Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B.

BACKGROUND: Apolipoprotein B (apoB) is an important structural component of low-density lipoprotein cholesterol (LDL-C) and plays a key role in LDL-C transport and removal. Reduction in apoB synthesis is expected to reduce circulating LDL-C, a proven risk factor of cardiovascular disease. In the present study, we describe the outcome of the first-in-humans study on the safety and efficacy of an antisense oligonucleotide inhibitor of apoB. METHODS AND RESULTS: This study was a double-blind, randomized, placebo-controlled, dose-escalation investigation conducted at a single site in 36 volunteers with mild dyslipidemia. The study utilized an initial single dose of 50 to 400 mg of ISIS 301012, a 20-mer oligonucleotide, followed by a 4-week multiple-dosing regimen with the same assigned dose. Safety was assessed by the incidence, severity, and relationship of adverse events to dose. Efficacy was determined by changes in serum apoB and LDL-C relative to baseline and placebo. The most common adverse event was erythema at the injection site (21 of 29 subjects). ApoB was reduced by a maximum of 50% (P=0.002) from baseline in the 200-mg cohort. This decrease in apoB coincided with a maximum 35% reduction of LDL-C (P=0.001). LDL-C and apoB remained significantly below baseline (P<0.05) up to 3 months after the last dose. CONCLUSIONS: Administration of an antisense oligonucleotide to human apoB resulted in a significant, prolonged, and dose-dependent reduction in apoB and LDL-C. Although injection-site reactions were common, adherence to protocol was unaffected.

Lack of pharmacokinetic interaction for ISIS 113715, a 2'-0-methoxyethyl modified antisense oligonucleotide targeting protein tyrosine phosphatase 1B messenger RNA, with oral antidiabetic compounds metformin, glipizide or rosiglitazone.

BACKGROUND: ISIS 113715 is a 20-mer phosphorothioate antisense oligonucleotide (ASO) that is complementary to the protein tyrosine phosphatase 1B (PTP-1B) messenger RNA and subsequently reduces translation of the PTP-1B protein, a negative regulator of insulin receptor. ISIS 113715 is currently being studied in early phase II clinical studies to determine its ability to improve or restore insulin receptor sensitivity in patients with type 2 diabetes mellitus. Future work will investigate the combination of ISIS 113715 with antidiabetic compounds. METHODS: In vitro ultrafiltration human plasma protein binding displacement studies and a phase I clinical study were used to characterise the potential for pharmacokinetic interaction of ISIS 113715 and three marketed oral antidiabetic agents. ISIS 113715 was co-incubated with glipizide and rosiglitazone in whole human plasma and tested for increased free drug concentrations. In a phase I clinical study, 23 healthy volunteers received a single oral dose of an antidiabetic compound (either metformin, glipizide or rosiglitazone) both alone and together with subcutaneous ISIS 113715 200 mg in a sequential crossover design. A comparative pharmacokinetic analysis was performed to determine if there were any effects that resulted from coadministration of ISIS 113715 with these antidiabetic compounds. RESULTS: In vitro human plasma protein binding displacement studies showed only minor effects on rosiglitazone and no effect on glipizide when co-incubated with ISIS 113715. The results of the phase I clinical study further indicate that there were no measurable changes in glipizide (5 mg), metformin (500 mg) or rosiglitazone (2 mg) exposure parameters, maximum plasma concentration and the area under the concentration-time curve, or pharmacokinetic parameter, elimination half-life when coadministered with ISIS 113715. Furthermore, there was no effect of ISIS 113715, administered in combination with metformin, on the urinary excretion of metformin. Conversely, there were no observed alterations in ISIS 113715 pharmacokinetics when administered in combination with any of the oral antidiabetic compounds. CONCLUSION: These data provide evidence that ISIS 113715 exhibits no clinically relevant pharmacokinetic interactions on the disposition and clearance of the oral antidiabetic drugs. The results of these studies support further study of ISIS 113715 in combination with antidiabetic compounds.

Bringing interdisciplinary and multicultural team building to health care education: the downstate team-building initiative.

PURPOSE: To evaluate the impact of the Downstate Team-Building Initiative (DTBI), a model multicultural and interdisciplinary health care team-building program for health professions students. METHOD: A total of 65 students representing seven health disciplines participated in DTBI's first three years (one cohort per year since implementation). During the 18-session curriculum, students self-evaluated their group's progress through Tuckman's four team-development stages (FORMING, STORMING, NORMING, PERFORMING) on an 11-point scale. Students completed matched pre- and postintervention program evaluations assessing five variables: interdisciplinary understanding, interdisciplinary attitudes, teamwork skills, multicultural skills, and team atmosphere. After participation, students completed narrative follow-up questionnaires investigating impact one and two years after program completion. RESULTS: Each year's team development curve followed a similar logarithmic trajectory. Cohort 1 remained in team development stage 3 (NORMING) while Cohorts 2 and 3 advanced into the final stage-PERFORMING. A total of 34 matched pre- and postintervention evaluations showed significant change in all major variables: Team atmosphere and group teamwork skills improved most (48% and 44%, respectively). Interdisciplinary understanding improved 42%. Individual multicultural skills (defined by ability to address racism, homophobia, and sexism) started at the highest baseline and improved the least (13%). Group multicultural skills improved 36%. Of 23 responses to the follow-up surveys, 22 (96%) stated DTBI was a meaningful educational experience applicable to their current clinical surroundings. CONCLUSIONS: DTBI successfully united students across health discipline, ethnicity, socioeconomic class, gender, and sexual orientation into functioning teams. The model represents an effective approach to teaching health care team building and demonstrates benefits in both preclinical and clinical years of training.