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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.

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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]

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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]

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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]

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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]

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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]

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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]

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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]

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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]

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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]

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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]

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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]

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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.

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PMID: 11451694 [PubMed - indexed for MEDLINE]

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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]

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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]

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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.

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PMID: 10606152 [PubMed - indexed for MEDLINE]

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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]

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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]

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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]

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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]

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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]

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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]

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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]

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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]

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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]

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Pretreatment with enteral cholestyramine prevents suppression of the cellular immune system after partial hepatectomy.

Van Leeuwen PA, Boermeester MA, Houdijk AP, Meyer S, Cuesta MA, Wesdorp RI, Rodrick ML, Wilmore DW.

Department of Surgery, Free University Hospital, Amsterdam, The Netherlands.

OBJECTIVE: The authors tested the hypothesis that the beneficial effects of the endotoxin-binding agent cholestyramine on the postoperative course in rats that had undergone a partial hepatectomy was the result of improvement of cellular immune functions. SUMMARY BACKGROUND DATA: Major liver resection is associated with severe postoperative complications and a high incidence of systemic infections. Gut-derived endotoxins previously were shown to be involved in the pathogenic processes after partial hepatectomy in rats. In addition, enteral cholestyramine improved postoperative survival, but how its beneficial effects are mediated is not clear. METHODS: Rats that were force-fed for 7 days with either cholestyramine (150 mg/day) or 0.9% saline (equal volume) were randomized to undergo a partial hepatectomy or a sham operation. After 24 hours, the rats were killed and splenic mononuclear cells were tested in vitro for mitogenic responses and cytokine production. RESULTS: Proliferative responses of splenic B and T lymphocytes and lipopolysaccharide-stimulated production of tumor necrosis factor and interleukin-1 by splenocytes were lower in rats after partial hepatectomy than in sham-operated animals. An increased concanavalin A-stimulated production of interleukin-2 also was found after partial hepatectomy compared with sham levels. Pretreatment with enteral cholestyramine preserved cellular proliferative responsiveness of both B and T cells, and restored cytokine production by splenocytes to sham levels. CONCLUSION: Prophylactic treatment with enteral cholestyramine preserved cellular immune functions after partial hepatectomy in the rat, which may explain its beneficial effects on the postoperative course. Furthermore, the authors' results are consistent with the hypothesis that endotoxemia is involved in the pathogenesis of the cellular immune derangements after partial hepatectomy.

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PMID: 7717782 [PubMed - indexed for MEDLINE]

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Effectiveness of cholestyramine in the detoxification of zearalenone as determined in mice.

Underhill KL, Rotter BA, Thompson BK, Prelusky DB, Trenholm HL.

Centre for Food and Animal Research, Agriculture and Agri-Food Canada, Ottawa, Ontario.

Publication Types:
PMID: 7756775 [PubMed - indexed for MEDLINE]

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Effect of bile salt binding or protease inactivation on plasma cholecystokinin and gallbladder responses to bombesin.

Thimister PW, Hopman WP, Sloots CE, Rosenbusch G, Tangerman A, Willems HL, Lamers CB, Jansen JB.

Department of Gastroenterology, University Hospital, Nijmegen, The Netherlands.

BACKGROUND/AIMS: Bombesin-stimulated plasma cholecystokinin levels decrease after an initial increase despite continuous infusion of bombesin. The aim of this study was to determine if a feedback mechanism, mediated by bile salts or proteolytic enzymes, is responsible for this decline. METHODS: Bombesin (1.0 ng.kg-1.min-1) was infused into volunteers for 180 minutes on separate occasions. Cholestyramine, colestipol, camostate, or saline were perfused intraduodenally during the second hour of the tests. Cholestyramine was also administered without infusion of bombesin. RESULTS: Colestipol and cholestyramine, dependent on their bile salt-binding capacity, markedly enhanced (P < 0.05) bombesin-stimulated plasma cholecystokinin from 2.1 +/- 0.5 pmol/L to 6.4 +/- 2.2 pmol/L and 12.1 +/- 3.3 pmol/L (P < 0.05 vs. colestipol), respectively, and further decreased gallbladder volume (P < 0.05) from 9.4 +/- 1.6 mL to 2.0 +/- 0.4 mL and 2.2 +/- 0.5 mL, respectively. The protease inhibitor camostate had no effect. Bile salt precipitation also enhanced plasma pancreatic polypeptide responses (P < 0.01) but did not alter gastrin responses. Plasma cholecystokinin responses to cholestyramine without bombesin infusion varied considerably, but increments were highly correlated to decreases in gallbladder volume (r = 0.91; P < 0.005). CONCLUSIONS: Bile salt sequestration but not protease inactivation enhances plasma cholecystokinin and gallbladder responses to bombesin infusion in humans.

PMID: 7958672 [PubMed - indexed for MEDLINE]

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Luminal bile salts and neurotensin release in the isolated vascularly perfused rat jejuno-ileum.

Dakka T, Dumoulin V, Chayvialle JA, Cuber JC.

INSERM U-45, H™pital E. Herriot, Lyon, France.

Bile salts in the distal small intestine are strong stimulants of neurotensin (NT) release, but the underlying mechanisms are not known. They were investigated using an isolated vascularly perfused rat jejuno-ileum preparation. Luminal administration of crude ox bile extract (0.25-1.5%, wt/vol) produced a dose-dependent release of NT-like immunoreactivity (NT-LI), with a maximal effect after infusion of 1% bile extract (500% of basal). Pretreatment of the 1% bile extract with the bile salt-sequestering resin cholestyramine (2%, wt/vol) abolished NT-LI release. Taurocholate (TC), the major bile salt in rats, dose dependently increased the release of NT. The maximal secretion of NT-LI was observed after infusion of 20 mM TC (400% of basal). Taurodeoxycholate (20 mM) was as potent as TC in stimulating NT-LI release, but the threshold concentration of taurodeoxycholate for NT-LI secretion was lower than that of TC. Glycocholate and cholate were 2- to 3-fold less potent than TC in releasing NT-LI over the concentration range 5-20 mM. Luminal infusion of oleic acid (sodium salt; 100 mM) increased by 100% the level of NT-LI in the portal effluent, whereas 20 mM oleate had no effect. In contrast, the micellar form of oleic acid (20 and 100 mM) in bile extract (1%) or TC (20 mM) dose dependently reduced the release of NT-LI induced by bile extract or TC alone. Neither intraarterial tetrodotoxin (10(-6) M), EGTA (2 mM), verapamil (5 x 10(-5) M), nor atropine (10(-5) M) had any effect on TC-induced NT-LI release. These results show that the tauro-conjugated forms of cholic and deoxycholic acid are strong stimulants of NT-LI release. The N-cell response is blunted when bile salts are complexed in the lumen by oleic acid. Finally, bile salt-induced NT-LI release is not mediated by intramural nerves and is not dependent on the activation of calcium channels.

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PMID: 8299558 [PubMed - indexed for MEDLINE]

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Collagenous colitis: are bacterial cytotoxins responsible?

Andersen T, Andersen JR, Tvede M, Franzmann MB.

Department of Internal Medicine F, Gentofte County Hospital, Denmark.

In a case of collagenous colitis, cholestyramine treatment resulted in symptomatic and histological normalization. After discontinuation of cholestyramine, collagenous colitis relapsed. At this time fecal cytotoxic activity was demonstrated in McCoy cell lines. Symptoms, histologic changes, and cytotoxicity disappeared when cholestyramine treatment was reinstituted. We hypothesize that a bacterial toxin is responsible for the development of collagenous colitis.

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PMID: 8438843 [PubMed - indexed for MEDLINE]

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Multiple relapses of Clostridium difficile-associated diarrhea in a cancer patient. Successful control with long-term cholestyramine therapy.

Moncino MD, Falletta JM.

Department of Pediatrics, University of Louisville, Kentucky.

Clostridium difficile-associated diarrhea (CDAD) is caused by a toxin elaborated by the anaerobic organism Clostridium difficile. Although the vast majority of CDAD cases are now associated with antibiotic use, the administration of antineoplastic agents alone can result in clinical manifestations. While therapy with oral vancomycin is usually successful, one quarter of patients will relapse. We describe a 16-year-old girl with osteogenic sarcoma whose therapy was significantly complicated by multiple relapses of CDAD. All resulted in hospital admission. She failed several standard therapies for relapsed CDAD and was cured only after prolonged cholestyramine therapy. A subset of multiply relapsed CDAD patients may require prolonged therapy with cholestyramine to control the disease.

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PMID: 1456403 [PubMed - indexed for MEDLINE]

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Effect of dietary cholestyramine on the elimination pattern of ochratoxin A in rats.

Madhyastha MS, Frohlich AA, Marquardt RR.

Department of Animal Science, University of Manitoba Winnipeg, Canada.

Three experiments with rats established the effects of dietary cholestyramine on the disposition of ochratoxin A (OA) and its hydrolysed metabolite, alpha-ochratoxin (O alpha). In the first experiment OA (1 mg/kg) was incorporated into a diet that contained 0, 0.5, 1.0 and 2.0% cholestyramine. Cholestyramine markedly reduced blood concentrations of OA (1.6 to 0.75 micrograms/ml, P less than 0.0001) for all concentrations of the resin. The second experiment demonstrated that 2% cholestyramine added to the diet of rats markedly reduced cumulative urinary OA excretion (26 to 6 micrograms, P less than 0.01) and increased cumulative faecal OA excretion (8 to 38 micrograms, P less than 0.001). The third experiment established the efficacy of cholestyramine (2%) when added to diets containing two concentrations (0 and 6%) of a saturated fat (tallow). The bioavailability of OA as determined by area under the blood concentration curve over 216 hr was 424 micrograms/ml/hr for the control rats and 186 micrograms/ml/hr for the cholestyramine-treated rats (P less than 0.0001). Cholestyramine treatment increased the recovery of OA plus O alpha in the faeces plus urine over a 5-day period from 65.5 to 96.2% (P less than 0.0001). Cholestyramine also greatly increased the amount of OA plus O alpha and particularly of OA excretion in the faeces (105 to 160 micrograms, P less than 0.0001 for OA plus O alpha and 82 to 150 micrograms, P less than 0.0001 for OA) and resulted in a corresponding decrease in the excretion of these compounds in the urine. The concentration of fat in the diet had a much less dramatic effect than cholestyramine, was mainly detected in the urine and was affected by an interaction with cholestyramine (P less than 0.0001). Cholestyramine greatly reduced the concentration of OA plus O alpha (37 v. 8 micrograms) when the content of dietary fat was low but to a much lesser degree when it was high (19 v. 12 micrograms). These results suggest that the concentration of fat in the diet may affect the pattern of OA excretion in the urine. Cholestyramine added to the diet greatly increases the amount of OA eliminated in the faeces and reduces the amount in the urine, and as a result it decreases the amount present in the systemic circulation.

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PMID: 1398352 [PubMed - indexed for MEDLINE]

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Hepatic failure and coma after liver resection is reversed by manipulation of gut contents: the role of endotoxin.

van Leeuwen PA, Hong RW, Rounds JD, Rodrick ML, Wilmore D.

Laboratory for Surgical Metabolism and Nutrition, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115.

Despite significant improvements in the surgical care of patients, hepatic failure after extensive liver resection continues to be associated with a high morbidity and death. We postulated that hepatic failure after liver resection was related to gut-derived endotoxemia. Rats were randomized to receive oral gavage twice daily with one of the following preparations: (1) 0.9% saline; (2) neomycin sulfate and cefazolin; (3) cholestyramine; (4) lactulose. After 7 days of gavage, animals underwent either a two-thirds partial hepatectomy or sham operation. At time 0 (preresection), 10, 20, and 30 hours after resection, aortic blood was obtained for determination of ammonia, glutamine, and endotoxin levels. In selected animals, portal vein or inferior caval blood was obtained simultaneously with the aortic sample to evaluate the glutamine and ammonia exchange across the intestine and hind limb. Germ-free rats also underwent a partial hepatectomy or sham operation, and blood was obtained for glutamine and ammonia exchange at 0 and 20 hours after resection. Hepatectomy in the saline-pretreated rats resulted in a sixfold increase in plasma glutamine, increased uptake of glutamine and release of ammonia by the gut, increased release of glutamine by the hind-limb, and a high mortality rate. Pretreatment with agents that altered gut contents reduced the endotoxemia, maintained normal glutamine and ammonia levels, and reduced the mortality rate. Germ-free rats had a similar response to that seen in treated animals. Altering the gut contents in this model reduced the level of endotoxemia, blunted the catabolic response, and enhanced survival.

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PMID: 1858027 [PubMed - indexed for MEDLINE]

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[Cholestyramine adsorbs Escherichia coli and Vibrio cholerae toxins by way of ion exchange mechanism]

[Article in French]

Brouillard MY, Rateau JG.

Laboratoires Allard: Questran, FacultŽ de MŽdecine St-Antoine, Paris.

The use of cholestyramine in the treatment of enterocolitis is justified by its ability to fix the LT toxin of Vibrio cholerae and ETEC, the ST toxin of ETEC and the verotoxin of EHEC at the pH of intestinal fluid. To elucidate the nature of the ion-exchange mechanism in the binding of the toxins on the resin, we try to eluate the toxins with 0.1 M to 0.9 M NaCl solution at pH 7. Irrespective of their presence or absence in the different fractions, the biological activity of the toxins was assessed in cell culture and in the new-born mouse test. Desorption of the LT toxin from Vibrio cholerae is obtained with 0.6 M to 0.8 M of NaCl, with 0.3 M to 0.5 M of NaCl for the LT, 0.4 M to 0.5 M for the VT and 0.6 M for the TS toxins. The eluated toxins are biologically active; these facts demonstrate that the adsorption of toxin on cholestyramine result of a ion-exchange mechanism.

Publication Types:
PMID: 2181919 [PubMed - indexed for MEDLINE]

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Multiple relapses of Clostridium difficile-associated diarrhea responding to an extended course of cholestyramine.

Pruksananonda P, Powell KR.

University of Rochester, School of Medicine and Dentistry, Department of Pediatrics, NY 14642.

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PMID: 2496393 [PubMed - indexed for MEDLINE]

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A model system for studying the bioavailability of intestinally administered microcystin-LR, a hepatotoxic peptide from the cyanobacterium Microcystis aeruginosa.

Dahlem AM, Hassan AS, Swanson SP, Carmichael WW, Beasley VR.

Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois, Urbana 61801.

Sprague-Dawley rats were used to evaluate a model system for studying the hepatotoxicity caused by microcystin-LR (MCYST-LR), a toxin produced by the cyanobacterium (blue-green alga) Microcystis aeruginosa, and for evaluating the in vivo therapeutic potential of cholestyramine resin (CTR) which was found to bind the toxin in vitro. Female rats were treated with either toxin or an equivalent volume of the saline vehicle by direct administration into the lumen of an in situ isolated ileal loop. Male rats were dosed with toxin as described above, and then animals were dosed in the ileal loop with either cholestyramine resin (CTR, 50 mg/rat) or an equivalent vehicle. The survivors in both studies were killed six hours after dosing and hepatotoxicity was assessed by change in relative liver weights. In all groups given toxin alone, there was a significant increase in liver weight and males and females were equally susceptible. Liver weights of the toxin plus CTR treated rats were similar to those in vehicle-treated rats. When the toxin was administered into a similarly isolated jejunal loop, liver weight was significantly less than that found when an equivalent dose was administered into the ileal loop suggesting an intestinal site specificity for toxin absorption.

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PMID: 2502775 [PubMed - indexed for MEDLINE]

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[Ability of cholestyramine to bind Escherichia coli and Vibrio cholerae toxins]

[Article in French]

Brouillard MY, Rateau JG.

FacultŽ de MŽdecine Saint-Antoine, Laboratoire d'Histologie, Paris.

Cholestyramine treatment of new born's infectious diarrhea has been shown to be effective. The study of in vitro binding of bacterial toxins from Vibrio Cholerae and from three strains of Escherichia coli suggest an ionic adsorption of the four toxins to this anion-exchange resin. This immediate binding is effective at the pH of intestinal fluid, therefore the protection of the enterocytes from the biological action of the toxins result of the toxins sequestering effect of the Cholestyramine.

Publication Types:
PMID: 3041907 [PubMed - indexed for MEDLINE]

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Evidence for an enterohepatic circulation of ochratoxin A in mice.

Roth A, Chakor K, Creppy EE, Kane A, Roschenthaler R, Dirheimer G.

Institut de Biologie MolŽculaire et Cellulaire du CNRS, Strasbourg, France.

The distribution and elimination of [3H]ochratoxin A (OTA) from stomach content and tissue, intestine content and tissue, liver, bile, serum and urine of Swiss male mice which had received a single low dose of OTA by intubation was followed as a function of time. The profiles of radioactivity do not show a smooth decline after the absorption period, but an oscillating pattern with rapid declines followed by increases which favour the assumption of an enterohepatic circulation. Between 28% and 68% of conjugated OTA together with OTA cleavage products were found in bile giving evidence for biliary excretion of OTA and its metabolites in mice. When given i.m. to mice [3H]OTA is already found after 30 min in bile and intestine contents and its elimination patterns show several peaks confirming the biliary excretion and the enterohepatic circulation. Cholestyramine, which is known to prevent the enterohepatic circulation of drugs and toxins, changes the profile of elimination of OTA which no longer presents the cyclic pattern. This result is also in favour of an enterohepatic circulation of OTA. When phenylalanine is given together with OTA by oral gavage the toxicokinetics of the mycotoxin change completely in the different body fluids, in stomach and intestine content and tissues. Phenylalanine seems to facilitate the gastric absorption of OTA and the gastro-intestinal transit. It increases also its early excretion into urine and bile. However, its elimination pattern no longer shows the oscillating pattern. Thus phenylalanine seems to inhibit the intestinal reabsorption of OTA conjugates.

Publication Types:
PMID: 3344528 [PubMed - indexed for MEDLINE]

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[Experimental study in the rabbit of the effect of cholestyramine in the treatment of infectious diarrhea caused by cholera]

[Article in French]

Rateau JG, Brouillard M, Morgant G, Aymard P.

Cholestyramine is a non-absorbable anion exchange resin. Cholestyramine treatment of new born's infectious diarrhea has been shown to be effective. Cholera toxin induces, in the adult rabbit ileal loop, histological, water electrolytes and enzymatic modifications similar to that observed in patients with acute infectious diarrhea. Using this experimental model, we try to exhibit the reduction of the pathologic secretory action of the toxin on intestinal loop, after contact with the resin. A prolonged contact of the cholera toxin with the resin does not abolish completely the activation of adenyl-cyclase induced by the toxin alone. However significant reduction of goblet cell degranulation, and of the secretory effect allowed to reduce the loss of water and electrolytes.

Publication Types:
PMID: 3777873 [PubMed - indexed for MEDLINE]

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Endogenous gut-derived bacterial endotoxin tonically primes pancreatic secretion of insulin in normal rats.

Cornell RP.

This laboratory has proposed that endogenous gut-derived bacterial endotoxin primes the pancreatic secretion of insulin in normal rats. Endogenous lipopolysaccharide (LPS) is continually absorbed from the gut into intestinal capillaries, and low-grade portal venous endotoxemia is the status quo. Under physiologic conditions, Kupffer cells of the liver totally phagocytize and degrade endotoxin from the portal circulation. Evidence from this and other laboratories indicates that administration of exogenous LPS to humans and rats enhances pancreatic secretion of both insulin and glucagon. Conversely, findings of the present study demonstrate that restriction of endogenous LPS in fasted rats depresses the basal and arginine-stimulated concentrations of plasma insulin. Techniques used to restrict gut-derived LPS availability included chronic daily gavage with neomycin and cefazolin for gut sterilization and with cholestyramine or lactulose to reduce endotoxin within the gut. In addition, induction of endotoxin tolerance was produced by progressively higher doses of LPS intraperitoneally (i.p.), and polymyxin B was administered subcutaneously (s.c.) daily to neutralize the lipid A portion of circulating LPS. Finally, isolator-reared, defined flora rats, which were gram-negative-bacteria-deficient, and, therefore, LPS-deficient, were compared with conventional counterparts. Basal plasma insulin but not glucagon levels were consistently and significantly reduced in endogenous LPS-restricted animals. Glucose-stimulated plasma insulin was decreased only after parenteral treatment by tolerance induction and polymyxin B administration. Both plasma insulin and glucagon were depressed in response to arginine challenge in most LPS-restricted rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication Types:
PMID: 3905458 [PubMed - indexed for MEDLINE]

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Transcriptional regulation of the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene in rat liver.

Clarke CF, Fogelman AM, Edwards PA.

This study addresses whether transcriptional control of the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene in rat liver plays a role in determining the level of reductase mRNA. Isolated rat liver nuclei were allowed to elongate nascent RNA transcripts in the presence of [alpha-32P]CTP, and radiolabeled nuclear reductase RNA was quantitated by filter hybridization. Rats fed a diet supplemented with the drugs cholestyramine and mevinolin and having 20-60-fold induced levels of reductase mRNA exhibited levels of reductase transcription which were 20-fold higher than in rats fed an unsupplemented diet. Over 90% of the transcription of the reductase gene was inhibited by concentrations of alpha-amanitin which selectively inhibit RNA polymerase II. Administration of mevalonolactone (the end product of the reaction catalyzed by reductase) to rats fed cholestyramine and mevinolin caused an 80% decrease in the rate of reductase transcription by approximately 1 h. We conclude that under these conditions changes in reductase transcription are primarily responsible for the regulation of reductase mRNA levels.

Publication Types:
PMID: 3850901 [PubMed - indexed for MEDLINE]

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Restriction of gut-derived endotoxin impairs DNA synthesis for liver regeneration.

Cornell RP.

The influence of restricting gut-derived endotoxin availability on liver regeneration after partial hepatectomy was evaluated. Partial hepatectomy was performed by 67% liver resection of ether-anesthetized rats. Liver regeneration was quantified after partial hepatectomy by [3H]thymidine incorporation into hepatic DNA; endotoxemia due to absorption of endogenous endotoxin from the gut into the portal circulation was determined by qualitative lysate assay of perchloric acid-extracted plasma samples, and plasma levels of the hepatotrophic factors insulin and glucagon were measured by radioimmunoassay. Treatments to restrict gut-derived endotoxin included chronic gavage with neomycin and cefazolin for gut sterilization, chronic gavage with cholestyramine to bind endotoxin within the gut, subcutaneous administration of polymyxin B to neutralize the lipid A portion of circulating endotoxin, intraperitoneal induction of endotoxin tolerance by progressively higher doses of endotoxin, and experimentation with isolator-reared defined flora Fisher rats that were Gram-negative bacteria deficient and therefore endotoxin deficient. All treatments to restrict endogenous endotoxin impaired DNA synthesis in regenerating livers particularly 21 h posthepatectomy when replication was increasing most rapidly in normal rats. We hypothesize that impairment of DNA synthesis after partial hepatectomy in endotoxin-restricted animals was due to the observed lack of normal systemic endotoxemic as well as hyperinsulinemic and hyperglucagonemic responses to 67% liver resection.

Publication Types:
PMID: 3904484 [PubMed - indexed for MEDLINE]

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Antibiotic-associated pseudomembranous colitis.

Amin NM.

All antibiotics, except parenteral aminoglycosides, sulfonamides and vancomycin, can induce pseudomembranous colitis. The worst offenders are clindamycin, ampicillin, amoxicillin and the cephalosporins. The cytotoxin produced by Clostridium difficile has been identified as the cause of pseudomembranous colitis. Treatment includes an antimicrobial to eradicate the organism and cholestyramine or colestipol to bind the toxin.

PMID: 3993509 [PubMed - indexed for MEDLINE]

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Antibiotic-associated colitis.

Bartlett JG.

Publication Types:
PMID: 6391879 [PubMed - indexed for MEDLINE]

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Studies with enterotoxigenic microorganisms: effects of candidate antidiarrhoeals in experimental animals in vivo.

Burke V, Gracey M.

Chlorpromazine or aspirin alone, when given to rats parenterally, reduced intestinal fluid secretion induced by cell-free preparations of enterotoxigenic organisms including Escherichia coli, Aeromonas hydrophila, Staphylococcus pyogenes, and Salmonella typhimurium. A combination of chlorpromazine-aspirin given parenterally caused much more marked reduction of fluid secretion. Indomethacin also had significant antisecretory effects against a range of bacterial enterotoxins, while loperamide was effective against heat-labile toxin (LT)-positive E. coli and A. hydrophila. Nicotinamide increased net fluid absorption in the presence of E. coli LT, A. hydrophila, and S. typhimurium. Of the adsorbents tested, aluminum hydroxide showed a positive effect only with E. coli LT and A. hydrophila, while cholestyramine affected net fluid flux only with E. coli ST (heat-stable toxin). Charcoal was effective against all microorganisms tested but only when premixed with the perfusate before the experiments. Aspirin and chlorpromazine probably act at multiple sites to decrease intestinal secretion, and the combination of low doses of these drugs with possibly different sites of action may have advantages over a single agent used in high dosage.

Publication Types:
PMID: 6237185 [PubMed - indexed for MEDLINE]

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Systemic absorption of oral cholestyramine.

McDonald GB, Vracko R.

A patient with Clostridium difficile -toxin colitis was treated with oral cholestyramine, but died of other causes 15 days later. At autopsy, the colitis had resolved, but cholestyramine particles were found within the vessels of most body tissues, most prominently in his ulcerated distal esophagus. Clusters of bacteria were found adjacent to some of the cholestyramine particles, suggesting a common portal of entry.

Publication Types:
PMID: 6724264 [PubMed - indexed for MEDLINE]

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Treatment of antibiotic-associated pseudomembranous colitis.

Bartlett JG.

The experience of this laboratory with the treatment of Clostridium-induced colitis in experimental animals and in patients was reviewed. Optimal results in hamsters were achieved with the antibiotics vancomycin, metronidazole, and tetracycline. Cholestyramine was less effective. The outcome for animals given corticosteroids and Clostridium sordellii antitoxin systemically was not different from that for untreated control animals. The second facet of the study was a retrospective review of therapy in 272 patients with C. difficile-induced diarrhea or colitis. No specific therapy was given to 56 patients who had mild symptoms or were improving at the time the toxin was detected. The therapy most frequently used was oral vancomycin, which was given to 189 patients, including 100 with confirmed pseudomembranous colitis. The response rate was 97%, but 46 patients (24%) relapsed when treatment was discontinued. Response to cholestyramine was favorable in 12 of 19 patients. The results with metronidazole and bacitracin were uniformly good, although the experience was limited.

PMID: 6718937 [PubMed - indexed for MEDLINE]

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[Nonspecific therapy of acute infectious diarrhea]

[Article in German]

Gyr K.

The non-specific therapy of acute infectious diarrhoea is outlined with regard to the mechanism of action and effectiveness. Special attention is given to rehydratation therapy and oral rehydration mainly. Among the groups of adsorbents, agents acting on intestinal flora and agents interfering at the toxin receptor site, Bismuth-subsalicylate is about the only substance with a proven efficacy.

Publication Types:
PMID: 6594747 [PubMed - indexed for MEDLINE]

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Detoxification of chlordecone poisoned rats with chlorella and chlorella derived sporopollenin.

Pore RS.

Chlorella protothecoides accelerated the detoxification of chlordecone poisoned rats, decreasing the half-life of the toxin from 40 to 19 days. The ingested algae passed through the gastrointestinal tract unharmed , interrupted the enteric recirculation of the persistent insecticide, and subsequently eliminated the bound chlordecone with the feces. The detoxification was similar to that obtained with cholestyramine. Laboratory preparations were made to determine whether cell-free components retained the therapeutic properties of the whole cells. Acid and alkaline hydrolysis of the algae destroyed the cells except for the resistant cell wall components. One component was sporopollenin , a carotenoid polymer of limited natural occurrence among microorganisms and plants. Plant sporopollenin was not active, but algal cell walls and sporopollenin retained the therapeutic activity of the whole cells. The cells and cell walls have potential as detoxifying drugs for animals poisoned by chlordecone and other xenobiotic compounds with similar properties.

Publication Types:
PMID: 6202479 [PubMed - indexed for MEDLINE]

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Pseudomembranous colitis: pathogenesis and therapy.

Tedesco FJ.

Publication Types:
PMID: 7043127 [PubMed - indexed for MEDLINE]

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Medical management of antimicrobial-associated diarrhea and colitis.

Gotz VP, Rand KH.

Gastrointestinal complications, including diarrhea, may occur with virtually all antimicrobial agents. Such diarrhea may represent either a common, nonspecific adverse effect, or it may be one of the manifestations of antimicrobial-associated colitis (AAC), a potentially fatal complication. Clostridium difficile and a cytotoxin neutralized by Clostridium sordellii antitoxin has been isolated from the stools of nearly all patients with antibiotic-associated pseudomembranous colitis, many patients with AAC, and approximately 20% of those with antimicrobial-induced diarrhea. Demonstration that C. difficile is responsible for cytotoxin production has allowed for specific therapy for these disorders. General treatment measures include discontinuation of the causative antimicrobial agent(s), bowel rest, and supportive care with fluids, electrolytes and colloids, if necessary. Antiperistaltic agents and corticosteroids are not recommended. Various antimicrobials demonstrate potential efficacy in treating AAC in humans. Oral vancomycin is the most widely tested and is currently the treatment of choice. It achieves high concentrations in the feces and is very active against C. difficile in doses of 125-500 mg by mouth every six hours. Other potentially useful but inadequately tested antimicrobials include metronidazole (500 mg by mouth every eight hours) and bacitracin (25,000 units by mouth every six hours). Tetracycline has been employed with some success in nonspecific antibiotic-associated diarrhea, although it is as yet untested in humans with AAC and may induce diarrhea itself. Both miconazole and rifampin are highly effective against C. difficile in vitro but have not been evaluated in AAC. Anion-exchange resins bind the cytotoxin found in stools of patients with AAC. Cholestyramine has been used with variable response in oral doses of 4 g every six to eight hours. Since these resins may also bind vancomycin, resulting in lowered vancomycin concentrations in the stool, combination therapy should be used cautiously. With specific therapy directed against the toxin and aggressive supportive therapy, surgical intervention is rarely necessary. More recently, investigations have been directed at using bacterial preparations to suppress C. difficile by restoring the normal flora. The development of immunological agents (i.e., vaccines, toxoids, antitoxins) for the prevention or treatment of AAC would be a significant advance in therapy.

Publication Types:
PMID: 6765392 [PubMed - indexed for MEDLINE]

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Pseudomembranous (antibiotic-associated) colitis.

Saco LS, Herlihy KJ, Powell DW.

We have come to understand the cause of antibiotic-associated pseudomembranous colitis (PMC) only in the last decade. Clostridium difficile produces the intestinal dysfunction and the characteristic finding of exudative plaques on the mucosa by elaborating a toxin in the colon. This report reviews the development of our knowledge of this disease and the rapid adoption of a rational therapy once the cause was specified. C. difficile or its toxin can be cultured or isolated from the stools of 90% of the patients with PMC. This organism is almost never found in healthy people or in any other conditions except inflammatory bowel disease, where its significance is not yet known. The detection of pseudomembranes by sigmoidoscopy establishes the diagnosis. The laboratory technics that confirm the presence of C. difficile and its toxin are being incorporated into many laboratories around the country. Treatment of diagnosed PMC is relatively simple and usually completely effective. The offending antibiotic is stopped, a proper fluid and electrolyte balance maintained, and oral vancomycin begun, 125 to 500 mg four times a day. Cholestyramine can also be used as an adjunct to this regimen. Relapse can occur in patients treated with oral vancomycin, necessitating a repeat course of therapy.

Publication Types:
PMID: 7016935 [PubMed - indexed for MEDLINE]

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Antibiotic-associated pseudomembranous colitis in children.

Viscidi RP, Bartlett JG.

Ten cases of antibiotic-associated pseudomembranous colitis in children are reviewed. The ages ranged from 4 years to 17 years; the most frequently implicated antimicrobial agents were penicillins in six children and clindamycin in two. Stool assays showed specimens from all ten patients yielded a cytopathic toxin which was neutralized by Clostridium sordellii antitoxin with titers ranging from 1:40 to 1:40,000. Bacterial cultures of nine specimens uniformly yielded Clostridium difficile with a median concentration of 10(5.4) organisms per gram of wet weight. All nine isolates of C difficile showed a vitro production of a cytopathic toxin which was similar to or identical with that which was detected in the original stool specimen. All ten patients recovered. Six were treated with oral vancomycin and showed a good therapeutic response; one patient, however, suffered two relapses when treatment was discontinued, requiring a total of three courses of oral vancomycin. Two patients received cholestyramine and responded well. These observations provide supportive evidence that C difficile is responsible for antibiotic-associated pseudomembranous colitis in children and document efficacy of the newer therapeutic modalities in this patient population as well.

PMID: 7243476 [PubMed - indexed for MEDLINE]

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[Role of Clostridium and its toxin in pseudo-membranous colitis (author's transl)]

[Article in French]

Bryskier A, Doll J, Labro MT, Andrieu J.

At present many authors consider that pseudo-membranous colitis is of bacterial origin. The main pathogenic agent is Clostridium difficile. It is not easy to isolate this organism in the stool, selective media are under study. It liberates a lipo-glycoprotein exotoxin during lysis. It is only partially purified, its structure is not fully elucidated. Its molecular weight is not yet precisely determined. It consists of several polymerised polypeptide fragments of molecular weight 50 000. It is a thermolabile acid and alkaline sensitive cytotoxin which acts on the cell membranes and the ileo-caeco-colonic mucosa of man and animals. Clostridium difficile is transmissible by a small number of high risk carrier subjects who are potentially patients with pseudo-membranous colitis. Antibiotic therapy may lead to unbalance of the ecosystem represented by the bacterial flora of the digestive tract and favour the multiplication of a resistant strain to the administered antibiotic. The appearance of pseudo-membranous colitis requires the association of sufficient bacterial development (equal or greater than 10(7) germs per gram of stools) and the liberation of a cytotoxin. The pathogenic treatment consists of antibiotic therapy by Vancomycin or Metronidazole which seems, at present, the most active on the germs and a toxin absorbent, such as Cholestyramine, Coliptol hydrochloride or Heavy metals.

Publication Types:
PMID: 7011118 [PubMed - indexed for MEDLINE]

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Antibiotic-associated pseudomembranous colitis in siblings.

Schussheim A, Goldstein EJ.

Pseudomembranous colitis induced by antibiotics is not commonly diagnosed in children. Recent developments have clarified the pathogenesis and suggested that agents such as cholestyramine are therapeutically useful. Two siblings with pseudomembranous colitis were carefully studied and may serve to alert pediatricians to an approach to this entity.

Publication Types:
PMID: 7454484 [PubMed - indexed for MEDLINE]

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Clinical and laboratory observations in Clostridium difficile colitis.

Bartlett JG, Taylor NS, Chang T, Dzink J.

Publication Types:
PMID: 7435423 [PubMed - indexed for MEDLINE]

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Binding of Clostridium difficile cytotoxin and vancomycin by anion-exchange resins.

Taylor NS, Bartlett JG.

Cholestyramine and colestipol were tested for binding of Clostridium difficile cytotoxin with use of batch absorption and column chromatography. The toxin was bound by both resins and could not be eluted from cholestyramine with either an ionic of a pH gradient. Vancomycin bound to cholestyramine more strongly than to colestipol. Cholestyramine and vancomycin were also tested for therapeutic efficacy in the hamster model of clindamycin-induced cecitis. Both compounds delayed death and reduced levels of cytotoxin in stool; these effects were greatest for vancomycin. Use of the two compounds in combination reduced concentrations of biologically active vancomycin in stool, but the levels still exceeded the minimum inhibitory concentration for C. difficile. These data suggest that the therapeutic benefit of cholestyramine in some patients with antibiotic-associated pseudomembranous colitis is due to its binding of the C. difficile cytotoxin. Since anion-exchange resins also bind vancomycin, caution is necessary if resins are used concurrently with vancomycin for therapy.

Publication Types:
PMID: 7365273 [PubMed - indexed for MEDLINE]

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[Postantibiotic pseudomembranous colitis and related forms of diarrhea following use of antibiotics. II. Microbiological aspects]

[Article in Dutch]

Rietra PJ, Meuwissen SG, Zanen HC.

Publication Types:
PMID: 545159 [PubMed - indexed for MEDLINE]

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The ability of cholestyramine resin and other adsorbents to bind Escherichia coli enterotoxins.

Mullan NA, Burgess MN, Bywater RJ, Newsome PM.

Several adsorbent materials were evaluated for their ability to bind Escherichia coli enterotoxins. Cholestyramine, a strong anion-exchange resin, bound the heat-labile and the heat-stable types of enterotoxin and reduced significantly their effects in some animal models. However, its efficacy in the treatment of diarrhoeic piglets appeared to be adversely affected by the presence of milk in the alimentary tract.

PMID: 390155 [PubMed - indexed for MEDLINE]

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[Antibiotic-induced pseudomembranous Clostridium difficile colitis. A new etiopathogenetically definable infectious disease]

[Article in German]

Werner H.

Pseudomembranous colitis has been recognized as a complication of antimicrobial therapy since 1952. Most recently, evidence has been accumulated showing that a heat labile toxin is involved. Though little is known so far about the normal ecology of C. difficile and the host factors of potential importance in the development of colitis by this anaerobe, antimicrobial agent-induced suppression of the normal gut flora seems to be a major factor leading to the intestinal proliferation of resistant toxinogenic C. difficile. Factors independent of susceptibility are, however, probably responsible for cases of pseudomembranous colitis associated with penicillin, ampicillin, and other antibiotics active against C. difficile. In monitoring antibiotic therapy, the application of selective media for the isolation of C. difficile from faecal specimens and proper tools for the demonstration of toxin and the study of immunity might prove to be fruitful from both a diagnostic and therapeutic viewpoint. In established pseudomembranous colitis treatment consists of oral vancomycin (2 g/day), cholestyramine and, if necessary, intensive intravenous regimen.

Publication Types:
PMID: 488887 [PubMed - indexed for MEDLINE]

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Cholestyramine therapy for antibiotic-associated colitis.

Burbige EJ.

Publication Types:
PMID: 447055 [PubMed - indexed for MEDLINE]

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[Role of bacterial endotoxins in liver pathology]

[Article in Polish]

Kiczka W.

Publication Types:
PMID: 388366 [PubMed - indexed for MEDLINE]

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Therapy of antibiotic-associated pseudomembranous colitis.

Tedesco FJ, Napier J, Gamble W, Chang TW, Bartlett JG.

Seven patients treated with oral cholestyramine for antibiotic-associated pseudomembranous colitis are reported. Response was variable with only one patient having a totally satisfactory clinical outcome. Five of seven patients had continued systemic signs with fever and leukocytosis throughout the course of cholestyramine. Two observations were relatively consistent. First, six of the seven patient had a decrease in the number of daily stools during therapy. Second, all patients showed persistence of the cytopathic toxin in stools obtained after three to seven days of cholestyramine therapy. Six patients who were subsequently treated with oral vancomycin had a prompt clinical improvement and clearance of the cytopathic toxin in the stool.

Publication Types:
PMID: 263131 [PubMed - indexed for MEDLINE]

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Partial purification of a toxin found in hamsters with antibiotic-associated colitis. Reversible binding of the toxin by cholestyramine.

Humphrey CD, Condon CW, Cantey JR, Pittman FE.

A toxin with cytotoxic and enterotoxic activities was isolated from cecal contents of hamsters receiving lincomycin. The toxin was partially purified by ultracentrifugation, ultrafiltration, (NH4)2SO4 precipitation, and gel filtration. Cytotoxic activity, assayed on monolayers of HeLa cells, was restricted to material that eluted in the molecular weight range of 107,000 +/- 6,000 daltons. Cytotoxicity of crude AAC toxin could be demonstrated at concentrations as low as 0.04 microgram/ml. The toxin was heat labile (55 degrees-60 degrees C for 0.5 hr) and sensitive to trypsinization, acidification at pH 3, or alkalinization at pH 9. Cytotoxic activity was inhibited by Clostridium sordellii antitoxin. Enterotoxic activity of the crude toxin and the cytotoxic fraction from gel filtration was demonstrated by fluid secretion in ligated rabbit ileal loops. Studies were done in vitro with cholestyramine resin, vancomycin, or gentamicin to determine if the toxin was bound or denatured by these drugs. It was demonstrated that cholestyramine bound the toxin, significantly reducing its cytotoxicity. Reversible binding of the cytotoxic material was demonstrated by salt gradient elution. Neither vancomycin nor gentamicin had any effect on the in vitro cytotoxic activity of the toxin.

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PMID: 34553 [PubMed - indexed for MEDLINE]

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Clindamycin-induced colitis.

Fekety R, Silva J, Browne RA, Rifkin GD, Ebright JR.

The hamster model of enterocolitis after the administration of clindamycin was used to study various drugs used in treatment of the disease in humans. Current evidence strongly suggests toxigenic, clindamycin-resistant Clostridium difficile is a cause of the disease in hamster and man. This organism is susceptible to vancomycin and metronidazole, and the disease could be prevented in the hamster so long as the antibiotics were given orally. A fatal colitis almost invariably ensued once they were discontinued. Administration of cholestyramine significantly prolonged survival of hamsters, but did not pervent death or colitis. Corticosteroids or atropine-diphenoxylate (Lomotil) did not alter the disease. The hamster model may be useful in studying other kinds of treatment of this disease.

PMID: 760500 [PubMed - indexed for MEDLINE]

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Ultrastructural changes in rat liver cells induced by Proteus mirabilis endotoxin.

Lipinska-Piotrowska I.

Changes in individual organella of rat hepatocytes developing under the effect of Proteus mirabilis endotoxin (Pme) were observed under electron microscope. The effect of drugs which diminish liver cell injury by Pme (polymyxin, cholestyramine and hydrocortisone) on the changes was studied.

PMID: 220929 [PubMed - indexed for MEDLINE]

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[Intestinal loss syndromes]

[Article in German]

Ewe K.

Publication Types:
PMID: 95368 [PubMed - indexed for MEDLINE]

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Anion-exchange resins in antibiotic-associated colitis.

Chang TW, Onderdonk AB, Bartlett JG.

Publication Types:
PMID: 79047 [PubMed - indexed for MEDLINE]

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[Histopathological and histochemical changes in rat liver under the influence of endotoxin and following treatment with hydrocortisone, polymyxin and cholestyramine]

[Article in Polish]

Lipinska-Piotrowska I, Piatek T.

Publication Types:
PMID: 184414 [PubMed - indexed for MEDLINE]

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[Value of cholestyramine in the treatment of refractory diarrhea in infants and the newborn]

[Article in French]

Blanckaert D, Farriaux JP.

Publication Types:
PMID: 772596 [PubMed - indexed for MEDLINE]

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Endotoxin binding by charged and uncharged resins.

Nolan JP, McDevitt JJ, Goldmann GS, Bishop C.

Cholestyramine (Dowex 1-X2), a strongly basic anion-exchange resin, has previously been shown to bind bacterial endotoxin, preventing both its toxicity and intestinal absorption. Because hemoperfusion through charged and uncharged resins is practical, a study was undertaken to test the endotoxin-binding characteristics of a number of resins. The resin to be tested was washed and swelled overnight, and 1 mg/ml of 51Cr-labeled endotoxin was added and the mixture, agitated and incubated at 37 degrees for a specific time period. In the Dowex 1 series, the 1-X2 was superior to the 1-X4 and 1-X8 in its ability to bind E. coli endotoxin, removing about 90% from solution in 15 min. Increasing mesh size seemed to offer more binding sites for each Dowex 1 resin. Activated charcoal adsorbed about 90% of the endotoxin also, but Amberlite XAD-2 showed little binding capacity. Injection of filtrate from unlabeled E. coli and S. typhosa resin-treated solution into rats, demonstrated that both Dowex 1-X2 and activated charcoal prevented the transaminase rise noted in animals injected with solutions not so treated. It is concluded that Dowex 1-X2 resin and activated charcoal efficiently remove endotoxin in vitro, and may offer a unique method for removing circulating endotoxin in vivo.

Publication Types:
PMID: 1096167 [PubMed - indexed for MEDLINE]

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Letter: Cholestyramine therapy for intractable diarrhea.

Dehghanian J.

PMID: 4414144 [PubMed - indexed for MEDLINE]

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Cholestyramine therapy for intractable diarrhea.

Tamer MA, Santora TR, Sandberg DH.

PMID: 4812005 [PubMed - indexed for MEDLINE]

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Effect of cholestyramine on endotoxin toxicity and absorption.

Nolan JP, Ali MV.

PMID: 4552124 [PubMed - indexed for MEDLINE]

74: R. Shoemaker (author), J. Schaller and P. Schmidt (co-authors). Mold Warriors. Baltimore, MD: Gateway Press, 2005.

74: R. Shoemaker. Desperation Medicine. Baltimore, MD: Gatway Press. 2001


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