Are needle-free injections a useful alternative for growth hormone therapy in children? Safety and pharmacokinetics of growth hormone delivered by a new needle-free injection device compared to a fine gauge needle.

The clinical safety, use and pharmacokinetics of a new needle-free device for delivery of growth hormone (GH) were compared with those of conventional needle injection devices. In an open-label, randomized, 4-period crossover study, 18 healthy adults received single subcutaneous injections of Genotropin administered by the Genotropin ZipTip needle-free device and by conventional injection. Bioequivalence was established between the devices. In a separate open-label, randomized, multicenter, 2-period crossover study, pediatric patients underwent 2-weeks Genotropin treatment administered by the Genotropin ZipTip and by a fine-gauge needle device (>95% used the Genotropin Pen). In total, 128/133 patients who were treated completed the study. Genotropin ZipTip was well tolerated and >50% of patients found no difference between the devices for all parameters assessed. After study completion, >20% patients preferred to continue using Genotropin ZipTip. Although statistical analyses demonstrated superiority of the Genotropin Pen versus Genotropin ZipTip for bleeding, pain, soreness, and bruising, Genotropin ZipTip was considered to provide a safe and bioequivalent alternative to needle injection.

Pramlintide, a synthetic analog of human amylin, improves the metabolic profile of patients with type 2 diabetes using insulin. The Pramlintide in Type 2 Diabetes Group.

OBJECTIVE: To examine the effects of 4 weeks of subcutaneous administration of pramlintide, a synthetic analog of human amylin, on metabolic control in patients with type 2 diabetes using insulin. RESEARCH DESIGN AND METHODS: Serum fructosamine, HbA1c, and fasting plasma lipids were measured in 203 patients in a randomized double-blind placebo-controlled parallel-group multicenter trial using doses of 30 micrograms q.i.d., 60 micrograms t.i.d., and 60 micrograms q.i.d. RESULTS: Statistically significant reductions in serum fructosamine concentrations were observed in the pramlintide 30 micrograms q.i.d. group (17.5 +/- 4.9 mumol/l, P = 0.029), the pramlintide 60 micrograms t.i.d. group (24.1 +/- 4.9 mumol/l, P = 0.003), and the 60 micrograms q.i.d. group (22.6 +/- 4.1 mumol/l, P = 0.001) compared with the placebo group (3.5 +/- 3.8 mumol/l). There were also statistically significant shifts in the proportion of patients with an abnormal serum fructosamine concentration at baseline that normalized at week 4 within the pramlintide 60 micrograms t.i.d. group and the 60 micrograms q.i.d. group. Consistent with the fructosamine results, there were statistically significant reductions in HbA1c in the pramlintide 30 micrograms q.i.d. group (0.53 +/- 0.07%, P = 0.0447), the pramlintide 60 micrograms t.i.d. group (0.58 +/- 0.07%, P < 0.0217), and the pramlintide 60 micrograms q.i.d. group (0.51 +/- 0.08%, P = 0.0242) compared with the placebo group (0.27 +/- 0.08%). Total cholesterol concentrations were also statistically significantly reduced in both the pramlintide 60 micrograms t.i.d. group (8.4 mg/dl, P < 0.01) and 60 micrograms q.i.d. group (10.5 mg/dl, P < 0.01) compared with placebo (1.2 mg/dl). Body weight decreased in both of the pramlintide 60 micrograms groups, but the trend did not achieve statistical significance. The incidence of hypoglycemia was similar in all treatment groups. CONCLUSIONS: Reductions in serum fructosamine, plasma total and LDL cholesterol concentrations, and HbA1c support the hypothesis that pramlintide may improve metabolic control in patients with type 2 diabetes using insulin.

Cyclical etidronate in the treatment of postmenopausal osteoporosis: efficacy and safety after seven years of treatment.

PURPOSE: To determine the efficacy and safety of cyclical etidronate for up to 7 years in the treatment of postmenopausal osteoporosis and to examine the effects of discontinuing treatment after 2 or 5 years of therapy. PATIENTS AND METHODS: Patients were randomized at entry into the original study in 1986 to blinded treatment for 2 years with either a calcium (placebo) or an intermittent cyclical etidronate regimen, which most patients continued for a third year. Following this phase of the study, patients were enrolled into an open-label, follow-up study (years 4 and 5), during which all patients received cyclical etidronate treatment. In the present double-blind study (years 6 and 7), patients were rerandomized to receive intermittent cyclical therapy with either etidronate or placebo; all patients received calcium. The treatment regimen consisted of 400 mg/day etidronate or placebo for 14 days, followed by 76 days of elemental calcium (500 mg/day); this cycle was repeated approximately 4 times in each year. Of the 193 patients who continued in years 6 and 7 of the study, 93 were randomized to receive cyclical etidronate and 100 were randomized to receive calcium only. For purposes of efficacy analyses, patients were categorized by their total years of cumulative etidronate treatment (7, 5, 4, or 2 years). There were 51, 46, 42, and 54 patients in the 7-, 5-, 4-, and 2-year groups, respectively. Annual assessments included lumbar spine bone mineral density (BMD), as measured by densitometry, and vertebral radiographs. RESULTS: The groups receiving cyclical etidronate during this 2-year study period (7- and 4-year groups) had statistically significant mean percent increases in spinal BMD of 1.8% and 2.2%, respectively (P < 0.05) at the week 104 observation time. The 5- and 2-year groups, which did not receive etidronate during this period, had mean values of 1.4% and 0.2%, respectively (not significant) at week 104. In the 7-, 5-, 4-, and 2-year groups, the increases in spinal BMD at the end of 7 years were 7.6%, 8.6%, 8.1%, and 3.9%, respectively; these values were statistically significant for all groups compared with original baseline (year 0) (P < 0.05). BMD of the femur and wrist was maintained throughout the 7-year period. The incidence and rate of vertebral fractures were lowest in patients with the longest exposure to etidronate. Etidronate was well tolerated during the study, with low incidences of gastrointestinal side effects and nonvertebral fractures. CONCLUSIONS: Long-term cyclical etidronate is a safe, effective, and well-tolerated treatment for postmenopausal osteoporosis. Bone mass is maintained for at least 2 years after treatment with etidronate is stopped; however, further gains in spinal bone mass are seen in patients who continue therapy.

Increased specificity and sensitivity of insulin antibody measurements in autoimmune thyroid disease and type I diabetes.

Insulin autoantibodies (IAA), a marker for insulin-dependent diabetes mellitus (IDDM), have been reported in other diseases such as thyroid disease and after treatment with sulfhydryl containing medications. Reported prevalences of IAA in non-diabetics vary widely, probably due in part to methodological differences between laboratories. In addition, certain sera may have a high non-specific binding to insulin. We compared a radioimmunoassay (RIA) for IAA which included non-specific binding with an RIA that incorporated a competitive displacement with cold insulin to remove non-specific binding. Using the RIA which measured specific plus non-specific binding, IAA positivity was found in 22/92 (23.9%) of sera from thyroid disease patients, 16/124 (12.9%) of random masked sera from a hospital laboratory, 27/335 (8.1%) of first degree relatives of IDDM patients, 63/178 (35.4%) of subjects with newly diagnosed IDDM, and 0/92 (0%) of normal controls. Insulin antibodies (IA) were found in 80/99 (80.8%) of insulin-treated diabetic subjects. In contrast, using the displacement assay which allowed measurement of specific binding, the frequency of IAA positivity was lower for subjects with thyroid disease (7/92 (7.6%)), random hospital sera (12/124 (9.8%)), and for first degree relatives of IDDM patients (8/335 (2.4%)), while higher for subjects with newly diagnosed IDDM (71/178 (39.9%)). Subjects with insulin-treated diabetes (78/99 (78.8%)) and normal subjects (1/92 (1.1%)) showed little change. Strikingly, three of the eight (37.5%) relatives of IDDM patients that were positive in the RIA measuring specific binding were detected only because cold displacement was utilized. We conclude: (1) subjects with thyroid disease and first degree relatives of IDDM patients frequently have high non-specific binding for IAA in an RIA not employing a cold displacement step, (2) in some newly diagnosed IDDM patients and first degree relatives of IDDM patients, IAA may be missed by an assay not optimized to measure specific binding, and (3) displacement with cold insulin increases both the specificity and sensitivity of RIAs measuring insulin autoantibodies.

Nonprogression of subclinical beta-cell dysfunction among first-degree relatives of IDDM patients. 5-yr follow-up of the Seattle Family Study.

It is unknown among first-degree relatives of individuals with insulin-dependent diabetes mellitus (IDDM) whether the disease process occurs in relatively few but always progresses to clinical IDDM or whether subclinical disease is more common but remains nonprogressive in many cases. Islet cell antibodies (ICAs) were found in 21 of 724 (2.9%) first-degree relatives during screening in the greater Seattle area between 1983 and 1988. Measures of beta-cell function (glucose disappearance rate [Kg], fasting insulin, acute insulin response to intravenous arginine [AIRarg], acute insulin response to intravenous glucose [AIRgluc], slope of glucose potentiation of AIRarg) and insulin sensitivity were obtained. Twenty individuals, 9 ICA+ relatives and 11 ICA- relatives, were evaluated prospectively. When expressed in relation to the expected AIRgluc based on each subject's sensitivity index, AIRgluc in 18 of 20 relatives fell below 100%, indicating inappropriately low insulin secretion (subclinical beta-cell dysfunction). After a median follow-up of 42 mo, 10 of 11 ICA- relatives remained ICA-. None showed deteriorating beta-cell dysfunction, and none developed diabetes. Five ICA+ relatives showed persistent immunologic positivity. beta-Cell function remained remarkably stable in all except 2 relatives. One was a 15-yr-old boy who developed IDDM shortly after screening and before evaluation of beta-cell function could be carried out. The other was an 18-yr-old monozygotic twin who developed IDDM after 27 mo. Both of these individuals had ICAs of 80 Juvenile Diabetes Foundation U and had been discordant for less than 5 yr.(ABSTRACT TRUNCATED AT 250 WORDS)

Systematic variation and differences in insulin-autoantibody measurements.

Insulin autoantibodies (IAAs) are currently the subject of intensive investigation as potential markers for autoimmune insulitis. However, the results of different reports vary widely. In an attempt to elucidate the reasons for the discrepant reports and to initiate standardization procedures, the International Diabetes Workshop (IDW) undertook two studies in which 22 centers worldwide measured IAA in coded samples. The variance in binding signal from the 49 sera in study 1 was considerable, even when results were standardized, but was largely systematic and attributable to basic differences in assay type (liquid phase versus solid phase) and to differences in the ligand used (human vs. nonhuman insulin). In study 2, 5 sera were prepared and presented blindly to compare dilution curves, insulin-species specificity, interference from irrelevant serum proteins, precision, and dose-dependent displaceability. Many assays, both liquid and solid phase, were influenced by marked and unpredictable nonspecific binding, revealed by loss of parallelism between dilution curves in pooled normal serum and buffer, by variable binding signals with different normal sera, and by difficulty in distinguishing human insulin-specific from cross-reactive IAA sera. It was concluded from the experience of both studies that variance could probably be reduced by using a standard curve with derived common units, a single species of ligand, and methodology to minimize the effect of nonspecific binding. Variation related to assay type was probably due to liquid- versus solid-phase systems being differentially more sensitive to certain aspects of antigen-antibody binding; this issue will be addressed in future serum exchanges and workshops.