Biological activity of AC3174, a peptide analog of exendin-4.

Exenatide, the active ingredient of BYETTA (exenatide injection), is an incretin mimetic that has been developed for the treatment of patients with type 2 diabetes. Exenatide binds to and activates the known GLP-1 receptor with a potency comparable to that of the mammalian incretin GLP-1(7-36), thereby acting as a glucoregulatory agent. AC3174 is an analog of exenatide with leucine substituted for methionine at position 14, [Leu(14)]exendin-4. The purpose of these studies was to evaluate the glucoregulatory activity and pharmacokinetics of AC3174. In RINm5f cell membranes, the potency of AC3174 for the displacement of [(125)I]GLP-1 and activation of adenylate cyclase was similar to that of exenatide and GLP-1. In vivo, AC3174, administered as a single IP injection, significantly decreased plasma glucose concentration and glucose excursion following the administration of an oral glucose challenge in both non-diabetic (C57BL/6) and diabetic db/db mice (P<0.05 vs. vehicle-treated). The magnitude of glucose lowering of AC3174 was comparable to exenatide. The ED(50) values of AC3174 for glucose lowering (60 minute post-dose) were 1.2 microg/kg in db/db mice and 1.3 microg/kg in C57BL/6 mice. AC3174 has insulinotropic activity in vivo. Administration of AC3174 resulted in a 4-fold increase in insulin concentrations in normal mice following an IP glucose challenge. AC3174 was also shown to inhibit food intake and decrease gastric emptying in rodent models. AC3174 was stable in human plasma (>90% of parent peptide was present after 5 h of incubation). In rats, the in vivo half-life of AC3174 was 42-43 min following SC administration. In summary, AC3174 is an analog of exenatide that binds to the GLP-1 receptor in vitro and shares many of the biological and glucoregulatory activities of exenatide and GLP-1 in vivo.

A Consumer Use Study of Over-The-Counter lovastatin (CUSTOM).

The Consumer Use Study of OTC Mevacor evaluated the ability of subjects to self-manage high levels of low-density lipoprotein (LDL) cholesterol by using a multifaceted cholesterol self-management program (the Mevacor Over-the-Counter Self-Management System; MOTC-SMS). This 26-week all-comers multicenter observational study was conducted in naturalistic storefront settings that used the fully functional MOTC-SMS to guide subjects' behavior. Of 3,316 subjects who evaluated the product (evaluators), 1,061 took >or=1 20-mg tablet of Mevacor OTC (users). Eighty-four percent of evaluators made appropriate initial use decisions. Most users demonstrated acceptable ongoing use behavior regarding treatment to goal, compliance/persistence, changes in health status, dietary patterns, and exercise habits. Throughout the study, 23 users (2%) demonstrated behavior that created the potential for suboptimal safety. After 26 weeks, median levels of LDL cholesterol were reduced by 25% among users who fasted. Of the 878 users who completed the study lipid test, 548 (62%) achieved the LDL cholesterol target goal (<130 mg/dl). Physician interactions were common. Mevacor OTC was well tolerated, with no observable adverse experiences from drug interactions or reports of myopathy. This actual use study demonstrates that the MOTC-SMS can effectively guide consumers to interact with health care professionals and to make appropriate initial and ongoing use decisions to manage their elevated levels of LDL cholesterol, with minimal potential or actual safety risk.

Enhanced amylin-mediated body weight loss in estradiol-deficient diet-induced obese rats.

In rodents, ovariectomy (OVX) elicits weight gain and diminished responsiveness to homeostatic signals. Here we characterized the response of obese OVX rats to peripheral amylin. Rats received sham surgery (SHAM), OVX, or OVX with hormonal replacement (17ß-estradiol, 2 µg per 4 d; OVX+E) and were infused with vehicle or amylin (50 µg/kg · d) for 28 d. Amylin reduced body weight (5.1 ± 1.1%) and food intake (10.9 ± 3.4%) in SHAM rats but was twice as efficacious in OVX rats in reducing weight (11.2 ± 1.9%) and food intake (23.0 ± 2.0%). There were no differences between amylin-treated SHAM and OVX+E rats. OVX decreased metabolic rate (∼24%) and increased respiratory exchange ratio relative to SHAM. Amylin partially normalized metabolic rate (13% increase) in OVX rats and decreased respiratory exchange ratio in OVX and SHAM rats. Regarding central mechanisms, amylin infusion corrected the OVX-induced decrease in hippocampal neurogenesis and increased immobility in the forced swim test. Additionally, amylin increased neurogenesis (∼2-fold) within the area postrema of OVX rats. To assess the contribution of endogenous leptin to amylin-mediated weight loss in OVX rats, amylin was administered to SHAM or OVX Zucker diabetic fatty rats. In SHAM rats, amylin infusion reduced food intake but not body weight, whereas in OVX Zucker diabetic fatty rats, food intake, body weight, and insulin were reduced. Overall, amylin induced greater body weight loss in the absence of estradiol via central and peripheral actions that did not require leptin. These findings support the clinical investigation of amylin in low estradiol (e.g. postmenopausal) states.