Potential of Naftifine Application for Transungual Delivery.

Naftifine is used to treat fungal skin infections as it inhibits dermatophytes, which are the cause of onychomycosis. However, naftifine's ability to permeate the human nail barrier has not been investigated, thus, the antimycotic potential is not clearly established. This work aims to evaluate the effect of penetration enhancing factors on the accumulation of naftifine hydrochloride through human nail clippings. Naftifine polymeric nail lacquers with Eudragit RL100 were developed as a suitable delivery system. Low penetration of naftifine into nail has been determined as less than 10% of applied drug dose accumulated in the nail layers. Incorporation of thioglycolic acid into formulations resulted in increased accumulation of antifungal agent in the nail layers by 100% compared with a control group. Salicylic acid did not effect naftifine accumulation in the human nail. The permeation of naftifine through the nail increased by threefold when the thioglycolic acid-containing formulation was applied and the nail was pretreated with a fractional CO2 laser. Structural changes of the nail barrier, induced by fractional CO2 laser, were visualized by microscopy. The results suggest, that naftifine nail penetration could be significantly increased when physical and chemical enhancing factors are applied.

A pilot, layerwise, ex vivo evaluation of the antifungal efficacy of amorolfine 5% nail lacquer vs other topical antifungal nail formulations in healthy toenails.

BACKGROUND: Studies investigating the penetration of amorolfine through the nail have shown the highest concentration in the uppermost layer and measurable antifungal activity even in the lower layers of the nail. OBJECTIVES: This pilot, ex vivo study compared the penetration of antifungal concentrations of amorolfine 5% nail lacquer in different layers of healthy, human cadaver toenails with that of terbinafine 10% nail solution, ciclopirox 8% nail lacquer and naftifine 1% nail solution. Moreover, the effect of nail filing prior to application on the penetration of amorolfine 5% was assessed. METHODS: Unfiled (n = 3) and filed (n = 3) nails were used for each antimycotic agent and amorolfine 5% nail lacquer, respectively. Twenty-four hours after topical application, the nails were sliced (10 µm), solubilised and added to agar plates seeded with Trichophyton rubrum. Zones of growth inhibition were measured. RESULTS: Only amorolfine penetrated the nails at sufficient concentrations to inhibit growth of T rubrum at different nail depths. In contrast, the comparators did not show antifungal efficacy. Nail filing resulted in larger zones of inhibition for amorolfine compared with those of intact nails. CONCLUSIONS: Unlike its comparators, a single application of amorolfine 5% nail lacquer resulted in antifungal efficacy within the nail plate. Nail filing increased the antifungal efficacy of amorolfine 5% nail lacquer.

Pulsed electric field-assisted sensitization of multidrug-resistant Candida albicans to antifungal drugs.

AIM: Determine the influence of pH on the inactivation efficiency of Candida albicans in pulsed electric fields (PEF) and evaluate the possibilities for sensitization of a drug-resistant strain to antifungal drugs. MATERIALS & METHODS: The effects of PEF (2.5-25 kVcm-1) with fluconazole, terbinafine and naftifine were analyzed at a pH range of 3.0-9.0. Membrane permeabilization was determined by flow cytometry and propidium iodide. RESULTS: PEF induced higher inactivation of C. albicans at low pH and increased sensitivity to terbinafine and naftifine to which the strain was initially resistant. Up to 5 log reduction in cell survival was achieved. CONCLUSION: A proof of concept that electroporation can be used to sensitize drug-resistant microorganisms was presented, which is promising for treating biofilm-associated infections.

The impact of allylamine-bile acid combinations on cell delivery microcapsules in diabetes.

OBJECTIVE: In a recent study, we developed a new microencapsulating method for ß-cell microencapsulation, but cell viability declined rapidly, post microencapsulation, due to potential polymer-polyelectrolyte chelation and non-porous microcapsules' membranes resulting in cell apoptosis. Thus, this study tested the effects of incorporating cationic polyamine at 1% w/v, on microcapsule strength and cell viability, in the absence or presence of an anionic tertiary bile acid (ATBA) with potential cell-protective effects. METHODS: 1% w/v polyamine was used without or with ATBA, to form ß-cell microcapsules and physical and biological analyses was carried out 50 h post microencapsulation. RESULTS: Microcapsules containing 1% w/v polyamine showed weak physical properties and low cell viability and ATBA incorporation resulted in >30% reduction in cell viability and increased levels of pro-inflammatory cytokines. CONCLUSION: Neither 1% w/v polyamine nor the presence of ATBA resulted in optimised cell viability, but rather reduced cell viability, enhanced inflammation and lowered insulin secretion.

An Open-Label, Multi-Center, Multiple-Application Pharmacokinetic Study of Naftifine HCl Gel 2% in Pediatric Subjects With Tinea Pedis.

BACKGROUND: Tinea pedis is the most common superficial fungal infection. Naftifine hydrochloride is a topical antifungal of the allylamine class, displaying fungicidal activity and clinically significant anti-bacterial and anti-inflammatory effects. Clinical data on topical antifungal therapy using naftifine for tinea pedis in a pediatric population is limited. OBJECTIVE: To assess trends in efficacy, tolerability, safety, and to quantify the pharmacokinetics (PK) of topical naftifine hydrochloride gel 2% in pediatric subjects with tinea pedis. METHODS: Twenty-eight subjects (22 pediatric and 6 adult controls) were enrolled and treated in the study. Approximately 2 grams of naftifine hydrochloride gel 2% was applied to each foot (4 grams total) for subjects with tinea pedis. Pharmacokinetic blood and urine samples were collected at various time points throughout the study. Efficacy was assessed based on potassium hydroxide, dermatophyte culture, and signs and symptom results at days 7, 14, and 28. Adverse event information was collected routinely.
RESULTS: The rate and extent of systemic exposure among the pediatric and adult control subjects was low. Adverse events were minimal and were not related to treatment. Positive results were observed as early as day 7; however the proportion of subjects achieving success generally increased over time through day 28 in both treatment groups. CONCLUSIONS: Naftifine hydrochloride gel 2% was found to be well tolerated and safe. Trends in clinical benefit were observed throughout the treatment period; however, continued improvement in efficacy rates were observed during the post-treatment period.

Effects of an anti-inflammatory VAP-1/SSAO inhibitor, PXS-4728A, on pulmonary neutrophil migration.

BACKGROUND AND PURPOSE: The persistent influx of neutrophils into the lung and subsequent tissue damage are characteristics of COPD, cystic fibrosis and acute lung inflammation. VAP-1/SSAO is an endothelial bound adhesion molecule with amine oxidase activity that is reported to be involved in neutrophil egress from the microvasculature during inflammation. This study explored the role of VAP-1/SSAO in neutrophilic lung mediated diseases and examined the therapeutic potential of the selective inhibitor PXS-4728A. METHODS: Mice treated with PXS-4728A underwent intra-vital microscopy visualization of the cremaster muscle upon CXCL1/KC stimulation. LPS inflammation, Klebsiella pneumoniae infection, cecal ligation and puncture as well as rhinovirus exacerbated asthma models were also assessed using PXS-4728A. RESULTS: Selective VAP-1/SSAO inhibition by PXS-4728A diminished leukocyte rolling and adherence induced by CXCL1/KC. Inhibition of VAP-1/SSAO also dampened the migration of neutrophils to the lungs in response to LPS, Klebsiella pneumoniae lung infection and CLP induced sepsis; whilst still allowing for normal neutrophil defense function, resulting in increased survival. The functional effects of this inhibition were demonstrated in the RV exacerbated asthma model, with a reduction in cellular infiltrate correlating with a reduction in airways hyperractivity. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that the endothelial cell ligand VAP-1/SSAO contributes to the migration of neutrophils during acute lung inflammation, pulmonary infection and airway hyperractivity. These results highlight the potential of inhibiting of VAP-1/SSAO enzymatic function, by PXS-4728A, as a novel therapeutic approach in lung diseases that are characterized by neutrophilic pattern of inflammation.

Sevelamer in a diabetologist's perspective: a phosphate-binding resin with glucose-lowering potential.

Sevelamer is a calcium-free and metal-free phosphate-binding oral drug used in the management of hyperphosphataemia in chronic kidney disease. Preclinical and clinical trials have shown glucose and lipid-lowering effects of sevelamer, thereby giving rise to a potential role of the drug in the treatment of patients with type 2 diabetes. These 'novel' effects are most probably derived from the bile acid-binding properties of sevelamer. The proposed potential is supported by the approval of the bile acid sequestrant colesevelam in the United States for the treatment of type 2 diabetes and hypercholesterolaemia. This article offers a brief review on the effects of sevelamer and a perspective on the potential mechanisms behind the glucose-lowering effect of the drug.

Detection and relevance of naftifine hydrochloride in the stratum corneum up to four weeks following the last application of naftifine cream and gel, 2%.

BACKGROUND: Two-week treatment using naftifine cream or gel, 2% has been shown to be efficacious in subjects with Tinea pedis and/or Tinea cruris, and in most cases, continued improvement has been observed following cessation of treatment for up to four weeks. One possible explanation for continuous post-treatment improvement is drug-levels remaining in the stratum corneum (SC) as a function of time. OBJECTIVE: The objective is to use tape stripping methodology to assess the amount of drug available in the SC over a 28 day period following the last dose. METHODS: This was an open-label, single-exposure study on subjects comparing the amount of drug that was absorbed into the SC following topical application for 2-weeks. Twelve subjects were dosed daily (6 with naftifine cream, 2% and 6 with naftifine gel, 2%). Subjects had twelve 8 cm2 test application sites demarcated on the upper back. Twenty-five individual sequential strips were obtained from each test site. Of these, 11 sites were dosed once daily with the drug (5.0µL/cm2) for days 1 to 14 and the final site served as the control. On days 15, 29, and 43, a site was stripped to collect the SC in order to process the amount of drug present. RESULTS: Naftifine was present on all tape strip samples collected over the 28 day period following two weeks of application. Furthermore, the most relevant, deeper tape strip sets reflecting the SC, showed potentially clinically relevant presence of naftifine in the skin for 28-days post-treatment. CONCLUSIONS: Naftifine was present in the tape strips on all sample collection days up to and including four weeks following the last drug application. These findings help explain the progressive improvement in clinical and mycological response rates during the treatment period and for up to four weeks post-treatment in the clinical trials using naftifine.

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.

Pharmacogenetics of the effects of colesevelam on colonic transit in irritable bowel syndrome with diarrhea.

BACKGROUND: Protein products of klothoß (KLB) and fibroblast growth factor receptor 4 (FGFR4) impact fibroblast growth factor 19-mediated feedback inhibition of hepatic bile acid (BA) synthesis. Variants of KLB and FGFR4 influence colonic transit (CT) in diarrhea-predominant irritable bowel syndrome (IBS-D). AIM: The purpose of this study was to test the hypothesis that colesevelam's slowing effects on CT in IBS-D patients is influenced by genetic variants in KLB and FGFR4. METHODS: We examined pharmacogenetic effects of KLB and FGFR4 coding variants (SNPs) on scintigraphic CT response to the BA sequestrant, colesevelam 1.875 g b.i.d. versus placebo (PLA) for 14 days in 24 female IBS-D patients. RESULTS: FGFR4 rs351855 and KLB rs497501 were associated with differential colesevelam effects on ascending colon (AC) half-emptying time (t(1/2), P = 0.046 and P = 0.085 respectively) and on overall CT at 24 h (geometric center, GC24: P = 0.073 and P = 0.042, respectively), with slower transit for rs351855 GA/AA (but not for GG) and rs497501 CA/AA (but not CC) genotypes. CONCLUSION: FGFR4 rs351855 and KLB rs4975017 SNPs may identify a subset of IBS-D patients with beneficial response to colesevelam.

Quantitative structure-property relationships modeling to predict in vitro and in vivo binding of drugs to the bile sequestrant, colesevelam (Welchol).

Quantitative structure-property relationship (QSPR) models were developed to correlate physicochemical properties of structurally unrelated drugs with extent of in vitro binding to colesevelam, and predicted values were compared with drug exposure changes in vivo following coadministration. The binding of 17 drugs to colesevelam was determined by an in vitro dissolution drug-binding assay. Data from several clinical studies in healthy volunteers to support administration of colesevelam in diabetic patients were also collected along with existing in vivo literature data and compared with in vitro results. Steric, electronic, and hydrophobic descriptors were calculated for test compounds, and univariate and partial least squares regression approaches were used to derive QSPR models to evaluate which of the molecular descriptors correlated best with in vitro binding. A quadrant analysis evaluated the correlation between predicted/actual in vitro binding results and the in vivo data. The in vitro binding assay exhibited high sensitivity, identifying those compounds with a low probability of producing relevant in vivo drug interactions. Drug lipophilicity was identified as the primary determinant of in vitro binding to colesevelam by the final univariate and partial least squares models (R(2) = 0.69 and 0.98; Q(2) = 0.48 and 0.59). The in vitro assay and in silico models represent predictive tools that may allow investigators to conduct only informative clinical drug interaction studies with colesevelam.

Colesevelam hydrochloride for the treatment of type 2 diabetes mellitus.

BACKGROUND: Colesevelam hydrochloride is a bile acid sequestrant approved in January 2008 by the US Food and Drug Administration (FDA) for the treatment of adult patients with type 2 diabetes mellitus (DM) in combination with a sulfonylurea, metformin, and/or insulin therapy. OBJECTIVE: The purpose of this article was to review the pharmacology, pharmacokinetics, efficacy, adverse effects and tolerability, drug-drug interactions, contraindications/precautions, dosage and administration, pharmacoeconomics, and the overall role of colesevelam in the management of adult patients with type 2 DM. METHODS: A literature search using MEDLINE (1966-October 27, 2008), PubMed (1950-October 27, 2008), Science Direct (1994-October 27, 2008), Web of Science (1980-October 27, 2008), American Diabetes Association Scientific Abstracts (2004-2008), and International Pharmaceutical Abstracts (1970-October 27, 2008) was performed using the term colesevelam. English-language, original research and review articles were examined, and citations from these articles were assessed. Manufacturer prescribing information and the FDA review of the new drug application for colesevelam were also examined. RESULTS: Colesevelam is a hydrophilic, water-insoluble polymer, with negligible absorption and systemic distribution, that is excreted primarily in the feces. Through a mechanism still under investigation, colesevelam effectively lowers glycosylated hemoglobin (HbA(1c)) when used in combination with a sulfonylurea, metformin, and/or insulin therapy. Three completed, published Phase III clinical trials investigating colesevelam for the treatment of type 2 DM were evaluated for information, data, and conclusions. At dosing of 1.875 g BID or 3.75 g once daily in combination with one of the aforementioned agents versus placebo, reductions in HbA(1c) in all 3 Phase III clinical trials of colesevelam ranged from 0.5% to 0.7% (P < 0.02). In clinical trials, colesevelam was well tolerated, with hypoglycemia occurring in approximately 3% of studied patients. CONCLUSIONS: When used in combination with a sulfonylurea, metformin, and/or insulin therapy, colesevelam has been reported to significantly reduce HbA(1c) in adult patients with type 2 DM. Colesevelam's role in the management of type 2 DM remains undefined, however; further investigation into its mechanism of action and long-term efficacy and safety should be performed.

The use of colesevelam hydrochloride in the treatment of dyslipidemia: a review.

Bile-acid sequestrants augment cholesterol excretion via enhanced conversion to bile acids, and act to lower low-density lipoprotein cholesterol (LDL-C), especially when combined with other cholesterol-lowering drugs. Colesevelam hydrochloride (HCL) has become the preferred drug of this class due to fewer gastrointestinal adverse effects. This article reviews the use of colesevelam in the treatment of dyslipidemia. Bile-acid sequestrants are a class of drugs developed to lower LDL-C levels. Two of the bile-acid sequestrants, colestyramine resin and colestipol, have been used since the 1980s, and have proven effective and safe as nonsystemic approaches to cholesterol reduction. However, tolerability and compliance issues related to palatability and gastrointestinal side effects have limited the use of these sequestrants. Colesevelam HCL (Daiichi Sankyo, Inc., Parsippany, NJ) is a nonabsorbed lipid-lowering agent that can be used in monotherapy or in combination with an HMG-CoA reductase inhibitor to reduce LDL-C in patients with primary hypercholesterolemia (Fredrickson type IIa). This article reviews the clinical efficacy and use of colesevelam HCL for the management of dyslipidemia.

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).

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.

Absorption of colesevelam hydrochloride in healthy volunteers.

OBJECTIVE: To assess whether colesevelam hydrochloride is absorbed in healthy volunteers. METHODS: A single-center, open-label, radiolabeled study was performed with 16 healthy volunteers. Subjects were administered non-radiolabeled colesevelam hydrochloride 1.9 g twice daily for 4 weeks, followed by a single dose of [14C]-colesevelam 2.4 g (480 pCi). These subjects continued to receive non-radioactive colesevelam 1.9 g twice daily for 4 days after administration of the radiolabeled dose. Blood, urine, and feces were collected immediately prior to administration of [14C]-colesevelam and at specified intervals after administration. The whole-blood equivalent concentration of colesevelam was calculated using data collected throughout the 96 hours following radiolabeled drug administration. The proportion of [14C]-colesevelam excreted through urine or feces was calculated based on the amount of radioactivity recovered up to 216 hours after the radiolabeled dose. RESULTS: The mean cumulative total recovery of [14C]-colesevelam in urine and feces was 0.05% and 74%, respectively. Excluding 2 subjects for whom cumulative recovery was <25%, the mean cumulative fecal recovery was 82%. The mean maximum whole-blood equivalent concentration of colesevelam was 0.165+/-0.10 microg equiv/g 72 hours after administration of [14C]-colesevelam, which was estimated to be 0.04% of the administered dose. All blood samples contained <4 times the number of background counts (dpm). CONCLUSIONS: The cumulative recovery data in urine and feces are consistent with the conclusion that colesevelam is not absorbed and is excreted entirely through the gastrointestinal system.

Colesevelam hydrochloride: a novel bile acid-binding resin.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of colesevelam hydrochloride, a bile acid-binding resin. METHODS: MEDLINE searches (1966-June 2000) and manufacturer prescribing literature were employed to find articles on colesevelam. Additional studies and abstracts were identified from the bibliographies of reviewed literature. STUDY SELECTION AND DATA EXTRACTION: All articles identified from data sources were evaluated, and all information deemed relevant was included in this review. Priority was given to randomized, double-blind, placebo-controlled studies. FINDINGS: Colesevelam HCl is a nonabsorbed hydrogel with bile acid sequestrant properties. Monotherapy using colesevelam in once-daily or two divided daily doses of 1.5-4.5 g has produced significant reductions in total cholesterol and low-density lipoprotein (LDL) cholesterol. Mean LDL cholesterol decreases to 20% have been noted when the patient is on 3.75-4.5 g/d. Increases in high-density lipoprotein (HDL) cholesterol have been observed (up to 9%), whereas triglycerides (TG) have increased significantly to 25% in some studies. In unpublished studies, combined use of colesevelam plus hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor have produced greater reductions in LDL cholesterol than either the statin or colesevelam administered alone. The efficacy of colesevelam monotherapy is slightly less than or similar to cholestyramine or colestipol in decreasing LDL cholesterol, although colesevelam is more potent on a gram-to-gram basis. Adverse effects have been minimal with colesevelam in published studies; this suggests an advantage over cholestyramine or colestipol therapy. Colesevelam appears to be more cost-effective than the packet dosage form of the brand formulation of the older bile acid resins. Care in selection of an appropriate agent should be exercised when considering the issues of adverse effects and palatability. CONCLUSIONS: Colesevelam alone or combined with an HMG-CoA reductase inhibitor is effective in the reduction of total and LDL cholesterol. Since colesevelam is formulated as a tablet, problems with palatability such as with the powder formulation of the bile acid-binding resins are likely to be eliminated.

Colesevelam.

Colesevelam, a bile acid sequestrant used in the treatment of patients with hypercholesterolemia, is a lipid-lowering polymer that has high affinity for bile acids. In animals colesevelam was not systemically absorbed after oral administration and was rapidly eliminated via the gastrointestinal tract. Colesevelam did not alter the serum concentrations or pharmacokinetic properties of drugs from several different classes in healthy volunteers. Colesevelam administered orally in patients with primary hypercholesterolemia significantly reduced serum levels of low density lipoprotein (LDL)-cholesterol and total cholesterol. This lipid-lowering activity was sustained during short (6 weeks) and longer term (24 weeks) treatment. Combination therapy with colesevelam plus hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (lovastatin, simvastatin or atorvastatin) was associated with additive reductions in serum levels of LDL-cholesterol and total cholesterol, relative to either agent alone. Colesevelam treatment was well tolerated and lacked severe gastrointestinal adverse events typical of other bile acid sequestrants (bloating, flatulence, heartburn and nausea). The most frequently reported adverse events were constipation and dyspepsia. In humans colesevelam did not induce clinically significant changes in serum levels of vitamins, coagulation parameters or liver enzymes.

Absorption, distribution and excretion of GT31-104, a novel bile acid sequestrant, in rats and dogs after acute and subchronic administration.

The absorption, distribution, and excretion of GT31-104, a novel bile acid sequestrant, was studied in rats and dogs after both acute and subchronic oral administration. The polyallylamine backbone of GT31-104 was labeled with tritium and one of the alkyl side chains was labeled with 14C. The mean blood and plasma concentration of [3H, 14C]GT31-104 in rats, in both treatment regimens, was negligible at all time points, with the highest amount observed being 0.69 microgram eq/g blood; in dogs the mean blood and plasma concentration of [3H, 14C]GT31-104 was below the limit of quantitation (< 0.001% total dose) at all time points. In both rats and dogs, the mean total urinary excretion of [3H, 14C]GT31-104 was approximately 0.06% of the total dose. The fecal excretion data indicates that both 3H- and 14C-derived radioactivity was excreted entirely in the feces. Mean total radioactivity excreted in the feces ranged from approximately 95 to 105% in the rats and 92 to 102% in the dogs. Across the different treatment regimens, in both species, tissue concentrations were negligible (< 0.01% total dose) and no differences in tissue profile were noted, indicating that there was no effect of pretreatment on [3H, 14C]GT31-104 absorption. GT31-104 was extracted with water, and the water-soluble portion contained radioactivity that would correlate to approximately 0.19% of the 3H dose and 0.41% of the 14C dose; this portion probably accounted for the negligible radioactivity observed systemically. Analysis of gastrointestinal (GI) tract tissues with contents indicated that GT31-104 is rapidly cleared from the GI tract. These data indicate that GT31-104 is not absorbed from the GI tract in rats and dogs.