The objective of this study was to assess the effect of mealtime amylin replacement with pramlintide on long-term glycemic and weight control in subjects with type 2 diabetes. This 52-week, randomized, placebo-controlled, multicenter, double-blind, dose-ranging study in 538 insulin-treated subjects with type 2 diabetes compared the efficacy and safety of 30-, 75-, or 150-microg doses of pramlintide, a synthetic analogue of the beta-cell hormone amylin, to placebo when injected subcutaneously three times daily (TID) with major meals. Pramlintide therapy led to a mean reduction in HbA1c of 0.9% and 1.0% from baseline to week 13 in the 75- and 150-microg dose groups, which was significant compared to placebo (p = 0.0004 and p = 0.0002, respectively). In the 150-microg dose group, there was a mean reduction in HbA1c of 0.6% from baseline to week 52 (p = 0.0068 compared to placebo). The greater reduction in HbA1c with pramlintide was achieved without increases in insulin use or severe hypoglycemia, and was accompanied by a significant (p < 0.05) reduction in body weight in all dose groups compared to placebo. Three times the proportion of subjects in the 150-microg pramlintide group compared to the placebo group achieved a concomitant reduction in both HbA1c and body weight from baseline to week 52 (48% versus 16%). The most common adverse event reported with pramlintide treatment was nausea, which was mild to moderate and dissipated early in treatment. The results from this study support the safety and efficacy of pramlintide administered three times a day with major meals, in conjunction with insulin therapy, for improving long-term glycemic and weight control in subjects with type 2 diabetes.

OBJECTIVE -To assess the postprandial glucose-lowering effect of the human amylin analog pramlintide when given with either regular insulin or insulin lispro in subjects with type 1 diabetes, with an emphasis on the optimal dose timing relative to meals.RESEARCH DESIGN AND METHODS -In this randomized, single-blind, placebocontrolled, five-way crossover study, 19 subjects with type 1 diabetes using regular insulin and 21 subjects with type 1 diabetes using insulin lispro underwent five consecutive mixed meal tests. In randomized order, subjects received subcutaneous injections of placebo at Ϫ15 min or 60 g pramlintide at Ϫ15, 0, ϩ15, or ϩ30 min relative to the meal after an overnight fast. Regular insulin or insulin lispro was injected at Ϫ30 and 0 min, respectively, at doses that were adjusted appropriately for both the content of the standardized meal and the anticipated effects of pramlintide. Plasma glucose concentrations were measured before and during the 4-h postmeal period.RESULTS -In both the regular insulin and insulin lispro groups, pramlintide injections at all four time points lowered the postprandial glucose excursion (36 to Ͼ100% reduction in incremental area under the concentration time curve from 0 to 4 h (AUC 0 -4 h ) compared with placebo. However, only preprandial injections of pramlintide (Ϫ15 and 0 min) were able to prevent the initial postprandial surge in glucose. The optimal time for pramlintide injection was 0 min, which reduced the postprandial glucose excursion by Ͼ100% compared with regular insulin plus placebo (incremental AUC 0 -4 h : Ϫ0.6 Ϯ 2.5 vs. 11.0 Ϯ 2.9 mmol ⅐ h Ϫ1 ⅐ l Ϫ1 , P Ͻ 0.0007) and by 75% compared with insulin lispro plus placebo (incremental AUC 0 -4 h : 2.5 Ϯ 2.1 vs. 10.0 Ϯ 2.5 mmol ⅐ h Ϫ1 ⅐ l Ϫ1 , P Ͻ 0.0098). No serious adverse events were reported.CONCLUSIONS -Pramlintide, given at or just before a meal, reduces the postprandial glucose excursion in subjects with type 1 diabetes, regardless of whether added to regular insulin or a rapid-acting insulin analog.

Current therapy for condylomata acuminata (genital warts) is not consistently effective. Therefore, we conducted a randomized, double-blind trial to compare interferon alpha-2b with placebo in the treatment of this disorder. Our rationale was that interferon has both antiproliferative and antiviral properties. The placebo or interferon (1 X 10(6) IU) was injected directly into one to three warts three times weekly for three weeks. The injections were well tolerated by both groups of patients. The side effects of fever, chills, myalgia, headache, fatigue, and leukopenia occurred more commonly in the interferon group than in the placebo group, but such effects rarely disrupted daily routines. Only 13 of 296 patients (4 percent) discontinued therapy because of side effects (11 in the interferon group and 2 in the placebo group). Twenty-six other patients were excluded from analysis because of a loss to follow-up or other deviations from protocol, thus leaving 257 patients in the final evaluation. At one week after the completion of therapy, interferon had produced a large and significantly greater reduction in mean wart area (a 62.4 percent decrease), as compared with placebo (a 1.2 percent increase in mean area) (P less than 0.001). At the conclusion of the study (13 weeks after the completion of therapy), the mean wart area was still decreased 39.9 percent below the initial size in the interferon group, whereas it had increased by 46 percent over base-line measurements in the placebo group (P less than 0.001). At the same time, all treated warts had completely cleared in 36 percent of the interferon recipients and in 17 percent of the placebo recipients (P less than 0.001), whereas treated warts progressed in 13 percent of the interferon recipients and in 50 percent of the placebo recipients (P less than 0.001). We conclude that injection of interferon alpha-2b directly into genital warts appears to be an effective and fairly well-tolerated form of therapy.

The effects of subcutaneous administration of 10, 30, or 100 microg q.i.d. pramlintide, an analog of human amylin, on plasma glucose regulation in patients with IDDM were evaluated in a multicenter trial. The plasma glucose response to a Sustacal test meal was significantly reduced compared with placebo both after 1 week and after 2 weeks of administration of 30 or 100 microg pramlintide. In addition, 24-h mean plasma glucose concentrations were significantly lowered in patients receiving 30 microg of pramlintide for 2 weeks compared with placebo, while the 100-microg pramlintide dose did not reach statistical significance for the 24-h glucose profiles. At 10 microg, pramlintide had no effect on the 24-h glucose profile or on the plasma glucose response to a Sustacal test meal. The reduction in 24-h glucose concentrations and glucose concentrations after the Sustacal test meal observed at the 30-microg pramlintide dose was not accompanied by an increased incidence of hypoglycemic events. The most frequent adverse events were dose-related and involved transient upper gastrointestinal symptoms. A majority (>80%) of the patients who reported these adverse events during week 1 did not report them in week 2. These data indicate that pramlintide effectively reduces plasma glucose concentrations as reflected in both a 24-h glucose profile and a Sustacal test meal while maintaining an acceptable safety profile.

A study was conducted to evaluate the effect of 30-mug, 100-mug, and 300-mug 2-minute bolus doses and 2-hour infusion doses of AC137 (25,28,29 tripro-amylin, human) on plasma AC137 concentrations and plasma glucose and lactate responses in patients with insulin-dependent diabetes mellitus (IDDM). The study design was an imbedded two-way cross-over wherein patients received placebo and active boluses in one period and placebo and active infusions in the other period. Two patients in each dose group received placebo throughout the two periods. Pharmacokinetics and pharmacodynamics (PK/PD) were determined during the 6-hour period after initiation of dosing. Data were fitted with a linked PK/PD model. Pharmacokinetics were linear over the dose range studied, and attenuation of glucose and lactate responses to a mixed meal was dose and concentration dependent. The results of the PK/PD model indicate that the attenuation of glucose and lactate responses was greater after AC137 infusion doses than after the same doses given as a bolus. Glucose and lactate responses to a mixed meal were essentially negated by the 300-mug infusion dose.