Impact of anion exchange adsorbents on regional citrate anticoagulation.

INTRODUCTION: Heparin and citrate are commonly used anticoagulants in membrane/adsorption based extracorporeal liver support systems. However, anion exchange resins employed for the removal of negatively charged target molecules including bilirubin may also deplete these anticoagulants due to their negative charge. The aim of this study was to evaluate the adsorption of citrate by anion exchange resins and the impact on extracorporeal Ca2+ concentrations. METHODS: Liver support treatments were simulated in vitro. Citrate and Ca2+ concentrations were measured pre and post albumin filter as well as pre and post adsorbents. In addition, batch experiments were performed to quantify citrate adsorption. RESULTS: Pre albumin filter target Ca2+ concentrations were reached well with only minor deviations. Citrate was adsorbed by anion exchange resins, resulting in a higher Ca2+ concentration downstream of the adsorbent cartridges during the first hour of treatment. CONCLUSIONS: The anion exchange resin depletes citrate, leading to an increased Ca2+ concentration in the extracorporeal circuit, which may cause an increased risk of clotting during the first hour of treatment. An increase of citrate infusion during the first hour of treatment should therefore be considered to compensate for the adsorption of citrate.

Cholestyramine decreases apparent total tract macronutrient digestibility and alters fecal characteristics and metabolites of healthy adult dogs.

Absorption of dietary lipids in the small intestine is dependent on the emulsification by bile acids (BA) and the formation of chylomicrons. Cholestyramine is a common drug used in humans-and potentially dogs-to treat BA malabsorption associated with chronic diarrhea. It is known to bind BA to form insoluble complexes, preventing their reabsorption and possibly proper emulsification and absorption of dietary fats. The objective of this study was to evaluate the effects of cholestyramine on 1) macronutrient apparent total tract digestibility (ATTD), and 2) fecal characteristics and metabolites of healthy adult dogs. We hypothesized that cholestyramine would decrease ATTD of fat and organic matter (OM), increase fecal dry matter (DM) content, and increase fecal output. Twelve healthy beagles (3.2 ± 0.8 yr; 10.4 ± 0.9 kg) were used in a randomized crossover design. All procedures were approved by the University of Illinois Institutional Animal Care and Use Committee before the study. The study included a baseline period and two 14-d experimental periods separated by a 14-d washout. All dogs were fed the same experimental diet, formulated to meet all nutrient needs recommended by AAFCO, throughout the study. Dogs were randomized into 2 groups [diet only (control) or diet + 11.4 g/d cholestyramine (8 g/d active ingredient)] in Period 1 and received the other treatment in Period 2. During the washout, all dogs were fed the diet only. Dogs were fed once daily (0800 h) to maintain BW. Total fecal output was collected during the last 4 d of each period for ATTD analysis. On day 14 of each of period, fresh fecal and blood samples were collected for metabolite analysis. Dogs fed cholestyramine had lower (P < 0.001) ATTD of DM, OM, energy, crude protein, and fat and lower (P < 0.01) fecal scores (firmer stools) than controls. Dogs fed cholestyramine had greater (P < 0.01) as-is and dry fecal output than controls. Dogs fed cholestyramine had lower (P < 0.05) fecal ammonia and phenol concentrations, but greater (P < 0.05) fecal indole, acetate, butyrate, and total short-chain fatty acid concentrations than controls. Fecal DM% and pH were greater (P < 0.01) in dogs fed cholestyramine. Our results indicate that cholestyramine, when given with a meal, is safe and well tolerated but significantly decreases nutrient digestibility and alters fecal characteristics. Future studies are required to explore the effects of cholestyramine on dogs with gastrointestinal disease.

Tolerability and efficacy of colestipol hydrochloride for accelerated elimination of teriflunomide.

BACKGROUND: Teriflunomide is an oral disease modifying therapy approved for the treatment of relapsing forms of multiple sclerosis. Teriflunomide' s pharmacokinetics (PK) contribute to its slow elimination, on average taking 6-8 months, though it can take up to 2 years in some instances. This slow elimination can become problematic in certain clinical situations - such as during pregnancy, when teriflunomide has potential teratogenic effects. In such scenarios, an accelerated elimination procedure (AEP) is recommended. Currently, AEPs with oral cholestyramine or activated charcoal are available but are restricted by adverse effects, limited administration routes, and dosing frequencies. METHODS: A single-center, PK interaction study was performed in a total of 14 healthy volunteers, to investigate colestipol hydrochloride (HCl) as an alternative to cholestyramine for the elimination of teriflunomide. Participants received teriflunomide for 14 days, followed by an AEP with colestipol HCl for 15 days. RESULTS AND CONCLUSIONS: The administration of colestipol HCl for 15 days was sufficient to reduce plasma teriflunomide concentrations by greater than 96%. Although colestipol HCl did not completely eliminate teriflunomide with the same effectiveness as cholestyramine, it may offer an alternative method for accelerated elimination of teriflunomide with potentially improved tolerability and more favorable dosing and administration options.

Cholestyramine alters bile acid amounts and the expression of cholesterol-related genes in rabbit intestinal and hepatic tissues.

OBJECTIVE: Cholestyramine (CHO), as a bile acid sequestering exchange resin, has been widely used to treat hypercholesterolemia. The aim of this study was to explore how CHO regulated serum cholesterol amounts and bile acid levels in animal models. METHODS: New Zealand White rabbits were randomly assigned to the control (given distilled water) and CHO-treated (given CHO solution 1 g/kg per day for 2 weeks) groups. To assess bile acid pool size, bile fistulas were constructed in five rabbits in each group. Serum cholesterol levels and biliary and fecal bile outputs were determined. Liver cholesterol 7α-hydroxylase ( CYP7A1 ), small heterodimer partner ( SHP ), bile salt export pump ( BSEP ), ileal bile acid-binding protein ( IBABP ) and LDL receptor ( LDL-R ) mRNA expressions were assessed by real-time polymerase chain reaction. CYP7A1 activity was also determined. RESULTS: CHO treatment decreased serum cholesterol levels by 12.1%. Although CHO did not change the bile acid pool size and biliary bile acid output, it significantly increased fecal bile acid output. Interestingly, CHO also significantly increased the expression and activity of CYP7A1, as well as IBABP and LDL-R mRNA expressions, but decreased hepatic SHP and BSEP gene expressions. CONCLUSION: CHO markedly alters bile acid and cholesterol amounts in rabbit intestinal and liver tissues, downregulating genes responsible for cholesterol homeostasis.

The effects of bile acid sequestrants on lipid profile and blood glucose concentrations: A systematic review and meta-analysis of randomized controlled trials.

AIM: To undertake a systematic review and meta-analysis of prospective clinical studies to determine the effect of bile acid sequestrants (BAS) on lipid profile and blood glucose concentrations. METHOD: PubMed-Medline, Web of Science, Cochrane Database and Google Scholar databases were searched (up until August 2016) to identify prospective studies evaluating the impact of BASs on the cardio-metabolic profile. Random effects model meta-analysis was used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. Heterogeneity was quantitatively assessed using the I2 index. Systematic review registration: CRD42016035973. RESULTS: From a total of 769 entries identified, 15 studies were included in the final analysis. The meta-analysis indicated a significant reduction in fasting serum triglyceride concentrations following treatment with BASs (weighted mean difference [WMD] 0.54mg/dL, 95% CI 0.43 to 0.65, heterogeneity p=0.021; I2 54.2%, n=11 studies). The WMDs for total serum cholesterol (TC) was -1.18mg/dL (95% CI -1.30 to -1.06, heterogeneity p=0012; I2 63.1%, n=11 studies), 0.126mg/dL (95% CI 0.02 to 0.22, heterogeneity p=0.231; I2 43.2%, n=11 studies) for HDL-cholesterol, and -0.24mg/dL (95% CI -0.35 to -0.14, heterogeneity p=0.562; I2 23.1%, n=10 studies) for LDL-cholesterol, and -2.10mg/dL (95% CI -2.84 to -1.36, heterogeneity p=0.200; I2 42.6%, n=11 studies) fasting blood glucose (FBG) and -0.83% (95% CI -1.08 to -0.57, heterogeneity p=0.856; I2 20.9%, n=11 studies) for HbA1c. These findings were robust in sensitivity analyses. CONCLUSIONS: This meta-analysis suggests that therapy with BAS significantly improves HDL-C, LDL-C, and glycemic markers including fasting blood glucose, HbA1c levels, while deteriorating triglyceride levels.

Protic acid resin enhanced 1-butyl-3-methylimidazolium chloride pretreatment of Arundo donax Linn.

To improve the cellulose digestibility of energy crop Arudo donax Linn. with cost-efficient, a novel pretreatment of protic acid resin Amberlyst 35DRY catalyzed inexpensive ionic liquid (IL) 1-butyl-3-methylimidazolium chloride ([C4mim]Cl) was developed in this work. The pretreatment was performed at 160°C with [C4mim]Cl for 1.5h, followed by Amberlyst 35DRY catalyzed at 90°C for 1h. The IL-Amberlyst pretreatment was demonstrated to be effective, evidenced by the reduction in cellulose crystallinity (31.4%) and increased porosity caused by extensive swelling the undissolved biomass and partial depolymerization of the longer cellulose chain of the dissolved biomass by Amberlyst. Consequently, a higher glucose yield (92.8%) was obtained than for the single [C4mim]Cl pretreatment (42.8%) at an enzyme loading of 20 FPU/g substrate. Overall, the enhanced pretreatment was competitive by using inexpensive and recyclable IL-Amberlyst 35DRY pretreated system with shorter processing time and reduced enzyme usage.

Dedicated removal of immunoglobulin (Ig)A, IgM, and Factor (F)XI/activated FXI from human plasma IgG.

BACKGROUND: Adverse events can be associated with treating critically ill patients with immunoglobulin (Ig)G. Some adverse events are due to contaminants like IgA and activated Factor (F)XI. Therefore, new purification strategies are needed for dedicated removal of these contaminants without impairing IgG recovery. STUDY DESIGN AND METHODS: An immunoglobulin fraction containing IgG, IgM, and IgA was prepared by caprylic acid precipitation of cryoprecipitate-poor plasma. The capacities of the cation exchangers (S HyperCel and CM Ceramic HyperD F) and anion exchangers (HyperCel STAR AX and Q HyperCel) to remove IgA, IgM, and spiked FXI were tested following a design of experiment approach using microplates and chromatographic column scale-up. FXI removal was also evaluated using Mustang S chromatographic membranes. IgG/IgG subclasses, IgA, IgM, and FXI were assessed by enzyme-linked immunosorbent assay, and caprylic acid, by gas chromatography. RESULTS: Extensive removal of IgA and IgM, but not FXI, was achieved by a two-step chromatographic process combining S HyperCel used in the IgG binding and elution mode and HyperCel STAR AX used in the IgG flow-through mode, providing high IgG and IgG subclass recovery (>85%), high purity (>99.5%), and efficient removal of IgA (<0.5%) and IgM (undetectable). Twenty-six-fold FXI removal was achieved by processing the resulting purified IgG fraction through Mustang S cation-exchanger membranes at pH 6.0 and 12.7 mS/cm. Caprylic acid was removed by S HyperCel. CONCLUSIONS: Combining S HyperCel and HyperCel STAR AX extensively removed IgA and IgM, with good IgG recovery. Mustang® S membranes can be used for dedicated removal of FXI.

Different effects of cholestyramine on postprandial secretions of cholecystokinin and peptide YY in women with bulimia nervosa.

OBJECTIVE: Patients with bulimia nervosa (BN) are reported to have decreased postprandial levels of cholecystokinin (CCK) and peptide YY (PYY). Fatty nutrients are the most powerful stimulus for releasing these peptides. Cholestyramine is an anion exchanger which adsorbs bile salts and reduces the digestion of lipids, affecting the secretion of both CCK and PYY. To further characterise the physiology of these peptides in BN, we aimed to investigate the effects of cholestyramine (12 g, per os) or placebo administered with a high-fat meal on CCK and PYY secretions in bulimic versus healthy women. RESULTS: Postprandial CCK levels significantly increased in both healthy and bulimic women after placebo + the high-fat meal, without any significant difference between the two groups. Cholestyramine administration significantly increased postprandial CCK responses in both healthy and bulimic women; however, significantly lower CCK levels were observed in BN. Postprandial PYY levels significantly increased after placebo administration in healthy women after the high-fat meal, whereas no significant changes were found in bulimic women. Cholestyramine, administered with the high-fat meal, significantly reduced postprandial PYY response in healthy women, but not in bulimic women. Finally, there was a negative correlation of the area under the curve with respect to the increase of PYY (after placebo administration) with binge frequency in the bulimic women. CONCLUSION: In BN an altered postprandial secretion of CCK may be evidenced when cholestyramine is combined with a high-fat meal. Instead, the postprandial secretion of PYY is significantly blunted and not affected by cholestyramine administration.

TGR5 potentiates GLP-1 secretion in response to anionic exchange resins.

Anionic exchange resins are bona fide cholesterol-lowering agents with glycemia lowering actions in diabetic patients. Potentiation of intestinal GLP-1 secretion has been proposed to contribute to the glycemia lowering effect of these non-systemic drugs. Here, we show that resin exposure enhances GLP-1 secretion and improves glycemic control in diet-induced animal models of "diabesity", effects which are critically dependent on TGR5, a G protein-coupled receptor that is activated by bile acids. We identified the colon as a major source of GLP-1 secretion after resin treatment. Furthermore, we demonstrate that the boost in GLP-1 release by resins is due to both enhanced TGR5-dependent production of the precursor transcript of GLP-1 as well as to the local enrichment of TGR5 agonists in the colon. Thus, TGR5 represents an essential component in the pathway mediating the enhanced GLP-1 release in response to anionic exchange resins.

Bile acid sequestrants: more than simple resins.

PURPOSE OF REVIEW: Bile acid sequestrants (BAS) have been used for more than 50 years in the treatment of hypercholesterolemia. The last decade, bile acids are emerging as integrated regulators of metabolism via induction of various signal transduction pathways. Consequently, BAS treatment may exert unexpected side-effects. We discuss a selection of recently published studies that evaluated BAS in several metabolic diseases. RECENT FINDINGS: Recently, an increasing body of evidence has shown that BAS in addition to ameliorating hypercholesterolemia are also effective in improving glycemic control in patients with type 2 diabetes, although the mechanism is not completely understood. Furthermore, some reports suggested using these compounds to modulate energy expenditure. Many of these effects have been related to the local effects of BAS in the intestine by directly binding bile acids in the intestine or indirectly by interfering with signaling processes. SUMMARY: A substantial effort is being made by researchers to fully define the mechanism by which BAS improve glycemic control in type 2 diabetic patients. A new challenge will be to confirm in clinical trials the recent discoveries coming from animal experiments suggesting a role for bile acids in energy metabolism.

Colestimide, an anion exchange resin agent, can decrease the number of LDL particles without affecting their size in patients with hyperlipidemia.

OBJECTIVES: Recent studies have demonstrated that not only plasma low-density lipoprotein (LDL) levels, but also the number of small dense LDL particles are involved in the development of arteriosclerosis. Anion exchange resins can reduce plasma LDL levels and affect LDL particle size via increasing triglycerides. In the present study, the effects of short-term colestimide administration on LDL particle size were investigated. METHODS: Obese patients with primary hyperlipidemia (n=21) were administered 3000 mg/day of colestimide for 1 month and fasting blood was obtained before and after the treatment. LDL particle size and number were measured by nuclear magnetic resonance (NMR) lipoprofile using magnetic resonance spectroscopy. RESULTS: Levels of plasma LDL cholesterol decreased from 155.5 mg/dl to 128.1 mg/dl (p<0.001) and levels of apolipoprotein B decreased from 139.2 mg/dl to 120.6 mg/dl (p<0.001) by colestimide administration. Levels of high-density lipoprotein (HDL) cholesterol and triglyceride were unaltered. LDL particle size did not change, whereas LDL particle numbers decreased from 1920.3 nmol/l to 1568.8 nmol/l (p<0.01). CONCLUSIONS: Short-term administration of colestimide to patients with hyperlipidemia reduced LDL particle numbers. LDL particle size was not changed.

Use of proteomics for validation of the isolation process of clotting factor IX from human plasma.

The use of proteomic techniques in the monitoring of different production steps of plasma-derived clotting factor IX (pd F IX) was demonstrated. The first step, solid-phase extraction with a weak anion-exchange resin, fractionates the bulk of human serum albumin (HSA), immunoglobulin G, and other non-binding proteins from F IX. The proteins that strongly bind to the anion-exchange resin are eluted by higher salt concentrations. In the second step, anion-exchange chromatography, residual HSA, some proteases and other contaminating proteins are separated. In the last chromatographic step, affinity chromatography with immobilized heparin, the majority of the residual impurities are removed. However, some contaminating proteins still remain in the eluate from the affinity column. The next step in the production process, virus filtration, is also an efficient step for the removal of residual impurities, mainly high molecular weight proteins, such as vitronectin and inter-alpha inhibitor proteins. In each production step, the active component, pd F IX and contaminating proteins are monitored by biochemical and immunochemical methods and by LC-MS/MS and their removal documented. Our methodology is very helpful for further process optimization, rapid identification of target proteins with relatively low abundance, and for the design of subsequent steps for their removal or purification.

Lack of relationship between blood glucose-lowering activity of colestimide and serum cholecystokinin (CCK) concentrations in patients with type 2 diabetes.

Colestimide has been reported to lower blood glucose levels in patients with type 2 diabetes and hypercholesterolemia. We investigated the mechanism of the hypoglycemic activity of colestimide by examining changes in serum cholecystokinin (CCK) and insulin concentrations before and after its 2-week oral administration. A total of seven type 2 diabetes inpatients with hypercholesterolemia received colestimide after their blood glucose levels had stabilized. We daily measured plasma glucose levels and serum lipid concentrations, calculated Body Mass Index (BMI), and determined whole-day changes in serum immunoreactive insulin (IRI) and CCK concentrations in all study subjects. We daily measured plasma glucose levels, as well as serum IRI and CCK concentrations at 10 time points for measurement. Plasma glucose levels, as well as serum IRI and CCK concentrations before and after the 2-week oral administration of colestimide were compared. The means of total cholesterol levels and BMI decreased significantly after administration. At time points for measurement (10 : 00 and 12 : 00), plasma glucose levels decreased significantly after administration (P=0.026 and P=0.009, respectively). Diurnal changes in serum IRI and CCK concentrations were not observed after administration, except for the IRI concentration at 20: 00. The effect of colestimide on CCK may not explain the mechanism of its blood glucose-lowering activity in patients with type 2 diabetes and hypercholesterolemia.

Evaluation of expanded bed adsorption chromatography for extraction of prothrombin complex from Cohn Supernatant I.

This study evaluated the feasibility of substituting expanded bed adsorption (EBA) chromatography for an existing chromatographic purification process for the isolation of prothrombin complex concentrate (PCC) from Cohn Supernatant I. The EBA chromatography (Streamline) resins were compared to the current DEAE-cellulose resin for the extraction of PCC from Cohn SNI. EBA chromatography resins efficiently bound PCC from Cohn SNI at a significantly higher flow rate of up to 300 cm/h compared to 30 cm/h for the current DEAE-cellulose process. Composition and yield of the recovered PCC reflected the elution conditions used. The results indicate that EBA chromatography could be used to efficiently produce PCC comparable to existing products.

Decreased biliary excretion of tributylmethyl ammonium in cholestyramine pretreated rats due to reduced formation of ion-pair complexes with hepatic bile salts.

The hypothesis that higher molecular weight (MW) quaternary ammoniums (QAs) form lipophilic ion-pair complexes with bile salts in the liver, and are subsequently excreted into bile via a canalicular transporter, P-gp, was re-examined in the present study for its validity. The biliary excretion of tributylmethyl ammonium (TBuMA), a QA with a MW of 200, in bile salt-depleted rats was determined. Depletion was induced by a daily oral administration of a resin, cholestyramine, at a dose of 0.5 g/kg for 2 consecutive weeks, which decreased the concentration of total bile salts in the liver by 38%. When TBuMA was administered intravenously (12 micromol/kg) to these rats, the plasma level, area under the plasma concentration-time curve (AUC), systemic clearance (CL) and volume of distribution (V(ss)) of the compound remained unchanged, whereas bile flow (23.03 vs 16.94 microl/min, p<0.05) and biliary clearance (CL(bile), 12.75 vs 5.34 ml/min/kg, p<0.01) were decreased significantly. These results implied the biliary clearance of TBuMA in rats with bile salt depletion was significantly decreased as a result of decreased ion-pair complexation of TBuMA. The above results are consistent with our hypothesis and the existence of a MW threshold (i.e. 200+/-50 for rats) for the biliary excretion of QAs.

Stabilization effect of resin on the production of potent proteasome inhibitor NPI-0052 during submerged fermentation of Salinispora tropica.

Addition of acrylic resin Amberlite XAD-7 during the fermentation of Salinispora tropica significantly enhanced the production of NPI-0052 by 69 fold. Examination of the time course of resin addition to the Salinispora tropica fermentation demonstrated that the increase in the production of NPI-052 is due to the stabilization effect by resin but not the removal of an end product feedback repression. Delay in resin addition to the fermentation led to decreases in the production of NPI-0052 to the amounts that are synthesized prior to the resin addition.

Fluvastatin alters platelet aggregability in patients with hypercholesterolemia: possible improvement of intraplatelet redox imbalance via HMG-CoA reductase.

BACKGROUND: Hypercholesterolemia enhances platelet aggregability. Statins have beneficial effects on cardiovascular events. The purpose of this study is to investigate whether statins inhibit platelet aggregation and, if so, the mechanisms. METHODS AND RESULTS: Twelve patients with hypercholesterolemia were prospectively randomized in a crossover design to receive either fluvastatin (20 mg/d) or colestimide (3000 mg/d) for 12 weeks. The subjects were switched to the opposite arm for additional 12 weeks. Before and after first and second treatments, experiments were performed. Eleven age-matched volunteers with normal lipid profiles served as controls. ADP-induced platelet aggregation, platelet-derive nitric oxide (PDNO) release, intraplatelet levels of GSH and GSSG, and intraplatelet nitrotyrosine production during platelet aggregation were measured. Fluvastatin and colestimide equally lowered total and low density lipoprotein cholesterol levels in hypercholesterolemia. Platelet aggregation was greater in hypercholesterolemia than in normocholesterolemia before treatment and was altered by fluvastatin. PDNO release, intraplatelet glutathione level, and GSH/GSSG ratio were lower in hypercholesterolemia than in normocholesterolemia before treatment and were increased by fluvastatin. Intraplatelet nitrotyrosine formation was greater in hypercholesterolemia than in normocholesterolemia, and decreased by fluvastatin. Colestimide did not have such effects. In vitro application of fluvastatin dose-dependently inhibited platelet aggregation. Furthermore, in vitro application of fluvastatin dose-dependently inhibited platelet nitrotyrosine expressions and the inhibitory effects by fluvastatin were reversed by preincubation with geranylgeranylpyrophosphate. CONCLUSIONS: Fluvastatin altered platelet aggregability in hypercholesterolemic patients in a cholesterol-lowering independent manner, which was partly mediated by the improvement of intraplatelet redox imbalance.

Effects of colestimide and/or Bofu-tsusho-san on plasma and liver lipids in mice fed a high-fat diet.

Hypercholesterolemia is known to enhance the risk of coronary heart disease and fatty liver. Colestimide is an anion-exchange resin, which is not absorbed in the small intestine, decreases the intestinal reabsorption of bile acids synthesized from cholesterol in the liver and consequently increases bile acid excretion into the feces. Bofu-tsusho-san, a traditional Japanese herbal remedy, contains 18 components and has long been used as an anti-obesity agent. In the present study, we investigated the effects of colestimide and/or Bohu-tsusho-san in young male mice fed a high-fat diet. The high-fat diet supplemented with both colestimide and Bofu-tsusho-san markedly reduced the plasma levels of lipids, the liver weight and number of fatty droplets in the liver cytoplasm, and the body growth, compared with animals fed a high-fat diet alone. Neither medicine affected the blood biochemistry. Thus, the hypocholesterolemic action of colestimide, sometimes bringing light flatulence, which is improved by simultaneous administration of Bofu-tsusho-san, which activates the thermogenesis of brown adipose tissue, is suggested to reduce body mass and liver lipids, lowering the plasma levels of lipids.