Cholestyramine Research Articles

A New Bile Acid Sequestrant

Bile acid sequestrants such as cholestyramine and colestipol hydrochloride are effective in reducing LDL cholesterol (LDL-C) by 10 percent to 30

Increased Fecal Bile Acid Excretion and Changes in the Circulating Bile Acid Pool Are Involved in the Hypocholesterolemic and Gallstone-Preventive Actions of Psyllium in Hamsters

The lipid-lowering effect of psyllium (PSY) is well established. Enhanced fecal bile acid excretion and a stimulation of hepatic bile acid synthesis are discussed as primary mechanisms of this action. To further examine the effect of bile acid excretion and specifically of compositional alterations in the bile acid pool on the cholesterol-lowering and gallstone-preventing action of PSY, male golden Syrian hamsters were fed lithogenic diets containing 5 g/100 g fat, 0.4 g/100 g cholesterol and 0 (control), 4 or 6% PSY or 1% cholestyramine (CHY). PSY significantly lowered plasma total cholesterol and triacylglycerol at a magnitude comparable to that induced by CHY. Although hepatic cholesteryl ester accumulation was completely inhibited by CHY, PSY did not prevent the hepatic storage of esterified cholesterol. PSY and CHY caused distinct alterations in the bile acid profile. PSY caused a selective reduction of taurine-conjugated bile acids, especially of taurochenodeoxycholate. As a result, the glycine:taurine conjugation and the cholate:chenodeoxycholate ratios were significantly higher in PSY-fed hamsters. PSY and CHY normalized the lithogenic index and prevented cholesterol gallstone formation compared with controls. Daily fecal bile acid excretion was ∼400% greater in hamsters fed 6% PSY, whereas CHY caused an 11-fold increase. Daily neutral sterol excretion did not differ in PSY-fed hamsters but was >100% greater in those fed CHY than in controls. These data emphasize the potent lipid-lowering effect of PSY. Increased fecal bile acid excretion and alterations of the circulating bile acid pool by removal of dihydroxy bile acids (e.g., taurochenodeoxycholate) appear to be main modulators of the hypocholesterolemic action of PSY by leading to an up-regulation of hepatic bile acid synthesis.

Determination of 7α-Hydroxycholesterol in Dog Plasma by High-Performance Liquid Chromatography with Fluorescence Detection

A new method was developed for the determination of 7α-hydroxycholesterol (7-HC) in dog plasma by means of high-performance liquid chromatography (HPLC) with fluorescence detection. 7-HC extracted with organic solvent from plasma was purified with Bond Elut 2OH and converted to a sensitive fluorescent derivative containing double coumarin groups at the C-3 and C-7 positions of the steroid nucleus with 7-methoxycoumarin-3-carbonyl azide. After removal of the excess reagent with Bond Elut NH2, the 7-HC derivative was separated by reverse-phase HPLC method. The detection limit of the authentic 7-HC-3,7-coumarin derivative was 4 pg (S/N= 5), approximately four times less than that of the 7-HC-3-anthroyl derivative yielded by reaction of 7-HC with 1-anthroylcyanide. The newly developed method was used to investigate the effects of consecutive oral administrations of cholestyramine (CA) on 7-HC levels in dog plasma. The plasma 7-HC levels of the CA-treated group were two times greater than those of the control group.

The hypocholesterolemic and antiatherogenic effects of chiolazol H, a chemically functionalized insoluble fiber with bile acid sequestrand properties in hamsters

Cholazol H (Alpha-Beta Technology, Worcester, MA), a chemically functionalized, insoluble dietary fiber with bile acid sequestrant properties, was studied in 30 male F 1 B Golden Syrian hamsters for its effect on plasma lipid concentrations and early atherogenesis in experiment 1. In experiment 2, 30 male Golden Syrian hamsters were studied for the effects on plasma lipids and fecal excretion of bile acids. In experiment 1, three groups of 10 hamsters each were fed a chow-based hypercholesterolemic diet supplemented with 5% coconut oil and 0.1% cholesterol for 6 weeks. After 6 weeks, hamsters were continued on the diet with either 0% drug (hypercholesterolemic diet [HCD]), 0.5% cholestyramine (CSTY), or 0.5% Cholazol H for 8 weeks. Fasting plasma lipids were measured at weeks 6, 10, and 14, and early atherosclerosis (fatty streak formation) was measured at week 14. Relative to HCD, CSTY and Cholazol H significantly lowered plasma total cholesterol (TC) (−37%, P < .03, and −30%, P < .04, respectively) and plasma very—low and low-density lipoprotein-cholesterol (nonHDL-Cl (−45%, P < .02, and −36%, P < .03, respectively) with no significant effects on plasma HDL-C or triglycerides (TG). Despite similar reductions in nonHDL-C, only Cholazol H significantly prevented early atherosclerosis (−38%, P < .02) relative to HCD. In experiment 2, three groups of 10 hamsters each were fed a chow-based hypercholesterolemic diet supplemented with 10% coconut oil and 0.05% cholesterol and either 0% drug HCD, 0.5% CSTY, or 0.5% Cholazol H for 4 weeks. Fasting plasma lipids were measured at weeks 2 and 4, and fecal bile acids were measured at week 4. Both Cholazol H and CSTY were equally effective in significantly lowering plasma TC (−16%, P < .003, and −13%, P < .01, respectively) and nonHDL-C (−22%, P < .004, and −18%, P < .02, respectively), with no significant effect on HDL-C and TG relative to HCD. Cholazol H and CSTY produced a significantly greater concentration of fecal total bile acids (39%, P < .001, and 28%, P < .002, respectively) relative to HCD. Also, there was a 48% ( P < .002) and 65% ( P < .001) greater fecal concentration of cholic acid (CA) for Cholazol H—treated hamsters compared with HCD- and CSTY-treated hamsters, respectively. Cholazol H also significantly increased fecal concentration of deoxycholic acid (DCA; 56%, P < .02) compared with HCD. In summary, Cholazol H is as effective as CSTY for prevention of diet-induced hypercholesteorlemia and early atherosclerosis in hamsters.

Dietary Psyllium Increases Fecal Bile Acid Excretion, Total Steroid Excretion and Bile Acid Biosynthesis in Rats

Psyllium, a source of dietary fiber rich in soluble components results in lower serum cholesterol concentration in several species. Suggested mechanisms for the hypocholesterolemic effect include a greater excretion of fecal bile acids and total steroids, and up-regulation of bile acid biosynthesis. The activity of cholesterol 7α-hydroxylase (7αOHase), the rate limiting enzyme in bile acid biosynthesis, is higher in rats fed 5% psyllium. Whether this higher activity corresponds to an increase in mRNA levels has not been determined. Four groups of 10 rats were fed a semipurified diet containing 5% cellulose (CEL; control), 5% cellulose plus 1% cholic acid (CCA), 5% cellulose plus 2% cholestyramine (CHY) or 5% psyllium hydrocolloid (PSY) for 3 wk. Liver cholesterol concentration, fecal bile acid and total steroid excretion, 7αOHase activity and 7αOHase mRNA levels were measured. Liver cholesterol content in rats fed CCA was significantly higher than in all other groups. Rats fed CHY and PSY had significantly lower liver cholesterol content than those fed CEL. Total fecal steroid and bile acid excretions were significantly greater in rats fed CCA, CHY and PSY than in those fed CEL. Activities and mRNA levels of 7αOHase in rats fed CHY and PSY were significantly higher than in rats fed CEL or CCA. These data indicate that feeding psyllium to rats increases fecal bile acid and total steroid excretion as well as 7αOHase activity and 7αOHase mRNA levels.

The ACAT inhibitor, CI-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters

The hypocholesterolemic and anti-atherogenic properties of sulfamic acid ((2,4,6-tris (1-methylethyl) phenyl) acetyl) 2,6-bis(1-methylethyl) phenyl ester, the ACAT inhibitor, CI-1011, was tested in 120 male F 1B hamsters fed a hypercholesterolemic chow-based diet containing 10% coconut oil and 0.05% cholesterol plus: (i) no drug treatment (HCD); (ii) 3 mg/kg per day (HCD+3); (iii)10 mg/kg per day (HCD+10); (iv) 30 mg/kg per day (HCD+30) of CI-1011; or (v) 500 mg/kg per day of cholestyramine (CSTY). Plasma samples were collected at 8 and 10 weeks for measurement of total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). For the progression studies, animals were euthanized after 10 weeks for aortic fatty streak area and hepatic cholesterol analysis. For the regression study, a cohort of the HCD was treated with 30 mg/kg per day of CI-1011 (regression) for an additional 8 weeks. The HCD+3, HCD+10, HCD+30 and CSTY lowered plasma TC (25, 32, 34 and 32%, respectively), VLDL-C (62, 74, 71 and 75%, respectively), LDL-C (25, 38, 47 and 46%, respectively) and TG (48, 47, 42 and 45%, respectively). All treatments resulted in a significant lowering of aortic fatty streak area (68, 86, 93 and 94%, respectively) and reduction in hepatic cholesteryl esters (57, 65, 67 and 70%, respectively). Regression of aortic fatty streak area was 90% after 8 weeks of HCD+30 treatment. Also during the regression phase, plasma TC, LDL-C and TG were lowered 23, 33 and 47%, respectively, as well as, hepatic cholesteryl esters (76%). Significant correlations between plasma LDL-C concentration and aortic fatty streak area ( r=0.62, P<0.004) in the HCD+10 group, suggest that CI-1011 altered aortic lipid infiltration primarily by its effect on plasma lipids. However the 30 mg/kg per day dose of CI-1011 which additionally reduced aortic fatty streak area by 51% relative to the 10 mg/kg per day dose was only associated with a 14% further decrease in plasma LDL-C. Finally the 10-fold regression of aortic fatty streak area was associated with only a 35% reduction in plasma LDL-C. These exceptions to the lipid-lesion relationship raise the possibility of additional effects of CI-1011, which may occur independent of or in concert with lipoprotein cholesterol lowering. It is concluded that in hypercholesterolemic hamsters, CI-1011 is approximately 50 times more potent than cholestyramine in cholesterol-lowering, reduction and regression of aortic fatty streak area.

DIETARY CHOLESTYRAMINE REDUCES OCHRATOXIN A-INDUCED NEPHROTOXICITY IN THE RAT BY DECREASING PLASMA LEVELS AND ENHANCING FECAL EXCRETION OF THE TOXIN

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.

DMP 504, a novel hydrogel bile acid sequestrant: II. Lipid-lowering pharmacology in the hamster

DMP 504 is a novel hydrogel bile acid sequestrant in development for the treatment of moderate hypercholesterolemia. The drug is a condensation polymer synthesized from 1,10-dibromodecane and 1,6-diaminohexane. In vitro binding studies demonstrate that DMP 504 is superior to cholestyramine (CS) with respect to equilibrium binding capacity and affinity for bile acids. The goals of the research reported herein were to assess the in vivo hypolipidemic activity of DMP 504, to elucidate the mechanism of action of DMP 504, and to determine the potency of DMP 504 relative to CS in hamsters. Six dose groups each of DMP 504 and CS were included in the study, along with an untreated control group. The DMP 504 doses ranged from 20–1,000 mg/kg/day for 14 days; CS doses ranged from 50–2,000 mg/kg/day for 14 days. There were 48 animals per dose group; drugs were administered in the feed. At the midpoints of the dose-response curves, DMP 504 was superior to CS with respect to increasing the output of fecal bile acids (7-fold) and sterols (3-fold), increasing the activity of hepatic cholesterol 7α-hydroxylase activity (C7αOH) (6-fold), and decreasing the circulating levels of total serum cholesterol (6-fold), non-HDL cholesterol (6-fold), and HDL cholesterol (4-fold). Neither DMP 504 nor CS had significant effects on serum triglycerides or apo-B. In summary, DMP 504 is a new bile acid sequestrant that is mechanistically similar to CS, but is, on average, 6-fold more potent. Drug Dev. Res. 41:65–75, 1997. © 1997 Wiley-Liss, Inc.

DMP 504, a novel hydrogel bile acid sequestrant: III. Safety, tolerability, and cholesterol‐lowering in healthy hypercholesterolemic subjects

This multiple-dose study of DMP 504, a hydrogel bile acid sequestrant, employed a randomized, double-blind, sequential-cohort design with placebo (blinded) and open-label cholestyramine (CS) controls. Ninety-three healthy primary hypercholesterolemic subjects (serum LDL cholesterol 130 to 200 mg/dL; triglycerides ≤280 mg/dL) maintaining a stable diet (NCEP Step One) for 3 weeks received either DMP 504 or placebo DMP 504 in capsules, or CS powder for suspension (16 g/d). The DMP 504 dose (0.9, 1.8, 2.7, 3.6, 5.4, 7.2 g/d) escalated with sequential enrollment of cohorts (DMP 504 n = 10, placebo n = 2, and CS n = 3 for Cohorts I–V; DMP 504 n = 8, placebo n = 2 for Cohort VI). An additional cohort (VII) included DMP 504 3.6 g/d, n = 9, and placebo, n = 2. LDL cholesterol (LDL-C) decreased in a dose-dependent manner (–15.8% to –34.1%; r = –0.56; P < 0.001) over the dose range 0.9 g/d to 7.2 g/d after 2 weeks of dosing with DMP 504 and +0.8% to –19.7% (r = –0.48; P < 0.001) over doses 0.9 g/d to 5.4 g/d after 6 weeks. LDL-C did not change with placebo but declined with cholestyramine by –28.3% at 2 weeks and –23.9% at 6 weeks. Plasma 7-α-hydroxy-4-cholesten-3-one, a marker of hepatic cholesterol 7-α-hydroxylase activity, increased dose-dependently with DMP 504 and with CS; change in LDL-C correlated inversely with 7-α-hydroxy-4-cholesten-3-one (r = –0.46; P < 0.001). There was no dose-limiting toxicity with DMP 504. One subject (DMP 504 2.7 g/d) withdrew because of gastrointestinal disturbance. Subject complaints were largely gastrointestinal in nature (flatulence, abdominal discomfort, diarrhea/constipation) occurring in 53% of the 64 DMP 504, 60% of 15 CS, and 29% of 14 placebo subjects. The novel hydrogel DMP 504 can induce significant LDL cholesterol lowering at doses of several grams/day with an acceptable side effect profile. Drug Dev. Res. 41:76–84, 1997. © 1997 Wiley-Liss, Inc.

DMP 504, a novel hydrogel bile acid sequestrant: III. Safety, tolerability, and cholesterol-lowering in healthy hypercholesterolemic subjects

This multiple-dose study of DMP 504, a hydrogel bile acid sequestrant, employed a randomized, double-blind, sequential-cohort design with placebo (blinded) and open-label cholestyramine (CS) controls. Ninety-three healthy primary hypercholesterolemic subjects (serum LDL cholesterol 130 to 200 mg/dL; triglycerides ≤280 mg/dL) maintaining a stable diet (NCEP Step One) for 3 weeks received either DMP 504 or placebo DMP 504 in capsules, or CS powder for suspension (16 g/d). The DMP 504 dose (0.9, 1.8, 2.7, 3.6, 5.4, 7.2 g/d) escalated with sequential enrollment of cohorts (DMP 504 n = 10, placebo n = 2, and CS n = 3 for Cohorts I–V; DMP 504 n = 8, placebo n = 2 for Cohort VI). An additional cohort (VII) included DMP 504 3.6 g/d, n = 9, and placebo, n = 2. LDL cholesterol (LDL-C) decreased in a dose-dependent manner (–15.8% to –34.1%; r = –0.56; P < 0.001) over the dose range 0.9 g/d to 7.2 g/d after 2 weeks of dosing with DMP 504 and +0.8% to –19.7% (r = –0.48; P < 0.001) over doses 0.9 g/d to 5.4 g/d after 6 weeks. LDL-C did not change with placebo but declined with cholestyramine by –28.3% at 2 weeks and –23.9% at 6 weeks. Plasma 7-α-hydroxy-4-cholesten-3-one, a marker of hepatic cholesterol 7-α-hydroxylase activity, increased dose-dependently with DMP 504 and with CS; change in LDL-C correlated inversely with 7-α-hydroxy-4-cholesten-3-one (r = –0.46; P < 0.001). There was no dose-limiting toxicity with DMP 504. One subject (DMP 504 2.7 g/d) withdrew because of gastrointestinal disturbance. Subject complaints were largely gastrointestinal in nature (flatulence, abdominal discomfort, diarrhea/constipation) occurring in 53% of the 64 DMP 504, 60% of 15 CS, and 29% of 14 placebo subjects. The novel hydrogel DMP 504 can induce significant LDL cholesterol lowering at doses of several grams/day with an acceptable side effect profile. Drug Dev. Res. 41:76–84, 1997. © 1997 Wiley-Liss, Inc.

DMP 504, a novel hydrogel bile acid sequestrant: I. equilibrium binding properties and computer simulation of human bile flow

DMP 504 is a novel bile acid sequestrant under development for the treatment of primary hypercholesterolemia. The resin is a soft-textured hydrogel that is synthesized from 1,10-dibromodecane and 1,6-diaminohexane. The equilibrium binding parameters for DMP 504 have been determined and compared to cholestyramine (CS) with respect to the major trihydroxy bile acid, glycocholate (GC), and the major dihydroxy bile acid, glycochenodeoxycholate (GCDC). DMP 504 had a greater maximum binding capacity (Bmax) than CS for GC (5.47 ± 0.06 vs. 2.76 ± 0.17 moles/kg) and GCDC (5.71 ± 0.14 vs. 3.26 ± 0.11 moles/kg). DMP 504 had a greater affinity, i.e., a lower Kd, than CS for GC (1.78 ± 0.04 vs. 5.24 ± 0.64 mM) and GCDC (0.19 ± 0.01 vs. 0.52 ± 0.06 mM). Similar values were obtained for the taurine conjugates of cholate and chenodeoxycholate. Since the interaction of bile acids with DMP 504 was highly cooperative, the binding isotherms were analyzed with a model that included a cooperativity parameter (W) to allow for interactions between adjacently bound bile acids. The DMP 504 binding isotherms showed greater cooperativity than CS for GC (5.10 ± 0.42 vs. 1.81 ± 0.47) and GCDC (6.28 ± 1.68 vs. 2.40 ± 0.76). A mathematical model of human bile flow, using the values for Bmax, Kd, and W determined in this study predicted that DMP 504 would be approximately threefold more potent than CS in a clinical setting. Drug Dev. Res. 41:58-64, 1997. © 1997 Wiley-Liss, Inc.

Effect of Cholestyramine on the Pharmacokinetics and Pharmacodynamics of Bezafibrate in Rats.

The interaction between bezafibrate (BF) and cholestyramine (CT), an anionic exchange resin, was evaluated both in vitro and in vivo.In an in vitro study, the incubation of 100 or 1000 μg/ml of BF solution with 200 mg of CT at various pH (2.0, 5.0 and 7.0) solutions was performed at 37° for 10 min in order to evaluate the binding ability of BF to CT. After incubation, 100 μg/ml of BF bound to CT by 85.41, 89.40 and 92.14% at pH 2, 5 and 7, respectively, and 1000 μg/m1 of BF bound to CT by 66.28 and 69.02%, at pH 5 and 7, respectively.Next, the effect of CT on the pharmacokinetics and pharmacodynamics of BF was examined in experimentally induced hypercholesterolemic rats. When BF (50 mg/kg/day p. o.) and CT (600 mg/kg/day p.o.) were continuously administered to rats once a day for 7 days, CT caused a significant reduction in the cholesterol-lowering effect of BF in accordance with a significant decrease in the plasma level of BF, compared with the administration of BF alone. The decreased plasma BF level closely reflected the cholesterol-lowering effect of BF. Even when CT was given 3h after BF, the pharmacokinetics and pharmacodynamics of BF were not sufficient to achieve a full recovery of the BF level. The present observations thus suggest that CT should be used with extreme caution in patients receiving BF.

The Effect of Activated Charcoal and Cholestyramine on the Pharmacokinetics of Leflunomide

Clinical Pharmacology & Therapeutics (1996) 59, 204–204; doi: 10.1038/sj.clpt.1996.315

Drug interaction between simvastatin and cholestyramine in vitro and in vivo.

The interaction between simvastatin (SV), a prodrug lactone, HMG-CoA reductase inhibitor which converts to the active hydroxy acid form (SVH) in vivo, and cholestyramine (CT), an anionic exchange resin, was evaluated both in vitro and in vivo. In an in vitro SV-stability study, it was shown that SV degraded gradually to SVH in an aqueous solution at pH 2 and 7. To evaluate the binding ability of SV or SVH to CT, the incubation of 5 micrograms/ml of SV or SVH solution with 200 mg of CT in various pH (2.0, 5.0 and 7.0) solutions was performed at 37 degrees C for 10 min. After incubation, the concentration of SV decreased by 59.02% (pH 2), 63.90% (pH 5) and 67.36% (pH 7), respectively, and an interaction between SV and CT was suggested. The values were much larger than those expected from the stability test of SV in the absence of CT. SVH was found to bind more strongly to CT. The binding ability of SVH to CT was 66.71% (pH 2), 87.44% (pH 5) and 92.11% (pH 7), respectively. Judging from these results, SV was considered to interact with CT by the following procedure: SV underwent hydrolysis to SVH in aqueous solution, then CT activated the hydrolysis by binding the formed SVH, resulting in a significant reduction in concentration of SV. On the other hand, an in vivo animal experiment also demonstrated a significant reduction (about 50% with AUC) in the concentration of SVH in plasma following the coadministration of SV (500 mg/kg p.o.) and CT (600 mg/kg p.o.), compared with the administration of SV alone. This phenomenon suggested that a combination therapy using SV and CT might result in a smaller cholesterol-lowering effect of SV.

ウルソデオキシコール酸・コレスチラミン併用療法によって頑固な皮膚掻よう感が消失した原発性胆汁性肝硬変の一症例 血清胆汁酸分画の解析

症例は51歳,女性で皮膚掻痒感を主訴とし,血清胆道系酵素の上昇と抗ミトコンドリア抗体,抗PDH抗体陽性所見及び肝生検により原発性胆汁性肝硬変(PBC) stage I-IIと診断された.ウルソデオキシコール酸UDCA (600mg/日)毎食後経口投与開始後,血清胆道系酵素値,AST, ALT, IgMが改善されたが,強い皮膚掻痒感は持続したため,UDCAを毎食間に,CS (12g/日)を毎食前に経口投与する併用療法を開始し,同併用療法開始後皮膚掻痒感は速やかに軽減し始め,30日後に完全に消失した.血清胆汁酸の経時的分析の結果,治療開始前健常時に上昇していた血清総胆汁酸値はUDCA投与によりさらに上昇し,その60%はUDCAにより置換された.さらに,UDCA・CS併用療法によって血清総胆汁酸値はほぼ健常者の値に減少し,UDCAは全分画の約30%に保たれ,同時にCDCAの減少が認められた.生検肝における胆管上皮細胞の乳頭状増生の超微形態像は胆汁成分の再吸収促進を示唆する所見として興味深い.本症例で試みられたUDCA・CS併用療法は,両薬剤の投与の仕方によっては血清総胆汁酸プールを健常レベルに低下させながらUDCAを30%以上に保ち,特に脂質親和性CDCA濃度低下をさせ,それによって皮膚掻痒感の改善とともにUDCAによる血液生化学的検査値の改善を維持することが可能であり,今後皮膚掻痒感を伴うPBCの治療に有用であると考えられた.

Comparison of the effect of fluvastatin, an hydroxymethyl glutaryl coenzyme A reductase inhibitor, and cholestyramine, a bile acid sequestrant, on lipoprotein particles defined by apolipoprotein composition

In a double-blind, parallel-group, randomized study, the effects of fluvastatin (FLUV) 20 and 40 mg/d on lipoprotein particle levels were compared with those of cholestyramine (CME) 16 g/d. Lipoparticles were defined by apolipoprotein composition as either those containing both apolipoprotein (apo) B and apo E or CHI (lipoprotein [Lp] E-B or Lp CIII-B) or those containing apo Al alone (Lp AI) or in association with apo AII (Lp AI-AII). After an 8-week dietary stabilization period, 100 hypercholesterolemic patients were treated with FLUV 20 mg/d for 6 weeks and 40 mg/d for an additional 6 weeks and were compared with 48 hypercholesterolemic subjects treated with CME 16 g/d. Treatment with FLUV (40 mg/d) or CME (16 g/d) for 12 weeks was associated with a significant reduction in plasma cholesterol and low-density lipoprotein (LDL) cholesterol and a significant increase in high-density lipoprotein (HDL) cholesterol. However, plasma triglyceride levels decreased following FLUV treatment, whereas they increased with CME. These changes were associated with a significant reduction in the levels of apo B (FLUV, −24%, P < .001; CME, −26%, P < .001), apo E (FLUV, −36%, P < .001; CME, −32%, P < .001), and apo CIII (FLUV, −21%, P < .001; CME, −6%, NS). The decreased levels of apo E and apo CIII were mainly due to a decrease in the apo B-containing fraction as assessed by the decrease in apo E (FLUV, −40%, P < .001; CME, −24.4%, P < .001) and apo CIII (FLUV, −50%, P < .05; CME, −33%, NS) that coprecipitated with apo B-containing lipoproteins and by the decrease in plasma levels of Lp E-B (FLUV, −25.8%, P < .001; CME, 2.3%, NS) and Lp CIII-B (FLUV, −48.8%, P < .001; CME, −34.1%, P < .001). With regard to apo AI-containing particles, significant effects were observed. Treatment with FLUV or CME increased plasma levels of apo AI (FLUV, +4.7%, P < .001; CME, +8.7%, P < .001) and Lp AI (FLUV, +10%, P < .001; CME, +25.5%, P < .001) and decreased Lp AI-AII (FLUV, −5.7%, NS; CME, −11.5%, P < .05). FLUV or CME decreased apo E bound to HDL (−36.8%, P < .001, and −50%, P < .001, respectively). In summary, treatment with FLUV or CME was associated with beneficial changes in plasma lipid, lipoprotein, apolipoprotein, and lipoparticle levels. FLUV is more efficient in reducing levels of atherogenic apo B-containing particles, whereas CME has a greater effect in increasing the levels of Lp AI.

Changes in serum lipoprotein(a) in hyperlipidemic subjects undergoing long-term treatment with lipid-lowering drugs

Though the exact physiology and pathology of lipoprotein(a) [Lp(a)] remains unknown, it has been demonstrated that increased serum Lp(a) levels are correlated with an increased risk of atherosclerotic vascular disease. The effects of lipid-lowering drugs on Lp(a) levels is unclear because of inconsistencies between study designs. This study analyzes the effects of the commonly used lipid-lowering drugs pravastatin (PRAV), lovastatin (LOV), and cholestyramine (CHOL) on serum Lp(a) and other serum lipid levels in a parallel study design. Hyperlipidemic men (n = 32) were enrolled from three centers and treated for 48 weeks in a multicenter clinical trial using PRAV, LOV, CHOL, or a placebo (for the first 16 weeks only). Baseline serum low-density lipoproteins (LDL-C), high-density lipoproteins (HDL-C), and triglycerides were 199 +/- 38, 40 +/- 9, and 160 +/- 70 mg/dl, respectively. At the end of 48 weeks, serum plasma LDL-C declined in patients randomized to PRAV, LOV, and CHOL, respectively, by 31%, 29%, and 23% (all p < 0.001); HDL increased by 4%, 11%, and 11% (all p < 0.001); and TG changed by -16%, -28%, and +43% (all p < 0.001). Subjects in PRAV and LOV changed Lp(a) by 9% and 3%, respectively. Although there was an initial Lp(a) decline in the first 8 weeks of CHOL therapy (p < 0.05, ANOVA), this returned to baseline after 48 weeks. In this parallel study design PRAV, LOV, and CHOL are effective LDL-lowering medications with minimal effects on plasma Lp(a).

High-dose fluvastatin and bezafibrate combination treatment for heterozygous familial hypercholesterolemia

<h2>Abstract</h2> This study assessed the long-term use of fluvastatin, alone or in combination with bezafibrate, in patients with severe familial hypercholesterolemia who, in a previous study, did not achieve target levels (European Atherosclerosis Society) of low density lipoprotein cholesterol (LDL-C) with fluvastatin at 60 mg/day plus bezafibrate 200 mg/day, with or without cholestyramine (CME) at 8 g/day. This open-label study comprised 3 periods: period I, 6 weeks of fluvastatin at 40 mg twice daily (at breakfast and at bedtime); period II, fluvastatin at 80 mg/day (40 mg at breakfast, 40 mg at bedtime), and bezafibrate at 200 mg/day (at lunchtime) for 6 weeks in patients not achieving LDL-C target levels; and period III, force-titration of fluvastatin to 80 mg/day (as in period II) and bezafibrate at 400 mg/day (slow release) in patients receiving combination treatment. Patients were excluded if, during the previous study, they had experienced a serious drug-related adverse event or deterioration in liver or kidney function (liver enzymes >3 times upper limit of normal). The standard physical and laboratory evaluations were performed at regular intervals. Lipid profiles were determined from 12-hour fasting blood samples. All adverse events occurring or worsening during the study, whether spontaneously reported or elicited by questioning, and regardless of relationship to study medication, were recorded. So far, data up to week 36 of this 88-week study indicate a progressive reduction of LDL-C levels from 300.0 ± 48.7 (baseline) to 205.3 ± 41.9 mg/dL (80 mg fluvastatin), 192.7 ± 24.8 mg/dL (80 mg fluvastatin plus 200 mg bezafibrate for 6 weeks), and 184.4 ± 28.2 mg/dL (80 mg fluvastatin plus 400 mg bezafibrate for 24 weeks). Similarly, the LDL-C:high density lipoprotein cholesterol ratio improved from 8.1 ± 2.1 to 4.5 ± 1.1. With this high-dose combination treatment, only 6 patients had LDL-C levels >200 mg/dl. During this period of the study, no adverse events were recorded and all medications were well tolerated. The compliance rate, as determined by capsule or tablet counting, was >92.7% for fluvastatin and >84.9% for bezafibrate. In conclusion, these results suggest that high-dose fluvastatin combined with bezafibrate is safe and effective in the treatment of patients with heterozygous familial hypercholesterolemia.

High-dose fluvastatin and bezafibratecombination treatment for heterozygous familial hypercholesterolemia

This study assessed the long-term use of fluvastatin, alone or in combination with bezafibrate, in patients with severe familial hypercholesterolemia who, in a previous study, did not achieve target levels (European Atherosclerosis Society) of low density lipoprotein cholesterol (LDL-C) with fluvastatin at 60 mg/day plus bezafibrate 200 mg/day, with or without cholestyramine (CME) at 8 g/day. This open-label study comprised 3 periods: period I, 6 weeks of fluvastatin at 40 mg twice daily (at breakfast and at bedtime); period II, fluvastatin at 80 mg/day (40 mg at breakfast, 40 mg at bedtime), and bezafibrate at 200 mg/day (at lunchtime) for 6 weeks in patients not achieving LDL-C target levels; and period III, force-titration of fluvastatin to 80 mg/day (as in period II) and bezafibrate at 400 mg/day (slow release) in patients receiving combination treatment. Patients were excluded if, during the previous study, they had experienced a serious drug-related adverse event or deterioration in liver or kidney function (liver enzymes >3 times upper limit of normal). The standard physical and laboratory evaluations were performed at regular intervals. Lipid profiles were determined from 12-hour fasting blood samples. All adverse events occurring or worsening during the study, whether spontaneously reported or elicited by questioning, and regardless of relationship to study medication, were recorded. So far, data up to week 36 of this 88-week study indicate a progressive reduction of LDL-C levels from 300.0 ± 48.7 (baseline) to 205.3 ± 41.9 mg/dL (80 mg fluvastatin), 192.7 ± 24.8 mg/dL (80 mg fluvastatin plus 200 mg bezafibrate for 6 weeks), and 184.4 ± 28.2 mg/dL (80 mg fluvastatin plus 400 mg bezafibrate for 24 weeks). Similarly, the LDL-C:high density lipoprotein cholesterol ratio improved from 8.1 ± 2.1 to 4.5 ± 1.1. With this high-dose combination treatment, only 6 patients had LDL-C levels >200 mg/dl. During this period of the study, no adverse events were recorded and all medications were well tolerated. The compliance rate, as determined by capsule or tablet counting, was >92.7% for fluvastatin and >84.9% for bezafibrate. In conclusion, these results suggest that high-dose fluvastatin combined with bezafibrate is safe and effective in the treatment of patients with heterozygous familial hypercholesterolemia.

Marked effects of acute but not chronic oral cholestyramine (CH) on gallbladder (GB) and antroduodenal motility: [formula omitted]1,3, PC van de Meeberg 1, KJ van Erpecum 1, AJPM Smout 1, LMA Akkermans 2, G Palasciano 3, GP van Berge-Henegouwen 1. Depts. Gastroenterology 1 & Surgery 2, University Hospital Utrecht, Netherlands. Clinica Medica I, University of Bari Medical School, Italy 3

Marked effects of acute but not chronic oral cholestyramine (CH) on gallbladder (GB) and antroduodenal motility: [formula omitted]1,3, PC van de Meeberg 1, KJ van Erpecum 1, AJPM Smout 1, LMA Akkermans 2, G Palasciano 3, GP van Berge-Henegouwen 1. Depts. Gastroenterology 1 & Surgery 2, University Hospital Utrecht, Netherlands. Clinica Medica I, University of Bari Medical School, Italy 3