Efficacy and Safety of Naftifine HCl Cream 2% in the Treatment of Pediatric Subjects With Tinea Corporis.

BACKGROUND: Tinea corporis is fungal infection of body surfaces other than the feet, groin, scalp, or beard. Naftifine hydrochloride is a topical antifungal of the allylamine class used to treat tinea corporis, displaying fungicidal activity and clinically significant anti-bacterial and anti-inflammatory effects.
OBJECTIVE: To evaluate the efficacy and safety of two-weeks once daily application of naftifine cream 2% in the treatment of tinea corporis among pediatric subjects.
METHODS: At baseline, 231 subjects were randomly assigned 1:1 to naftifine cream 2% (n=116) and vehicle (n=115). Treatment effect consisting of mycologic determination (KOH and dermatophyte cultures) and scoring of clinical symptom severity was evaluated at baseline, week 2 (end of treatment) and week 3. Efficacy was analyzed in 181 subjects (n=88, naftifine; n=93, vehicle) with a positive baseline dermatophyte culture and KOH for whom week 3 assessments were available. Safety was evaluated by adverse events (AE) and laboratory values in 231 subjects (n=116, naftifine; n=115, vehicle).
RESULTS: Children with tinea corporis treated with naftifine cream 2% demonstrated significantly greater improvements from baseline over vehicle for mycological cure (P<0.0001) and treatment effectiveness (P=0.003) as early as 2 weeks (end of treatment). Response rates continued to increase post-treatment and were the highest 1-week after completion of the therapy (P=0.003 for complete cure; and P<0.001 for mycological cure and treatment effectiveness). Treatment related adverse events were minimal.
CONCLUSIONS: Treatment with naftifine cream 2% applied once daily for two weeks was well-tolerated and was effective in treating tinea corporis in children. Further improvement was observed 1-week after treatment completion for all key outcome measures (complete cure, mycological cure, treatment effectiveness, clinical cure, and clinical success) and clinical signs and symptoms (erythema, induration, and pruritus).

J Drugs Dermatol. 2016;15(6):743-748.

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.

Cholesterol treatment patterns and cardiovascular clinical outcomes associated with colesevelam HCl and ezetimibe.

INTRODUCTION: Pharmaceuticals are commonly used to help at-risk patients reduce low-density lipoprotein cholesterol (LDL-C) levels in an effort to prevent atherosclerotic coronary artery disease. Although both the cholesterol inhibitor ezetimibe and the newer generation bile acid sequestrant colesevelam hydrochloride (HCl) effectively reduce LDL-C levels in patients with hypercholesterolemia, real-world evidence based on clinical outcomes is lacking. METHODS: A retrospective analysis of healthcare insurance claims data from a large national healthcare payer was conducted to evaluate outcomes within 12 months among 2,067 patients with hypercholesterolemia after the initiation of treatment with colesevelam HCl (679 patients) as compared with ezetimibe (1,388 patients). Outcomes evaluated were (1) composite cardiovascular event which included myocardial infarction, stroke, angina, or revascularization and (2) macrovascular complication event which was a wider-encompassing measure that included all composite cardiovascular outcomes along with atherosclerosis, aneurysm, embolism, and peripheral vascular disease. RESULTS: An adjusted logistic regression model found lower odds of a composite cardiovascular event (odds ratio [OR] 0.54, 95 % confidence interval [CI] 0.30-0.97) within 12 months for subjects initiating treatment with colesevelam HCl compared with subjects initiating treatment with ezetimibe. The unadjusted OR was slightly lower (OR 0.52, 95 % CI 0.30-0.90). The odds ratio for the wider-encompassing macrovascular complication event occurring within 12 months of initiating treatment with colesevelam HCl or ezetimibe was not statistically significant (OR 0.821, 95 % CI 0.49-1.35). DISCUSSION: The evidence of lower risk for composite cardiovascular event rates for subjects treated with colesevelam HCl compared with those treated with ezetimibe suggests the potential need to consider risk of clinical outcomes, in addition to LDL-C levels, in real-world practice when choosing a pharmaceutical treatment.

Efficacy and safety of colesevelam in combination with pioglitazone in patients with type 2 diabetes mellitus.

Colesevelam improves glycemic control in patients with type 2 diabetes when added to existing metformin-, sulfonylurea-, or insulin-based regimens. We evaluated colesevelam's effects in subjects on stable pioglitazone-based therapy. This 24-week multicenter, double-blind, randomized, placebo-controlled study enrolled adults with type 2 diabetes who had suboptimal glycemic control [HbA1c ≥ 58 mmol/mol (7.5%) and ≤ 80 mmol/mol (9.5%)] on pioglitazone (30 or 45 mg) with or without 1-2 other oral antidiabetes medications. Subjects were randomized to colesevelam 3.8 g/day (n = 280) or placebo (n = 282) added to existing pioglitazone-based therapy. Primary efficacy variable was mean change in HbA1c from baseline to Week 24. Secondary variables included safety and tolerability, fasting plasma glucose changes, glycemic responses, and lipid profile. Tertiary variables included lipid particle profile changes by nuclear magnetic resonance. Colesevelam decreased HbA1c [least-squares mean treatment difference, - 3.5 mmol/mol (- 0.32%); p < 0.001] and fasting plasma glucose (- 14.7 mg/dl; p<0.001) vs. placebo at Week 24. More subjects receiving colesevelam vs. placebo achieved HbA1c reduction ≥ 7.7 mmol/mol (0.7%) (40% vs. 25%; p<0.001) or HbA1c < 53 mmol/mol (7.0%) (21% vs. 13%; p = 0.012). Colesevelam also decreased total cholesterol (mean treatment difference, - 6.5%), LDL-cholesterol (- 16.4%), non-HDL-cholesterol (- 9.8%), apolipoprotein B (- 8.8%), and total LDL particle concentration, and increased apolipoprotein A1 (+3.4%) and triglycerides (median treatment difference, + 11.3%) vs. placebo (all p < 0.001). There were no serious drug-related adverse events, and the majority of adverse events were mild or moderate. In subjects with type 2 diabetes inadequately controlled with pioglitazone-based therapy, add-on colesevelam therapy improved glycemic control and lipid parameters and was well tolerated. ClinicalTrials.gov identifier: NCT00789750.

Expanded colesevelam administration options with oral suspension formulation for patients with diabetes and hypercholesterolemia.

INTRODUCTION: Colesevelam HCl (colesevelam) is a bile acid sequestrant initially approved by the US Food and Drug Administration (FDA) in 2000 as an adjunct to diet and exercise to lower elevated low-density lipoprotein cholesterol (LDL-C) levels in adults with primary lipidemia, as monotherapy, or in combination with a statin. More recently, the drug was approved for use in adults with type 2 diabetes mellitus (T2DM) to improve glycemic control. Thus, colesevelam is currently the only single-agent monotherapy approved by the FDA to lower both LDL-C and glycated hemoglobin (A1c) levels in adults with T2DM and elevated LDL-C. Moreover, the formulation options for colesevelam have also expanded since its original approval. MATERIALS AND METHODS: A Medline search was conducted to provide evidence to support the efficacy and safety for the use of colesevelam tablets or oral suspension preparations when treating patients with lipidemia, T2DM, or both. No limitations were placed on publication date or any other parameter. RESULTS: Clinical studies have shown that colesevelam is efficacious in lowering LDL-C levels, improving the lipid profile, and improving glycemic control by reducing both A1c and fasting plasma glucose levels in T2DM. Equilibrium and kinetics data show that colesevelam is equivalent in its tablet and oral suspension formulation. CONCLUSION: Having 2 effective oral routes enhances convenience and improves compliance, both of which contribute to maximal therapeutic outcomes. These compliance benefits are due to the ease and flexibility of preparing the powder in various beverages and the pleasant taste from the inclusion of a low-calorie citrus flavoring.

Colesevelam and colestipol: novel medication resins in the gastrointestinal tract.

We report the morphologic description of the bile acid sequestrants (BAS) colesevelam and colestipol, as well as the largest series of cholestyramine. Histologically similar medication resins from 4 institutions were prospectively collected over 1 year (26 specimens, 15 patients). Comorbidities included hyperlipidemia (4/15), hypertension (4/15), inflammatory bowel disease (4/15), coronary artery disease (3/15), diarrhea (7/15), hypothyroidism (2/15), and ischemic bowel (1/15). Sites of involvement included the esophagus (1/26), stomach (1/26), small intestine (1/26), ileocecal valve (1/26), and colorectum (22/26). Associated histologic diagnoses included normal (8/26), chronic mucosal injury (11/26), acute inflammation (9/26), erosion/ulceration (6/26), and cytomegalovirus (2/26). The BAS resins were histologically indistinguishable from each other; they were all eosinophilic on hematoxylin and eosin (H&E) and lacked internal "fish-scales." To validate these observations, respective medications were submitted for histologic processing; the processed medications were identical to those in the patient specimens. Rare, irregular "fracture" lines presented diagnostic pitfalls by mimicking the true "fish-scales" of Kayexalate and sevelamer. Clues to the correct identification of BAS include recognition that the "fracture" lines were subtle, irregular, and restricted to large fragments or thick sections, likely representing a processing artifact. Moreover, Kayexalate is violet on H&E and black on acid fast bacillus, and sevelamer characteristically displays a 2-tone color on H&E and is magenta on acid fast bacillus. An association with inflammatory injury was seen (15/26). We believe that the BAS are innocent bystanders in complicated patients, although we cannot exclude their ability to cause mucosal injury in specific settings.

Colesevelam for the treatment of bile acid malabsorption-associated diarrhea in patients with Crohn's disease: a randomized, double-blind, placebo-controlled study.

BACKGROUND AND AIMS: Bile acid malabsorption (BAM)-associated diarrhea is an important clinical issue in patients with Crohn's disease (CD). We analyzed the efficacy and safety of the bile acid sequestrant colesevelam for treatment of BAM-associated diarrhea in CD patients in a randomized, double-blind, placebo-controlled study. METHODS: The primary endpoint was the proportion of patients with >30% reduction of liquid stools/day from baseline to termination visit at week 4. Secondary endpoints were reduction of the number of liquid stools/day, improvement of stool consistency and quality of life. RESULTS: 26 patients were analyzed in the intention-to-treat (ITT) analysis. The primary endpoint was reached by 10 patients (69.7%) in the colesevelam group compared to 3 patients (27.3%) in the placebo group (risk difference RD=.394, 95%CI:[-0.012; 0.706]; P=.0566). In the per-protocol analysis (n=22), the risk difference was statistically significant (RD=.470, 95%CI:[0.018; 0.788], P(H0: RD=0)=0.0364; 95% CI:[1.3;54.7]). Regarding secondary endpoints, in the ITT population colesevelam-treated patients had a significant reduction of liquid stools/day at week 4 (median 5.0 to 2.0; P=0.01), while patients treated with placebo had no significant reduction (median 4.0 to 3.0; P=0.42). Significantly more patients in the colesevelam group had improvement of stool consistency of at least one level in the Bristol stool chart, as compared to the placebo group (P=0.003). CONCLUSIONS: We found significant differences in favor for colesevelam treatment compared to placebo treatment for CD patients with BAM regarding the reduction of the number of liquid stools/day and stool consistency. ClinicalTrials.gov number: NCT01203254.

Safety and efficacy of colesevelam HCl in the treatment of elderly patients.

BACKGROUND AND OBJECTIVES: Colesevelam significantly lowers cholesterol in patients with hypercholesterolemia, and both cholesterol and hemoglobin A1C (A1C) in patients with type 2 diabetes mellitus (T2DM). The purpose of this post hoc analysis was to evaluate the efficacy and safety/tolerability of colesevelam in older (≥65 years) and younger (<65 years) adults. METHODS: We conducted post hoc analyses of pooled clinical trial data from seven phase II and III randomized, double-blind, placebo-controlled, primary hyperlipidemia and T2DM clinical trials. The hyperlipidemia safety/tolerability analysis included seven studies (≥65 years, n = 154; <65 years, n = 381); the efficacy analysis utilized one study with sufficient patients in both age groups for meaningful comparison. The T2DM analyses included four studies (safety/tolerability: ≥65 years, n = 249; <65 years, n = 880) or three studies (efficacy). In the hyperlipidemia studies, patients received colesevelam 1.5-4.5 g/day or placebo, alone or with a statin, for 4 weeks to 6 months. In the T2DM studies, colesevelam 3.75 g/day or placebo was added to existing antidiabetes therapies for 16 or 26 weeks. Low-density lipoprotein cholesterol (LDL-C), A1C, and adverse events were assessed. RESULTS: In the hyperlipidemia analysis, colesevelam versus placebo produced similar mean reductions from baseline in LDL-C in older (-16.6 vs. +0.5 %) and younger (-13.7 vs. +0.4 %) patients. In the T2DM analysis, older and younger patients had similar reductions from baseline in A1C (treatment difference -0.59 and -0.54 %, respectively; both p < 0.001) and LDL-C (-14.7 and -15.5 %, respectively; both p < 0.001) with colesevelam. In both analyses, adverse event incidence was generally similar between subgroups. In the T2DM analysis, hypoglycemia was slightly more frequent with colesevelam versus placebo in older patients (5.8 vs. 2.3 %); no reports of hypoglycemia were considered serious adverse events. CONCLUSIONS: In primary hyperlipidemia and in T2DM, colesevelam appeared to be generally as safe, well tolerated, and efficacious in patients aged ≥65 years as in those aged <65 years.

The effects of colesevelam HCl on the single-dose pharmacokinetics of glimepiride, extended-release glipizide, and olmesartan medoxomil.

Bile acid sequestrants can potentially bind to concomitant drugs. Single-dose studies evaluated the effects of colesevelam on the pharmacokinetics of glimepiride, glipizide extended-release (ER), and olmesartan medoxomil. Each study enrolled healthy subjects aged 18-45 years. The olmesartan medoxomil study used a randomized adaptive crossover design that initially compared olmesartan medoxomil alone versus simultaneously with colesevelam, then olmesartan medoxomil alone versus 4 hours before colesevelam. The other studies used a three-period crossover design (test drug alone, test drug simultaneously with colesevelam, and test drug 4 hours before colesevelam). For the colesevelam coadministration periods, 3,750 mg once daily was dosed throughout the pharmacokinetic sampling period. After each single dose of test drug, serial blood samples were collected for determination of plasma drug concentrations and calculation of pharmacokinetic parameters. Administering colesevelam simultaneously with glimepiride or glipizide ER resulted in minor reductions (18% and 13%, respectively) in total exposure that were negated by staggering colesevelam dosing by 4 hours. Administering colesevelam simultaneously with olmesartan medoxomil resulted in a major reduction (39%) in olmesartan exposure that was reduced by staggering colesevelam dosing by 4 hours. This reduction in olmesartan exposure is not predicted to have a clinically significant impact on blood pressure control.

Effect of colesevelam and niacin on low-density lipoprotein cholesterol and glycemic control in subjects with dyslipidemia and impaired fasting glucose.

BACKGROUND: Niacin monotherapy in patients with dyslipidemia and impaired fasting glucose (IFG) may result in hyperglycemia. Colesevelam has the unique dual approvals to lower low-density lipoprotein cholesterol (LDL-C) and to improve glycemic control in type 2 diabetes mellitus. OBJECTIVES: The aim of our study was to evaluate the effect of combined colesevelam and niacin treatment on LDL-C-lowering and glycemic control in subjects with IFG and dyslipidemia. METHODS: Men or women ≥ 18 years of age, with dyslipidemia (non-high-density lipoprotein cholesterol ≥ 100 mg/dL and ≤ 220 mg/dL; high-density lipoprotein cholesterol < 60 mg/dL) and fasting plasma glucose (FPG) ≥ 90 mg/dL and ≤ 145 mg/dL were randomly assigned 1:1 to colesevelam (3750 mg/d) with niacin titration (n = 70) or placebo with niacin titration (n = 70) over 12 weeks. Niacin was titrated from 500 mg/d up to a maximum of 2000 mg/d as tolerated, and all subjects took enteric-coated aspirin daily. Lipid and glycemic efficacy parameters were assessed as well as safety evaluations of adverse events, vital signs, alanine aminotransferase, aspartate aminotransferase, hematology, and urinalysis. RESULTS: Adjunct colesevelam had significantly greater LDL-C-lowering effect than niacin alone (placebo); -20.67% vs -12.86%, respectively (P = .0088). Niacin-mediated increases in FPG were significantly less with adjunct colesevelam (1.8 mg/dL vs 6.7 mg/dL; P = .0046), and fewer colesevelam subjects had increases of ≥ 10 mg/dL in FPG (8 vs 17, respectively). Adjunct colesevelam resulted in significantly smaller increases in hemoglobin A1c than placebo (0.06% vs 0.18%, respectively; P = .005). Consistent with hemoglobin A1c and FPG changes, fructosamine levels significantly decreased with colesevelam treatment (-5.0 µmol/L) but increased with placebo (3.0 µmol/L; P =.0255). CONCLUSIONS: Colesevelam as an adjunct to niacin therapy further lowers LDL-C while obviating the adverse effects of niacin on glucose metabolism in patients with dyslipidemia and IFG.

Colesevelam in the treatment of hypercholesterolemia and hyperglycemia: a retrospective analysis from an ambulatory care medical network.

OBJECTIVE: To examine outcomes associated with colesevelam treatment among patients with hypercholesterolemia in real-world clinical practice. METHODS: This analysis was conducted as a retrospective, observational cohort study in an ambulatory-care medical network in Northern California. Patients with orders for colesevelam were identified in the electronic health record between January 2004 and December 2011. The date of the first order during the study period was designated the index date. Patients were evaluated for the following eligibility criteria: a diagnosis of hypercholesterolemia, ≥18 years of age at index date, baseline laboratory values ≤3 months before the index date, ≥12 months of treatment and follow-up, and no prior orders for colesevelam ≤12 months before the index date. Patients who were pregnant during the study period were excluded. Changes in LDL-C and percentage of patients at LDL-C goal were examined. Among patients with diabetes mellitus (DM), changes in glycated hemoglobin (HBA1C) and percentage of patients at HBA1C goal were also examined. RESULTS: Overall, 468 and 181 patients with hypercholesterolemia met the predefined inclusion criteria with treatment and follow-up through 12 and 24 months, respectively. LDL-C decreased significantly from baseline by a mean of 11.4 mg/dL and 15.7 mg/dL (P < 0.0001, for each) at 12 and 24 months, respectively, and the percentages of patients at LDL-C goal increased by 13.9% and 21.0%. Among patients with DM and a baseline HBA1C ≥8%, 113 and 39 had treatment and follow-up through 12 and 24 months, respectively. HBA1C decreased significantly by a mean of 0.72% (P = 0.0001) and 0.75% (P = 0.010) and 11.5% and 12.8% were at HBA1C goal at 12 and 24 months, respectively. This study is limited by its retrospective and observational study design. CONCLUSIONS: Colesevelam treatment in a real-world setting was associated with improvements in LDL-C and HBA1C through 24 months of follow-up.

The efficacy of colesevelam HCl in the treatment of heterozygous familial hypercholesterolemia in pediatric and adult patients.

BACKGROUND: Familial hypercholesterolemia (FH) is a common autosomal co-dominant genetic disorder that results in severely increased levels of LDL-C. Patients with FH are at an increased risk for premature coronary artery disease. Expert panels therefore recommend initiation of lipid-lowering therapy in childhood to reduce the very high lifetime risk of coronary artery disease. The bile acid sequestrant colesevelam is indicated to reduce elevated LDL-C levels in adults with primary hyperlipidemia and in boys and postmenarchal girls (aged 10-17 years) with heterozygous FH. OBJECTIVE: The purpose of this article was to review currently available data on the use of colesevelam in the treatment of heterozygous FH. METHODS: PubMed and Google Scholar were searched to identify clinical trials evaluating colesevelam in patients with heterozygous FH. RESULTS: The search returned 2 results (both multicenter, multinational studies): 1 study conducted in adults and the other in pediatric patients. In the study in adults with refractory FH, the addition of colesevelam to a maximally tolerated regimen of a statin plus ezetimibe provided a significantly greater reduction from baseline in LDL-C levels compared with placebo. Significantly greater reductions from baseline in LDL-C were also seen in pediatric patients with heterozygous FH receiving colesevelam (alone or in combination with statins) compared with placebo. Colesevelam was generally well tolerated in studies in patients with FH; consistent with other colesevelam studies, gastrointestinal disorders were the most common drug-related adverse events, but these events rarely led to study withdrawal. CONCLUSIONS: Currently available data demonstrate that colesevelam, alone or in combination therapy, is efficacious and well tolerated in the treatment of heterozygous FH in adults and pediatric patients, supporting its use as a treatment option in both of these patient populations.

Role of colesevelam in combination lipid-lowering therapy.

Hyperlipidemia is associated with an increased risk of cardiovascular events; reducing low-density lipoprotein cholesterol (LDL-C), the primary target for cholesterol-lowering therapy, lowers the risk for such events. Although bile acid sequestrants were the first class of drugs to show a mortality benefit related to LDL-C lowering, statins are now considered first-line pharmacological therapy for reducing LDL-C levels because of their potency and their remarkable record of successful outcomes studies. Nevertheless, a substantial proportion of patients do not achieve LDL-C goals with statin monotherapy. In addition, because of adverse effects (primarily myopathy), some patients may be unwilling to use or unable to tolerate statin therapy at all or may not tolerate a full therapeutic statin dose. Also, statins may increase risk of new-onset diabetes in patients at high risk for diabetes. Thus, there remains a need for other lipid-lowering drugs to be used in combination with or in place of statins. The purpose of this article is to review available data from the literature on the use of colesevelam, a second-generation bile acid sequestrant, in combination with other lipid-lowering agents. Colesevelam has been studied in combination with statins, niacin, fibrates, and ezetimibe (including some three-drug combinations). An additive reduction in LDL-C was seen with all combinations. Other observed effects of colesevelam in combination with other lipid-lowering drugs include reductions in apolipoprotein (apo) B (with statins, fibrates, ezetimibe, statin plus niacin, or statin plus ezetimibe) and high-sensitivity C-reactive protein (with statins), and increases in apo A-I (with statins, ezetimibe, or statins plus niacin). Triglyceride levels remained relatively unchanged when colesevelam was combined with statins, fibrates, ezetimibe, or statin plus ezetimibe, and decreased with the triple combination of colesevelam, statin, and niacin. Colesevelam offset the negative glycemic effects of statins and niacin in subjects with insulin resistance or impaired glucose tolerance. Colesevelam was generally well tolerated when added to other lipid-lowering therapies in clinical trials, with gastrointestinal effects such as constipation being the predominant adverse events. Since colesevelam is not absorbed and works primarily in the intestine, it has a low potential for systemic metabolic drug-drug interactions with other drugs. Colesevelam has been shown to not interact with the lipid-lowering drugs lovastatin and fenofibrate; where interaction may be anticipated, separating dosing times by 4 h reduces the impact of any interaction. Available data confirms that colesevelam has additive cholesterol-lowering effects when used in combination with other lipid-lowering therapies. Furthermore, in some patient populations, the additional glucose-lowering effect of colesevelam may be beneficial in offsetting hyperglycemic effects of other lipid-lowering drugs.

Efficacy and safety of naftifine HCl Gel 2% in the treatment of interdigital and moccasin type tinea pedis: pooled results from two multicenter, randomized, double-blind, vehicle-controlled trials.

BACKGROUND: Tinea pedis is the most common chronic fungal infection. Naftifine hydrochloride is a topical antifungal of the allylamine class, displaying fungicidal activity and clinically significant anti-bacterial and anti-inflammatory effects. OBJECTIVE: To evaluate the efficacy and safety of two-weeks once daily application of naftifine gel 2% in the treatment of tinea pedis. METHODS: At baseline, 1715 subjects were randomly assigned 2:1 to naftifine gel 2% (n=1144) and vehicle (n=571). Efficacy consisting of mycologic determination (KOH and dermatophyte cultures) and scoring of clinical symptom severity was evaluated at baseline and weeks 2, 4, and 6. Efficacy was analyzed in 1174 subjects (n=782, naftifine; n=392, vehicle) with a positive baseline dermatophyte culture and KOH for whom week 6 assessments were available. Safety was evaluated by adverse events (AE) and laboratory values in 1714 subjects (n=1143, naftifine; n=571, vehicle). RESULTS: Subjects treated with naftifine gel 2% for interdigital-type tinea pedis demonstrated greater improvement from baseline for complete cure (P=0.001), mycological cure (P<0.0001), and treatment effectiveness (P<0.0001) as early as 2 weeks when compared to vehicle; however the highest response rates were seen 4-weeks post treatment (P<0.0001, for all endpoints). Statistically significant results for complete cure, mycological cure, and treatment effectiveness (P<0.0001, for all endpoints) were also seen at week 6 among subjects with moccasin-type tinea pedis. Treatment related adverse events were minimal. CONCLUSIONS: Treatment with naftifine gel 2% applied once daily for two weeks is well-tolerated and is effective in treating both interdigital-type and moccasin-type tinea pedis. Continuous improvement is observed from the end of treatment to four-weeks after treatment cessation among key outcome measures (complete cure, mycological cure, and treatment effectiveness) as well as clinical signs and symptoms (erythema, scaling, and pruritus)

Diurnal glucose profiles using continuous glucose monitoring to identify the glucose-lowering characteristics of colesevelam HCl (Welchol).

OBJECTIVES: The study's purpose was to identify the antihyperglycemic affects of colesevelam-HCl (C-HCl) by characterizing the diurnal and postprandial glucose patterns in type 2 diabetic subjects treated concomitantly with metformin, sulfonylurea, or a combination of metformin/sulfonylurea. A secondary aim was to determine whether C-HCl significantly increased the risk of hypoglycemia. METHODS: A prospective, randomized, double-blind, placebo-controlled, crossover study employing continuous glucose monitoring (CGM) with ambulatory glucose profile (AGP) analysis was undertaken. Fifteen males and 6 females, age 60 ± 8 years, treated with metformin (n = 8), sulfonylurea (n = 2), or combination (n = 11) participated. RESULTS: Treatment with C-HCl led to reductions in glycated hemoglobin (HbA1c) (7.5 ± 0.3 to 7.0 ± 0.4% P<.0001), LDL (90.9 ± 18.6 to 68.9 ± 15.2 mg/dL, P<.0007) and total cholesterol (169.2 ± 24.4 to 147.8 ± 21.5 mg/dL, P<.001). Significantly lower normalized diurnal (21 mg/dL/hour, P = .0006), nocturnal (19 mg/dL/hour, P = .0005), and daytime (22 mg/dL/hour, P = .0008) glucose exposure was detected immediately upon C-HCl administration. Additionally, there was a significant (P<.004) decline in postprandial glucose excursions (averaging 15% or -36 mg/dL/hour) pronounced at dinner following C-HCl administration. There was a nonsignificant increase in the incidence of hypoglycemia (0.4-1%), with no difference due to antihyperglycemic medications. CONCLUSIONS: AGP analysis of CGM visually and quantitatively showed immediate and midterm impacts of C-HCl on basal and postprandial glucose patterns. This suggests a multifactorial glucose-lowering mechanism for C-HCl affecting both meal-related and basal glucose levels.

Colesevelam: a new and improved bile acid sequestrant?

Treatment with statins represents an essential component both of primary and secondary cardiovascular prevention strategies. However, a proportion of patients cannot reach low-density lipoprotein cholesterol (LDL-C) targets with the highest tolerable dose of a potent statin or is intolerant to statins. Several treatment options are available for these patients. Colesevelam is a relatively new bile acid sequestrant that decreases serum LDL-C levels. Moreover, colesevelam improves glycemic control and seems to be well-tolerated, at least in short-term studies. Therefore, colesevelam seems to be a useful tool for the management of high-risk patients who cannot achieve LDL-C targets with monotherapy with a potent statin.

Colesevelam improved lipoprotein particle subclasses in patients with prediabetes and primary hyperlipidaemia.

BACKGROUND: A randomised, double-blind, placebo-controlled study evaluated lipid- and glucose-lowering effects of colesevelam in patients with prediabetes and primary hyperlipidaemia. We report the effect of colesevelam on lipoprotein particle concentration and particle size (determined by nuclear magnetic resonance spectroscopy) in these patients. METHODS: Adults with prediabetes (World Health Organization criteria), low-density lipoprotein cholesterol (LDL-C) ≥ 100 mg/dL (≥2.6 mmol/L) and triglycerides < 500 mg/dL (<5.6 mmol/L) were randomised to colesevelam 3.75 g/day or placebo for 16 weeks. The intent-to-treat population comprised 103 colesevelam and 106 placebo recipients. RESULTS: At the end of the study, mean reduction from baseline in total LDL particle concentration was significantly greater with colesevelam versus placebo (mean treatment difference: -113 nmol/L; p = 0.02). Increases in total very low-density lipoprotein particle concentration (VLDL-P) and high-density lipoprotein particle concentration (HDL-P) did not differ significantly between the groups; however, with colesevelam versus placebo, there were significantly (p < 0.05) greater increases in large and medium VLDL-P and large HDL-P and reductions in small VLDL-P. Mean size increases were significantly greater with colesevelam for VLDL (mean treatment difference: 5.3 nm; p < 0.0001) and HDL (0.1 nm; p = 0.002). CONCLUSIONS: Colesevelam improved the overall atherogenic lipoprotein profile in adults with prediabetes and primary hyperlipidaemia, despite potentially less favourable changes in VLDL particles.

Colesevelam plus rosuvastatin 5 mg/day versus rosuvastatin 10 mg/day alone on markers of insulin resistance in patients with hypercholesterolemia and impaired fasting glucose.

BACKGROUND: Statin use has been associated with adverse effects on insulin sensitivity and the development of new-onset diabetes. Colesevelam exhibits favorable effects on glucose metabolism. It is not known whether the combination of colesevelam plus low-dose statin has different effects on insulin resistance versus higher-dose statin in patients with impaired fasting glucose (IFG) and hypercholesterolemia. METHODS: This was a prospective randomized open-label blinded end point (PROBE) study. Forty patients with hypercholesterolemia and IFG were randomized to receive rosuvastatin 5 mg/day plus colesevelam 3.75 g/day (RC, n=20) or rosuvastatin 10 mg (R, n=20) for 3 months. The primary end point was the difference in the change of homeostasis model assessment of insulin resistance (HOMA-IR) index between the groups. RESULTS: HOMA-IR index significantly decreased in the RC group (-32%, P=0.04 vs. baseline) but nonsignificantly increased (+15%, P=NS) in the R group. Insulin levels decreased in the RC group (-26%, P=NS) but increased in the R group (+15%, P=NS). Both changes in HOMA-IR and insulin differed significantly between groups (both p<0.05). Glucose levels decreased in the RC group (-5%, P=NS), whereas they remained unaltered in the R group. Similar reductions in low-density lipoprotein cholesterol were observed in both groups (-45%; P<0.001 vs. baseline). Triglycerides remained unchanged in the RC group but decreased in the R group (-24%, P<0.001 vs. baseline and P=0.02 vs. RC group). CONCLUSIONS: The combination of colesevelam with rosuvastatin 5 mg/day may be associated with favorable effects on markers of insulin resistance compared with rosuvastatin 10 mg/day in patients with hypercholesterolemia and IFG. Whether this is associated with less new-onset diabetes remains unknown.

Initial combination therapy with metformin plus colesevelam in drug-naïve Hispanic patients with early type 2 diabetes.

OBJECTIVE: To evaluate initial combination therapy with metformin plus colesevelam in drug-naïve Hispanic patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: Patients self-identified as Hispanic from a previous study were included in this exploratory post hoc analysis. Patients were randomized to metformin plus colesevelam or metformin plus placebo. The primary efficacy parameter was the mean change in glycated hemoglobin (HbA1c) levels from baseline. RESULTS: Metformin plus colesevelam had a greater mean HbA1c reduction (-1.2 ± 0.1%) than metformin plus placebo (-0.8 ± 0.1%; P = 0.001) from mean baselines of 7.7% and 7.6%, respectively. Low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, total cholesterol, and apolipoprotein (apo) B levels were also reduced (P < 0.0001 for all), while triglyceride (P < 0.0001) and apoA-I (P < 0.05) levels were increased with metformin plus colesevelam treatment compared with metformin plus placebo. With metformin plus colesevelam versus metformin plus placebo, more patients achieved an HbA1c of < 7.0% (75% vs 56%) and LDL-C of < 100 mg/dL (49% vs 14%; both P < 0.05). CONCLUSION: Metformin plus colesevelam may be an effective initial treatment option for Hispanic patients with early type 2 diabetes mellitus.

Clinical effects of colesevelam in Hispanic subjects with primary hyperlipidemia and prediabetes.

OBJECTIVE: To evaluate the efficacy and safety of colesevelam in Hispanic subjects with primary hyperlipidemia and prediabetes. MATERIALS AND METHODS: A 16-week, randomized, double-blind, placebo-controlled, multinational study evaluating colesevelam in participants with primary hyperlipidemia (low-density lipoprotein cholesterol [LDL-C] level ≥ 100 mg/dL) and prediabetes (fasting plasma glucose level ≥ 110 to ≤ 125 mg/dL, or 2-hour postload glucose level ≥ 140 to < 200 mg/dL during an oral glucose tolerance test) was conducted between January 14, 2008 and April 3, 2009. Participants were randomized 1:1 to colesevelam 3.75 g/day or placebo. The primary efficacy endpoint was mean change from baseline in LDL-C level with colesevelam compared with placebo. Participants who self-identified as Hispanic during enrollment were included in this exploratory analysis evaluating the efficacy of colesevelam in Hispanics with primary hyperlipidemia and prediabetes. RESULTS: From a total of 216 subjects with primary hyperlipidemia and prediabetes, 153 Hispanics were included in this post hoc analysis; 77 subjects were randomized to colesevelam and 76 subjects were randomized to placebo. At week 16, LDL-C levels were significantly reduced with colesevelam compared with placebo (mean treatment difference, -19.4%; P < 0.0001). Achievement of LDL-C level < 100 mg/dL was more frequent with colesevelam than with placebo (27% vs 11%; P = 0.002). In addition, significant mean reductions in non-high-density lipoprotein cholesterol, total cholesterol, and apolipoprotein B levels (P ≤ 0.0002 for all), and a significant median increase in triglyceride levels (P = 0.003), were seen with colesevelam compared with placebo. At study end, there was a significant mean reduction in glycated hemoglobin levels and median reduction in fasting plasma glucose levels with colesevelam compared with placebo (P ≤ 0.02 for both). A fasting plasma glucose level < 100 mg/dL was achieved in 44% of colesevelam recipients compared with 23% of placebo recipients (P < 0.05). Overall, colesevelam was well tolerated. CONCLUSION: Colesevelam may be a treatment option for Hispanic subjects with primary hyperlipidemia and prediabetes, mainly to reduce LDL-C levels, with added beneficial effect on glucose levels. TRIAL REGISTRATION: www.ClinicalTrials.gov identifier NCT00570739.