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 ion-pair formation with bile salts on the in vitro cellular transport of berberine

The objective of this study was to examine the effect of ion-pair complexation with endogenous bile salts on the transport of a quarternary ammonium organic cationic (OC) drug, berberine, across the Caco-2 and LLC-PK1 cell monolayers. The basolateral-to-apical (BL-AP) transport of berberine in Caco-2 cells was temperature dependent and 10-fold higher than that of the apical-to-basolateral (AP-BL) transport. Similar results were observed for the transport of berberine across the LLC-PK1 cells. Moreover, the BL-AP transport in the Caco-2 cells was significantly reduced by the cis-presence of P-glycoprotein (P-gp) inhibitors such as cyclosporine A, verapamil, and digoxin. These results suggest that an efflux transporter, probably P-gp, is involved in the Caco-2 cell transport. The K_m and V_max values for the carrier-mediated transport were estimated to be 83.4 mM and 7640 pmole/h/cm², respectively. The apparent partition coefficient (APC) of berberine between n-octanol and a phosphate buffer (pH 7.4) was increased by the presence of an organic anion (OA), taurodeoxycholate (TDC, a bile salt), suggesting the formation of a lipophilic ion-pair complex between an OC (berberine) and an OA (TDC). Despite the ion-pair complexation, however, the BL-AP transport of berberine across the Caco-2 and LLC-PK1 cells was not altered by the cis-presence of bile salts or the rat bile juice. This is consistent with the reportedly unaltered secretory transport of a quarternary ammonium compound, tributylmethylammonium (TBuMA), across the Caco-2 cell monolayers in the cis-presence of bile salts or the rat bile juice, but not with our previous report in which the secretory transport of TBuMA across the LLC-PK1 cell was increased in the cis-presence of TDC. Therefore, the effect of ion-pair formation with the bile components or bile salts on the secretory transport of OCs appears to depend on the molecular properties of OCs (e.g., molecular weight, lipophilicity and affinity to relevant transporters) and the characteristics of cell strains (e.g., expression and contribution of responsible transporters to the transport).     

Safety and efficacy of colesevelam hydrochloride in combination with fenofibrate for the treatment of mixed hyperlipidemia

OBJECTIVE: The aim of this study was to evaluate the amount of low-density lipoprotein cholesterol (LDL-C) reduction achieved by adding the specifically engineered bile acid sequestrant (SE-BAS) colesevelam HCl to a stable dose of fenofibrate in patients with mixed hyperlipidemia. RESEARCH DESIGN AND METHODS: Patients with mixed hyperlipidemia (n = 129) were enrolled in a randomized, double-blind, placebo-controlled, parallel-group study investigating the efficacy of fenofibrate plus colesevelam HCl versus fenofibrate monotherapy. After a 4- to 8-week washout period, subjects received fenofibrate 160 mg/day for 8 weeks and were then randomized to receive colesevelam HCl 3.75 g/day or placebo, in addition to fenofibrate 160 mg/day, for 6 weeks. MAIN OUTCOMES MEASURES: The primary efficacy endpoint was mean percent change in LDL-C during randomized treatment. Secondary endpoints included absolute and percent changes in mean levels of LDL-C, triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC), and apolipoproteins (apo) A-I and B during randomized treatment and from washout to end of randomized treatment. RESULTS: Of the 129 patients randomized to treatment, 119 completed the study. After 6 weeks of treatment, fenofibrate plus colesevelam HCl produced a mean percent change in LDL-C of -10.4% versus +2.3% with fenofibrate monotherapy (p < 0.0001). Fenofibrate plus colesevelam HCl was significantly more effective than fenofibrate alone at reducing levels of non-HDL-C, TC, and apo B (p < or = 0.0002). Colesevelam HCl did not significantly affect the TG-lowering effects of fenofibrate. Both treatment regimens were safe and well tolerated. CONCLUSIONS: Compared with fenofibrate monotherapy in patients with mixed hyperlipidemia, fenofibrate/colesevelam HCl combination therapy significantly reduced mean LDL-C, non-HDL-C, TC, and apo B levels without significantly affecting the TG-lowering or HDL-C-raising effects of fenofibrate. Fenofibrate/colesevelam HCl combination therapy is a safe, useful alternative for the treatment of mixed hyperlipidemia.     

Evaluation of colesevelam hydrochloride for the treatment of type 2 diabetes

INTRODUCTION: Type 2 diabetes often involves derangements in lipid levels in addition to insulin resistance and diminishing insulin secretion. Colesevelam hydrochloride, a bile acid sequestrant (BAS), is approved for adjunctive therapy to diet and exercise for glycemic control in type 2 diabetes. In clinical studies in patients with type 2 diabetes, colesevelam, added to existing metformin, sulfonylurea or insulin therapy, reduced hemoglobin A(1c) (HbA(1c)) by a mean of 0.5% and low-density lipoprotein-cholesterol (LDL-C) by 13-17%. AREAS COVERED: Information pertaining to colesevelam and other BAS was collected using a PubMed literature search of journal articles dating from 1960 to present. Additional articles were identified from bibliographies and from abstracts from American Diabetes Association conferences. The authors review the pharmacology of colesevelam as well as clinical efficacy, safety and tolerability data generated from clinical trials. EXPERT OPINION: Colesevelam induces moderate but significant improvements in HbA(1c) and LDL-C. Outcomes data are needed to determine whether or not colesevelam confers long-term protection against micro- and macrovascular complications. Although colesevelam does not induce weight gain, triglyceride levels tend to increase ~ 15%, the implications of which are unknown at this time. The mechanism(s) by which colesevelam improves glycemia are not yet understood but might involve enhanced meal-induced incretin secretion and altered farnesoid X receptor signaling.     

Advances in the design of fasted state simulating intestinal fluids: FaSSIF-V3

Biorelevant media are commonly used to simulate the physiological composition of human intestinal fluids (HIF) in in vitro solubility and dissolution investigations. In comparison with the surfactant solutions or blank buffers, these media are able to better reflect the physiological solubility and dissolution behavior of poorly soluble active pharmaceutical ingredients (APIs). The aim of this investigation was to review the composition of FaSSIF and FaSSIF-V2 according to recently summarized data about the physiological composition of fasted state human intestinal fluid and propose an updated version, FaSSIF-V3. Furthermore the surface tension was considered as a possible surrogate parameter to gauge the physiological correctness of new versions of biorelevant media.Various prototypes of FaSSIF-V3 were prepared with each of the following five bile salts: taurocholate (TC), glycocholate (GC), tauroursodeoxycholate (TUDC), taurochenodeoxycholate (TCDC) and glycochenodeoxycholate (GCDC) as well as replacing lecithin with its hydrolysis products, lysolecithin and sodium oleate. Two additional media consisting of a mixture of glycocholate (GC) and taurocholate (TG), with or without 0.2 mM cholesterol, were also investigated.Solubilities of ten model compounds in various prototypes of FaSSIF-V3 were measured using HPLC-UV and compared to the solubilities in the existing biorelevant media (FaSSIF and FaSSIF-V2), fasted HIF, blank buffer and a 0.5% sodium dodecyl sulfate (SDS) solution. Additionally, the influence on the surface tension properties of various combinations of bile salts, phospholipids and their hydrolysis products and cholesterol in these media was investigated and an attempt was made to calculate the CMC of the various generations of FaSSIF.The results demonstrated that the amount and the type of phospholipids as well as the type of bile salt had a significant influence on the solubility and surface tension in the various FaSSIF-V3 prototypes and existing biorelevant media. In contrast to results with biorelevant media, it was demonstrated that blank buffers generally underestimate and SDS solutions highly overestimate the physiological relevant solubilities of all investigated APIs.The prototype containing FaSSIF-V3-GC/TC_Chol was able to better reflect the solubilities of the most investigated APIs in fasted HIF than the existing media, and it also matched the physiological surface tension reported for the fasted human gut, and was designated FaSSIF-V3.     

Bile acid sequestrants based on cationic dextran hydrogel microspheres. 2. Influence of the length of alkyl substituents at the amino groups of the sorbents on the sorption of bile salts

Cationic dextran hydrogel microspheres with pendant quaternary ammonium groups having alkyl substituents (C(2)-C(12)) at quaternary nitrogen were synthesized. The in vitro sorption of sodium salts of four bile acids (glycocholic, cholic, taurocholic, and deoxycholic acids) with these hydrogels was studied as a function of substituent alkyl chain length and bile acid hydrophobicity. Sorption experiments were performed in phosphate buffer solutions (pH 7.4) containing one bile salt (individual sorption) or mixtures of several bile salts (competitive sorption). Parameters for individual sorption were calculated taking into consideration the stoichiometric and cooperative binding of bile salts to oppositely charged polymer hydrogels. The results show that the increase in the length of the alkyl chain of the substituent leads to an increase in both ionization constant K(0) and overall stability constant of binding K, but decreases the cooperativity parameter u. The competitive sorption studies indicate that the hydrogels display a good affinity for both dihydroxylic and trihydroxylic bile salts. The molar ratio of maximum amounts bound for the two types of bile acid is 2 to 1, which is much lower than those reported for other cationic polymers recommended as bile acid sequestrants. The binding constants for the sorption of bile salts by some dextran hydrogels are 20-30 times higher than those obtained for cholestyramine under similar sorption conditions.     

Rationale and design of a prospective clinical trial program to evaluate the glucose-lowering effects of colesevelam HCl in patients with type 2 diabetes mellitus

ABSTRACT

Background: Dyslipidemia and type 2 diabetes mellitus (T2DM) increase atherosclerotic coronary heart disease (CHD) risk. In patients with T2DM, improving lipid parameters reduces CHD risk, while optimizing glucose levels reduces microvascular complications and, possibly, macrovascular disease such as CHD. Unfortunately, many patients with T2DM do not achieve either lipid or glucose treatment targets.

Objective: Colesevelam HCl is a specifically engineered bile-acid sequestrant (BAS) indicated to reduce elevated low-density lipoprotein cholesterol concentrations. Earlier studies have demonstrated that BAS not only reduce cholesterol levels, but also lower glucose levels in patients with T2DM. These findings have prompted a robust, prospective phase 3 clinical trial program to further evaluate the safety and tolerability of colesevelam HCl when added to T2DM patients previously treated with metformin, insulin or a sulfonylurea. A limitation of these clinical trials is that none of them assessed colesevelam HCI monotherapy, nor directly compared the glucose-lowering effects of colesevelam HCI to established oral antidiabetes drugs. Nonetheless, this clinical trial program will better determine whether a single agent added to existing diabetes therapy can improve both lipid and glucose parameters in T2DM, which may allow more patients to achieve lipid and glucose treatment targets.

Conclusions: This phase 3 clinical trial program will evaluate colesevelam's glucose-lowering effects in patients with T2DM. In addition, based upon a review of the relevant medical literature through an online electronic PubMed search (without restriction to date other than otherwise occurs through PubMed), potential mechanisms as to how BAS may lower glucose levels are discussed.     

Rationale and design of a clinical trial to evaluate metformin and colesevelam HCl as first-line therapy in type 2 diabetes and colesevelam HCl in prediabetes

ABSTRACT

Objective: The complications of type 2 diabetes mellitus (DM) can begin early in the progression from impaired glucose tolerance to type 2 DM. Metformin is recommended as initial drug therapy for managing hyperglycemia in type 2 DM. The bile acid sequestrant colesevelam hydrochloride (HCl) is approved in the United States for glycemic control in adults with type 2 DM. Colesevelam HCl improves glycemic control and reduces low-density lipoprotein-cholesterol in patients inadequately controlled on metformin-, sulfonylurea-, or insulin-based therapy. This trial is designed to evaluate whether initial therapy with metformin?+?colesevelam HCl provides greater glucose control and additional lipid and lipoprotein benefits, as compared to metformin alone in drug-naïve patients with type 2 DM, and whether treatment with colesevelam HCl has a beneficial effect on lipid and glucose levels in drug-naïve patients with impaired glucose tolerance and/or impaired fasting glucose (prediabetes).

Research design and methods: In this multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, drug-naïve patients with type 2 DM will be randomized 1?:?1 to metformin?+?colesevelam HCl or metformin?+?matching placebo, while those with prediabetes will be randomized 1?:?1 to colesevelam HCl or placebo, for 16 weeks of treatment. The primary efficacy endpoint will be change in glycosylated hemoglobin (HbA_1c) in patients with type 2 DM and change in low-density lipoprotein-cholesterol levels in patients with prediabetes.

Conclusion: A potential limitation is that there is no direct comparator for the dual glucose- and lipid-lowering effect of colesevelam HCl in the prediabetes cohort. However, results of this trial will help to define the extent to which colesevelam HCl can help improve cardiometabolic risk factors for complications of type 2 DM in the first-line environment, and will also indicate the extent to which early intervention with colesevelam HCl can help to correct metabolic abnormalities associated with prediabetes.     

Effect of colesevelam HCl on single-dose fenofibrate pharmacokinetics

OBJECTIVE: The primary aim of this study was to determine whether there is an effect of colesevelam HCl (WelChol; Sankyo Pharma Inc., Parsippany, NJ, USA) on fenofibric acid (active metabolite of fenofibrate, TriCor, Abbott Laboratories, North Chicago, IL, USA) pharmacokinetics following single-dose fenofibrate when colesevelam HCl and fenofibrate are administered concomitantly, or when colesevelam HCl is administered 4 hours following fenofibrate therapy. METHODS: Thirty healthy volunteers were enrolled in a randomised, open-label, three-way crossover, drug interaction study. Subjects received one of three treatments at each of three dose administration periods: (i) treatment A -- fenofibrate 160 mg plus colesevelam HCl 3750 mg (6 x 625 mg tablets) administered with breakfast; (ii) treatment B -- fenofibrate 160 mg administered with breakfast, followed 4 hours later by colesevelam HCl 3750 mg (6 x 625 mg tablets) administered with lunch; or (iii) treatment C -- fenofibrate 160 mg administered with breakfast. Treatments were separated by a 10-day washout period. Blood samples were collected at predetermined time intervals, both before and after drug administration. Plasma concentrations of fenofibrate and fenofibric acid were measured using a validated liquid chromatography/mass spectroscopy/mass spectroscopy method. RESULTS: Area under the concentration-time curve (AUC) from time zero to the timepoint of the lowest quantifiable concentration (AUCt), AUC from time zero to infinity (AUCinfinity) and maximum plasma concentration (Cmax) for fenofibric acid were 92.1%, 93.9% and 79.8%, respectively, of control values when colesevelam HCl and fenofibrate were coadministered with breakfast; and 91.9%, 93.9% and 99.1%, respectively, when fenofibrate was administered followed 4 hours later by administration of colesevelam HCl. The 90% confidence intervals for the ratios of geometric means for AUCt, AUCinfinity and Cmax comparing the three treatments were contained within the 80-125% equivalence range, with the exception of Cmax for treatment A. Coadministration of fenofibrate with colesevelam HCl resulted in an approximate 20% reduction in Cmax of the active metabolite (fenofibric acid). There were no significant differences in the time to Cmax, elimination rate constant or elimination half-life between any of the treatment groups. CONCLUSIONS: Colesevelam HCl had no significant effect on fenofibrate bioavailability when administered either concomitantly with fenofibrate or 4 hours after fenofibrate.     

孟鲁司特钠咀嚼片体外溶出研究

目的 研究孟鲁司特钠咀嚼片体外溶出行为及其影响因素,为该品种新剂型开发和仿制药一致性评价提供参考。方法 考察pH、胆盐、表面活性剂等因素对孟鲁司特钠咀嚼片溶出的影响。结果 孟鲁司特钠在pH 7.5的介质中,随着胆盐浓度的增加,溶解度明显上升;孟鲁司特钠咀嚼片在pH 1.0盐酸溶液、pH 4.0醋酸盐溶液、pH 6.8磷酸盐溶液的溶出过程中,会迅速析出形成混悬液,而0.5%十二烷基硫酸钠水溶液会抑制其析出。结论 孟鲁司特钠咀嚼片的体外溶出受pH、胆盐、表面活性剂的影响较大,可以为其新型给药系统的开发和质量一致性评价提供参考。     

Colesevelam hydrochloride in clinical practice: a new approach in the treatment of hypercholesterolaemia

ABSTRACT

Objective: Hypercholesterolaemia is a major risk factor for atherosclerosis and coronary heart disease. Treatment with lipid lowering agents reduces the risk of vascular events. Colesevelam is a novel bile acid sequestrant (BAS) indicated for the treatment of hypercholesterolaemia, either as monotherapy or in combination with statins.

Scope: This article reviews the efficacy, tolerability and safety of colesevelam in clinical practice. The literature search was based on a PubMed search up to January 2008.

Findings: Colesevelam, used alone or in combination with other hypolipidaemic agents (statins, ezetimibe and fenofibrate), has an overall favourable effect on lipid profile. Specifically, colesevelam reduces total and low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B levels and increases high-density lipoprotein cholesterol and apolipoprotein AI. However, colesevelam may slightly raise triglyceride levels. Colesevelam can improve glycaemic control in diabetic patients. Moreover, it may have anti-inflammatory properties, as it can reduce high sensitivity C-reactive protein concentration. Colesevelam almost lacks the intense side effects of previously used BASs, thus resulting in better patient compliance. However, the dose regimen consisting of up to 7 tablets/day and high cost may limit its use.

Conclusions: Colesevelam is a safe alternative for those intolerant to other lipid lowering medication. This BAS also provides an option for patients who do not reach their LDL-C goal despite treatment with a statin.     

Colesevelam HCl: a non-systemic lipid-altering drug

Colesevelam HCl (WelChol, Sankyo Pharmaceuticals Inc.) is a bile acid sequestrant polymer, which has been shown to significantly lower low density lipoprotein cholesterol and favourably affect high-density lipoprotein cholesterol blood levels in monotherapy and in combination with statins (HMG-CoA reductase inhibitors). Although it is similar to other bile acid sequestrants in that it binds bile acids and is non-systemic, colesevelam HCl differs in that it has a unique polymer structure that allows for greater tolerability with less potential drug interactions than with resins. Currently, statins are the most commonly prescribed lipid-altering drugs. However, it is not uncommon that patients demonstrate true or perceived intolerances to statin therapy, that are often dose-related and may include elevations in liver or muscle enzyme blood levels, or myalgias or muscle weakness without muscle enzyme elevation. In rare circumstances, myopathy and even rhabdomyolysis can occur with statins. In addition, many statins also have important potential drug interactions. Finally, statin monotherapy is often not sufficient in achieving lipid treatment goals in many severely dyslipidaemic patients and the availability of colesevelam HCl provides a lipid-altering treatment addition to other lipid-altering drugs. From a clinical perspective, such combination therapy is often required to achieve treatment goals [1] in patients with more complicated or severe dyslipidaemia. Colesevelam HCl may also be an alternative in monotherapy for many patients with mild-to-moderate hypercholesterolaemia, as well as in some patients at potential risk from systemic exposure to alternative lipid-altering drugs (such as young children and fertile women).     

Beta-blockers and benzodiazepines location in SDS and bile salt micellar systems. An ESR study

The work here described aimed to find out the location of the different species of two families of pharmaceutical substances, namely two beta-blockers (atenolol and nadolol) and two benzodiazepines (midazolam and nitrazepam) in synthetic (sodium dodecyl sulphate, SDS) and natural (bile salts-sodium cholate and sodium deoxycholate) micellar aggregate solutions. Electronic spin resonance spectroscopy studies were carried out, at 25 degrees C and at an ionic strength of 0.10 M in NaCl, using 5-, 12- and 16-doxylstearic acid probes (AS). The immobilization degree of solubilized stearic acid spin probes was found to vary with the position of the nitroxide group in the sequence 5-doxylstearic acid>12-doxylstearic acid>16-doxylstearic acid for SDS and 12-doxylstearic acid>5-doxylstearic acid>16-doxylstearic acid for both bile salts investigated. Therefore, from the rotational correlational time values obtained, it can be inferred that the structure of bile salt micelles is markedly different from that of SDS micelles and the results suggest that the bile salt micelles studied have similar structure independently of differences in the molecular structure of the respective bile salts. Drug location studies were performed at pH 4.0 (SDS solutions) or 7.0 (bile salt solutions) and 10.8 in order to study the effect of the drug ionisation on its relative position on micelles. The results have shown that drug location is controlled by the (i) drug hydrophilicity and acid/base properties, with the more soluble compound in water (atenolol) exhibiting smaller variation of rotational correlational time (in SDS and bile salts solutions), and with both beta-blockers exhibiting smaller deviations in the protonated forms and (ii) the bile salt monomers, with the dihydroxylic bile salt (deoxycholate) producing larger differences. The work described herein allow us to conclude that the (protonated) beta-blockers are probably located on the surface of the detergent micelles, and linked to them by means of essentially electrostatic forces, while the (neutral) benzodiazepines are probably located deeper in the interior of the micelles.     

Stability of esomeprazole capsule contents after in vitro suspension in common soft foods and beverages

STUDY OBJECTIVE: To determine the in vitro stability of esomeprazole pellets from an opened capsule after suspension in various common soft foods and beverages. DESIGN: In vitro study. SETTING: Pharmaceutical company research laboratory. MEASUREMENTS AND MAIN RESULTS: Pellets from opened esomeprazole 20-mg capsules were suspended in 100 ml of tap water, milk (1.5% fat), orange juice, apple juice, yogurt, or cultured milk for 30 minutes, then added to 500 ml of hydrochloric acid to simulate gastric acid exposure. After a 2-hour incubation, the mixture was filtered through a sieve, and the collected pellets were dissolved in an alkaline solution. Esomeprazole concentrations were measured using reverse-phase liquid chromatography The stability of the esomeprazole pellets exceeded 98% in all beverages and soft foods except milk. CONCLUSION: Administration of the pellets from an opened esomeprazole capsule shortly after suspending them in tap water, yogurt, cultured milk, orange juice, or apple juice may be a practical alternative for patients who cannot swallow an intact capsule. Bioavailability studies comparing esomeprazole administered as an intact capsule to that of the pellets from an opened capsule suspended in these beverages or soft foods are recommended to confirm these findings.     

Colesevelam hydrochloride.

The pharmacology, pharmacodynamics, clinical efficacy, drug interactions, adverse effects, and dosage and administration of colesevelam hydrochloride are reviewed. Colesevelam hydrochloride is a nonabsorbed lipid-lowering agent approved for use alone or in combination with hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors for the reduction of low-density-lipoprotein (LDL) cholesterol in patients with primary hypercholesterolemia. Colesevelam forms nonabsorbable complexes with bile acids in the gastrointestinal (GI) tract, resulting in changes in plasma lipid levels, including total, LDL, and high-density-lipoprotein cholesterol and triglycerides. Colesevelam has been reported to be four to six times as potent as traditional bile acid sequestrants (BASs), perhaps because of its greater binding affinity for glycocholic acid. Unlike cholestyramine and colestipol, colesevelam appears to reduce LDL cholesterol in a dose-dependent manner. In clinical trials, colesevelam demonstrated efficacy either alone or in combination with HMG-CoA reductase inhibitors in the treatment of primary hypercholesterolemia. Combination therapy appeared to be more effective than monotherapy. Although infection, headache, and GI adverse effects have been reported for colesevelam, the rates do not differ significantly from those occurring with placebo. The constipation that typically hinders compliance with traditional BASs is minimal. In one study, the rate of compliance with colesevelam was 93%. There is little evidence of clinically significant interactions involving colesevelam. The maintenance dosage is three 625-mg tablets twice daily or six tablets once daily, taken with meals. Colesevelam provides an effective alternative to cholestyramine and colestipol while offering the potential for fewer adverse effects and better compliance. Studies are needed to directly compare colesevelam with traditional BASs.     

Dietary administration of colesevelam hydrochloride does not affect fertility or reproductive performance in rats

Colesevelam hydrochloride (HCl) (WelChol; Sankyo Pharma) is a novel, highly potent, bile acid-binding polymer used for the treatment of hypercholesterolemia. The primary aim of this study was to determine the effects of dietarily administered colesevelam HCl on fertility and reproductive performance parameters. To assess these effects, sexually mature Sprague-Dawley rats were randomized to one of five treatment groups: feed alone, feed plus control article (SigmaCell), or feed plus colesevelam HCl 200, 1000, or 2000 mg/kg/day. Male and female rats were administered the appropriate group agent for 28 and 15 days, respectively, and were subsequently paired together for cohabitation and mating. Females continued to receive the test agent in their dietary formulation through presumed gestation day (GD) 7. Presumed pregnant females underwent cesarean section on GD 20. Food consumption rate, body weight, gross necropsy, and standard preclinical tests for reproduction and fertility were performed for each test animal. No statistically significant differences were found between control and drug-treated groups for any tested endpoints of reproduction. All animals placed in cohabitation successfully mated. Uterine and litter end points were unaffected by dosages of colesevelam HCl as high as 2000 mg/kg/day. There were no significant differences between treatment group litter averages in the number of corpora lutea, implantation sites, litter size, live fetuses, body weights, early/late resorptions, and the number of dams with viable fetuses. In addition, no external alterations of fetal morphology were attributable to treatment with colesevelam HCl when administered up to the embryo implantation stage. In male animals, no significant differences were found between the colesevelam HCl and control study groups in the average caudal epididymal sperm count or sperm concentration, total number of motile and nonmotile sperm, and the total percentage of motile sperm. Based on these data, colesevelam HCl does not have any significant adverse reproductive or fertility effects in rats, even when administered at doses approximately 30 times greater than the approved clinical dose.     

Glucose and low-density lipoprotein cholesterol lowering in elderly patients with type 2 diabetes: focus on combination therapy with colesevelam HCl

The prevalence of type 2 diabetes mellitus is high among the elderly population. Treatment of elderly patients with type 2 diabetes presents challenges because of co-morbidities and the potential increase in the risk of adverse effects. Hyperlipidaemia is also common in the elderly population. Glucose- and lipid-lowering treatment in elderly patients should be individualized on the basis of the patient's life expectancy, health status and cardiovascular risk factors, and evidence-based guideline recommendations. Because elderly patients often have impaired renal and hepatic function, careful considerations must be made when selecting appropriate glucose- and lipid-lowering therapy. There are a number of potential safety issues associated with various glucose- and lipid-lowering therapies that are relevant to elderly patients, including increased risk of heart failure exacerbations, weight loss, increased risk of hypoglycaemia, increased risk of myopathy, and contraindications of some agents in patients with hepatic or renal impairment. The bile acid sequestrant colesevelam HCl is unique compared with other glucose- and lipid-lowering therapies because it is the only product approved by the US Food and Drug Administration, as an adjunct to diet and exercise, to lower both glucose and low-density lipoprotein cholesterol (LDL-C) in adults with type 2 diabetes and primary hyperlipidaemia, respectively. Furthermore, colesevelam has been shown to have similar glucose- and lipid-lowering efficacy in patients aged <65 years and those aged ≥65 years. Colesevelam was not associated with weight gain, was associated with a low incidence of hypoglycaemia, and can be safely combined with a broad range of glucose-lowering agents (metformin, sulfonylureas and insulin) and lipid-lowering statins. Currently, colesevelam is available in tablet form and as a powder for oral suspension formulation; the latter may be of benefit to elderly patients with swallowing difficulties. As colesevelam has both glucose- and lipid-lowering effects, its use may reduce the drug burden in elderly patients receiving multiple agents for glucose and lipid lowering. Colesevelam may be a valuable treatment option as an add-on to existing glucose- and/or lipid-lowering therapy to help improve haemoglobin A(1c) and to lower LDL-C levels in elderly patients with type 2 diabetes and primary hyperlipidaemia.     

Glutathione status of isolated rat hepatocytes affects bile acid-induced cellular necrosis but not apoptosis

An accumulation of hydrophobic bile acids is implicated in the pathogenesis of cholestatic liver diseases. In the present study, we determined if hydrophobic bile acid-induced cellular injury compromised hepatocyte glutathione (GSH) status, and if modulating intracellular GSH levels prevented or facilitated bile acid-induced cellular cytotoxicities. Freshly isolated rat hepatocytes incubated with >/=125 microM of the hydrophobic bile acid, glycochenodeoxycholic acid (GCDC), underwent a time- and dose-dependent decrease of intracellular GSH levels by 4-h incubation. This loss of intracellular GSH was not associated with an increase of intracellular GSH disulfide (GSSG). Rather, GCDC stimulated the dose-dependent accumulation of extracellular GSSG. The mechanism for extracellular GSSG accumulation by GCDC was through increased efflux of reduced GSH from hepatocytes into the media, where it subsequently oxidized to GSSG. Treatment of hepatocytes with GCDC (0-750 microM) did not directly alter GSH-dependent enzyme activities. The reduction of intracellular GSH with 125 microM GCDC correlated with extensive apoptosis at this concentration as determined by fluorescence microscopy of DAPI (4, 6-diamindino-2-phenylindole hydrochloride)-stained nuclei. Higher concentrations of GCDC (>/=500 microM) favored cellular necrosis and lipid peroxidation. Depleting GSH by treating hepatocytes with 1-bromoheptane increased their sensitivity toward GCDC-induced cellular necrosis, but not apoptosis. However, enhancing the hepatocyte GSH content by supplementation with GSH-ethylester (GSH-EE) failed to protect hepatocytes against either mode of cellular death. In conclusion, while GCDC-induced cytotoxicities were associated with an increased efflux of GSH from rat hepatocytes, GSH status modulated GCDC-induced necrosis, but not apoptosis.