C. difficile Latex Slide Test; Merica Diagnostic Limited, Guilford, England). The presence of toxin-A (CDTA) was determined using a MicroScreen CDTA Enzyme Immunoassay kit. RESULTS: The stools of 31 of these patients grew out enteric pathogens. Twenty-eight of these 31 were CCFA positive. Three different drug regimens (Ornidazole, Ornidazole + Cholestyramine, and Vancomycin) were used to treat these 28 C. difficile positive cases. The second group consisted of 37 hospitalized patients who had been in hospital for more than 30 days without any gastrointestinal symptoms. This group was used to identify the in-hospital carrier rate for C. difficile. Stools from these 37 cases were cultured on CCFA and were analyzed for the presence of CDTA by EIA. Colonization with C. difficile was detected in 4 cases. The third group consisted of 40 healthy subjects who served as a population-based control group. The stools obtained from these 40 cases were cultured on CCFA and analyzed for CDTA as were the stools for the other 2 groups. None were CDTA positive. One case was positive for the presence of non-toxigenic C. difficile. CONCLUSIONS: It can be concluded from these data that, in Turkey, C. difficile is responsible for 20% of antibiotic-associated diarrheas. Lincomycin, Azithromycin and Ampicillin were most often associated with the development of antibiotic-associated diarrhea. Ornidazole and Vancomycin were effective agents for C. difficile-associated diarrhea with the latter agent being associated with no relapses.
Publication Types:
PMID: 10228818 [PubMed - indexed for MEDLINE]
- 17: Artif Organs. 1999 Apr;23(4):310-8.
Cytokines and endotoxin removal by sorbents and its application in push-pull sorbent-based pheresis: the BioLogic-DTPF System.
Steczko J, Ash SR, Blake DE, Carr DJ, Bosley RH.
HemoCleanse, Inc., West Lafayette, IN 47906, USA. jsteczko@hemocleanse.com
The BioLogic-DTPF System (DTPF) combines the Biologic-DT hemodiabsorption system (DT) in series with the Biologic PF push-pull pheresis system (PF) in which PF membranes separate plasma for direct contact between plasma proteins and the sorbents. Preliminary studies conducted in bovine serum albumin (BSA) solution and in bovine plasma allowed charcoal and silica to be evaluated as adsorbents for the PF module. Equilibrium binding experiments in BSA showed a high capacity of cytokine (IL-1 beta, TNF alpha) binding by powdered charcoal, 70-90 ng/g. Kinetic binding studies in bovine plasma revealed relatively quick adsorption of IL-1 beta and IL-6 by charcoal with the capacity range of 1.2-2.0 ng/g for tested cytokines (IL-1 beta and TNF alpha). Further laboratory studies with plasma have shown that powdered silica has an even greater binding capacity, up to 13 ng/g for TNF alpha depending upon particle size, and more rapid binding for all tested cytokines than powdered charcoal. Cholestyramine is a more efficient sorbent for removal of endotoxin than either charcoal or silica. In vitro tests using whole blood have demonstrated that the DTPF, with powdered charcoal as the sorbent, clears cytokines (TNF alpha, IL-1 beta, and IL-6) at 12.6-23.4 ml/min, bilirubin at 17.8-34.7 ml/min, and creatinine at 53.6-82.6 ml/min. The removal of some cytokines during the first clinical trial is also discussed.
PMID: 10226695 [PubMed - indexed for MEDLINE]
- 18: Md Med J. 1998 Feb-Mar;47(2):64-6.
Treatment of persistent Pfiesteria-human illness syndrome.
Shoemaker R.
Patients with exposure to Pfiesteria toxin have developed an illness, Pfiesteria-human illness syndrome, characterized by skin lesions, headache, myalgias, conjunctival irritation, bronchospasm, abdominal pain, secretory diarrhea, recent memory loss, and difficulties with number sequencing. Not all patients demonstrated all features of the syndrome. The natural history of Pfiesteria-human illness syndrome shows that most patients' symptoms improve without treatment. This article reports the improvement of symptoms that had persisted for over one month in five patients, which the author attributes to treatment with cholestyramine. These patients were self-referred to the Pocomoke River Rash and Associated Illness Center, a clinic that opened on August 6, 1997, in response to the need for a central facility for diagnosis of human illness acquired from Pfiesteria. Until the Pfiesteria toxin(s) is isolated and characterized, and laboratory diagnostic tests are available, physicians must be able to recognize Pfiesteria-human illness syndrome and intervene when symptoms, particularly memory loss and diarrhea, cause significant impairment in daily activities. There are no precedents for the treatment of Pfiesteria or any dinoflagellate toxin-related human illness reported in the literature. The successful use of cholestyramine reported here may provide a model for understanding dinoflagellate toxin physiology in the human body. This paper reports an uncontrolled observational study. When identification of the toxin is completed, a basis for properly controlled studies will be available.
Publication Types:
PMID: 9524412 [PubMed - indexed for MEDLINE]
- 19: J Toxicol Environ Health A. 1998 Feb 6;53(3):231-50.
Dietary cholestyramine reduces ochratoxin A-induced nephrotoxicity in the rat by decreasing plasma levels and enhancing fecal excretion of the toxin.
Kerkadi A, Barriault C, Tuchweber B, Frohlich AA, Marquardt RR, Bouchard G, Yousef IM.
DŽpartement de Nutrition, UniversitŽ de MontrŽal, QuŽbec, Canada.
Ochratoxin A (OTA) is a mycotoxin that may contaminate animal feed (oat, barley, and rye) and food (wheat, rice, coffee, beer, pig meat), leading to major health problems (e.g., nephropathy) in several animal species including humans. Several methods have been tested to reduce the toxicity of OTA in animals but with limited success. In rats, the effect of cholestyramine (CHA), a bile acid-binding resin, was investigated on OTA-induced nephrotoxicity and bioavailability. Animals were fed semisynthetic diets containing two levels of OTA: 1 or 3 ppm. At each level of OTA, the diets were enriched with 0.1, 1, and 5% of CHA. The results showed that CHA decreased the concentration of OTA in plasma. At 1 and 3 ppm of OTA in the diet, CHA is effective at a level of 0.1% and 5%, respectively. The excretion of OTA and its metabolites (ochratoxin alpha and hydroxylated ochratoxin A) in bile and urine was also decreased by addition of 5% CHA in the diet. This was associated with an increase of OTA excretion in feces. Enzymuria and renal morphology revealed that dietary CHA can decrease OTA-induced nephrotoxicity, probably by reducing renal exposure to the toxin. In conclusion, CHA can reduce OTA concentrations in plasma as well as reducing nephrotoxicity, which may be attributed to a decrease of bioavailability and/or enterohepatic circulation of the toxin.
Publication Types:
PMID: 9482354 [PubMed - indexed for MEDLINE]
- 20: Ann Surg. 1997 Apr;225(4):391-400.
Gut endotoxin restriction prevents catabolic changes in glutamine metabolism after surgery in the bile duct-ligated rat.
Houdijk AP, Teerlink T, Bloemers FW, Wesdorp RI, van Leeuwen PA.
Department of Surgery, Free University Hospital, Amsterdam, The Netherlands.
OBJECTIVE: The objective of this study was to investigate the role of gut-derived endotoxemia in postoperative glutamine (GLN) metabolism of bile duct-ligated rats. SUMMARY BACKGROUND DATA: Postoperative complications in patients with obstructive jaundice are associated with gut-derived endotoxemia. In experimental endotoxemia, catabolic changes in GLN metabolism have been reported. Glutamine balance is considered important in preventing postsurgical complications. METHODS: Male Wistar rats were treated orally with the endotoxin binder cholestyramine (n = 24, 150 mg/day) or saline (n = 24). On day 7, groups received a SHAM operation or a bile duct ligation (BDL). On day 21, all rats were subjected to a laparotomy followed 24 hours later by blood flow measurements and blood sampling. Glutamine organ handling was determined for the gut, liver, and one hindlimb. Intracellular GLN muscle concentrations were determined. RESULTS: Compared to the SHAM groups, BDL rats showed lower gut uptake of GLN (28%, p < 0.05); a reversal of liver GLN release to an uptake (p < 0.05); higher GLN release from the hindlimb (p < 0.05); and lower intracellular muscle GLN concentration (32%, p < 0.05). Cholestyramine treatment in BDL rats maintained GLN organ handling and muscle GLN concentrations at SHAM levels. CONCLUSIONS: Disturbances in postoperative GLN metabolism in BDL rats can be prevented by gut endotoxin restriction. Gut-derived endotoxemia after surgery in obstructive jaundice dictates GLN metabolism.
PMID: 9114798 [PubMed - indexed for MEDLINE]
- 21: Scand J Gastroenterol Suppl. 1997;222:93-7.
Perioperative anti-endotoxin strategies.
Houdijk AP, Meijer C, Cuesta MA, Meyer S, Van Leeuwen PA.
Dept. of Surgery, Free University Hospital, Amsterdam, The Netherlands.
Lipopolysaccharides from the outer membrane of Gram-negative bacteria are potent stimuli for the production of numerous cytokines by the immune cells. The systemic inflammatory response to these gut-derived endotoxins is therefore dependent on the responsiveness of the immune system. This paper presents results on anti-endotoxin strategies and the responsiveness to endotoxin in animal models of liver failure. Following partial hepatectomy in the normal rat, anti-endotoxin treatment using the enteral endotoxin binder cholestyramine and the bactericidal permeability-increasing protein showed beneficial effects in terms of reducing the exaggerated metabolic and inflammatory responses. Similar beneficial effects of gut endotoxin restriction were found in bile duct ligated rats subjected to a laparotomy. The beneficial effects of anti-endotoxin strategies in these models were explained by completely different mechanisms. In partial hepatectomized rats the effects were explained by the direct inhibition of the stimulatory action of endotoxin on immune cells preventing an exaggerated inflammatory response. In contrast, in postoperative BDL rats the effects of anti-endotoxin therapy were explained by the restoration of endotoxin sensitivity of the immune cells resulting in an inflammatory response necessary for an adequate reaction to surgery. These different mechanism will be discussed in the light of the phenomenon of endotoxin tolerance.
Publication Types:
PMID: 9145457 [PubMed - indexed for MEDLINE]
- 22: Am J Physiol. 1996 Dec;271(6 Pt 1):G980-6.
Tumor necrosis factor unresponsiveness after surgery in bile duct-ligated rats.
Houdijk AP, Boermeester MA, Wesdorp RI, Hack CE, Van Leeuwen PA.
Department of Surgery, Free University Hospital, Central Laboratory of The Netherlands, Red Cross Blood Transfusion Service, Amsterdam, The Netherlands.
In obstructive jaundice, postoperative complications are related to gut-derived endotoxemia and possibly mediated by cytokines such as tumor necrosis factor (TNF) and interleukin-6 (IL-6). This study investigated the course of IL-6 and TNF after surgery in bile duct-ligated rats (BDL) treated with and without an enteral endotoxin binder (cholestyramine). Endotoxin in rat plasma was determined by blocking cytokine production in whole blood cell cultures stimulated by rat plasma using antibodies directed against the endotoxin (CD14) receptor. Surgery elicited a significant IL-6 response in saline-treated BDL rats (BDL-SAL). TNF, however, remained at its low preoperative levels. Cholestyramine treatment resulted in undetectable preoperative TNF and IL-6 levels, but levels of both cytokines were significantly raised after surgery. Endotoxin, as determined by the CD14 blockade test, was identified in the BDL-SAL group, before (time 0) and after surgery (2 and 4 h), whereas in the cholestyramine group endotoxin was only present at 2 h after surgery. The lack of a postoperative plasma TNF response in the BDL-SAL group in the continuous presence of endotoxin suggests endotoxin tolerance for TNF production in obstructive jaundice.
Publication Types:
PMID: 8997241 [PubMed - indexed for MEDLINE]
- 23: J Clin Gastroenterol. 1996 Apr;22(3):186-9.
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Whole-bowel irrigation as an adjunct to the treatment of chronic, relapsing Clostridium difficile colitis.
Liacouras CA, Piccoli DA.
Division of Gastroenterology and Nutrition, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, PA 19104, USA.
We report the successful treatment of two patients with chronic, intractable Clostridium difficile infection using whole-bowel irrigation with a polyethylene glycol solution (Golytely) as adjunctive therapy. Before this treatment, both patients had recurrent symptoms of diarrhea, weight loss, abdominal pain, and documented C. difficile toxin-positive stools despite multiple pharmacologic treatments. Each child was prescribed myriad drug therapies, including vancomycin, metronidazole, bacitracin, and rifampin. Cholestyramine and lactobacillus were also tried alone and in combination with antibiotics. In each case, symptoms recurred shortly after cessation of therapy. Whole-bowel irrigation was subsequently administered until profuse, clear liquid stools were produced. This treatment was followed by a 3-week course of oral vancomycin and lactobacillus. In both cases, the patient became asymptomatic within 3 days of therapy; they have remained symptom-free for 36 and 48 months, respectively. We suggest that whole-bowel irrigation clears active C. difficile organisms, toxins, and spores from the intestine and is effective as an adjunct to routine therapy for chronic, relapsing C. difficile infections.
Publication Types:
PMID: 8724255 [PubMed - indexed for MEDLINE]
- 24: Toxicol Lett. 1995 Dec;82-83:869-77.
Prevention of nephrotoxicity of ochratoxin A, a food contaminant.
Creppy EE, Baudrimont I, Betbeder AM.
Toxicology Department, University of Bordeaux, France.
Ochratoxin A (OTA) is a mycotoxin produced by ubiquitous Aspergilli, mainly by Aspergillus ochraceus and also by Penicilium verrucosum. It was found all over the world in feed and human food and blood as well as in animal blood and tissues. The most threatening effects of OTA are its nephrotoxicity and carcinogenicity, since this mycotoxin is nephrotoxic to all animal species studied so far and is increasingly involved in the Balkan endemic nephropathy (BEN), a human chronic interstitial nephropathy which is most of the time associated to urinary tract tumours. Since it seems impossible to avoid contamination of foodstuffs by toxigenic fungi, detoxification and detoxication for OTA are needed. To reduce or abolish the OTA-induced toxic effects, several mechanisms were investigated. The results of these investigations showed that some of the potential antidotes were efficient in preventing the main OTA toxic effects whereas some others were not. Promising compounds are structural analogues of OTA, and/or compounds having a high binding affinity for plasma proteins such as piroxicam, a non-steroidal anti-inflammatory drug (NSAID). Some enzymes such as superoxide dismutase (SOD) and catalase, radical scavengers, vitamins, prostaglandin (PG) synthesis inhibitors, (such as piroxicam), pH modificators, adsorbant resin such as cholestyramine etc. are efficient in vivo. Some of the results obtained in vivo were already confirmed in vitro and gave useful information on how to safely use these antidotes. The most generally acting compound seems to be A19 (Aspartame), a structural analogue of OTA and phenylalanine. When given to rats A19 (25 mg/kg/48 h) combined to OTA (289 micrograms/kg/48 h) for several weeks largely prevented OTA nephrotoxicity and genotoxicity. When given after intoxication of animals with OTA it washes out the toxin efficiently from the body. In vitro, A19 (10 micrograms/ml) prevents OTA (20-500 micrograms/ml) binding to plasma proteins. Its general action without any known side effect in humans and in animals, points at A19 to be the best candidate for preventing the OTA-induced subchronic effects.
Publication Types:
PMID: 8597155 [PubMed - indexed for MEDLINE]
- 25: Ann Surg. 1995 Mar;221(3):282-90.
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Pretreatment with enteral cholestyramine prevents suppression of the cellular immune system after partial hepatectomy.
Van Leeuwen PA,