LY2189265, a long-acting glucagon-like peptide-1 analogue, showed a dose-dependent effect on insulin secretion in healthy subjects.

AIM: To assess the safety, tolerability, pharmacokinetics, pharmacodynamics and potential immunogenicity of single, escalating subcutaneous injections of a once-weekly glucagon-like peptide-1 analogue in healthy subjects. METHODS: This phase 1, three-period, crossover, double-blind, placebo-controlled study investigated single, escalating subcutaneous doses of LY2189265 (LY) ranging from 0.1 to 12 mg; approximately six subjects were randomized to each dose. Parameters of safety, including adverse events, were assessed. The pharmacokinetic profile was assessed over 14 days. Pharmacodynamic parameters (glucose and insulin concentrations) were measured following a step-glucose infusion (day 3) and as part of an oral glucose tolerance test (OGTT) (day 5). RESULTS: LY was generally well tolerated with some increase in gastrointestinal symptoms with escalating doses. There were small dose-dependent increases in pulse rate with doses ≥1.0 mg and diastolic blood pressure with doses ≥3.0 mg. The half-life of LY was approximately 90 h, with C(max) occurring between 24 and 48 h in most subjects. Evidence of increase in glucose-dependent insulin secretion and suppression of serum glucose excursions were observed during an OGTT at all doses compared to placebo; no episodes of hypoglycaemia occurred. No subjects developed antibodies to LY2189265. CONCLUSIONS: LY showed an acceptable safety profile and exhibited the expected glucagon-like peptide-1 pharmacological effects on glucose suppression and insulin secretion with a half-life that supports once-weekly dosing.

A 5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long-acting glucagon-like peptide-1 analogue, in patients with type 2 diabetes.

AIM: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of LY2189265 (LY), a novel, long-acting glucagen-like peptide-1 analogue, administered once weekly to subjects with type 2 diabetes. METHODS: This was a placebo-controlled, parallel-group, subject- and investigator-blind study of LY in subjects (N = 43) with type 2 diabetes mellitus controlled with diet and exercise alone or with a single oral antidiabetic medication. Subjects taking metformin or thiazolidinediones continued on their therapy. Subjects receiving sulfonylurea, acarbose, repaglinide or nateglinide were switched to metformin prior to enrollment. Subjects received five once-weekly doses of 0.05, 0.3, 1, 3, 5 or 8 mg. Effects on glucose, insulin and C-peptide concentrations were determined during fasting and following standard test meals. The pharmacokinetics of LY and its effects on HBA1c, glucagon, body weight, gastric emptying and safety parameters were assessed. RESULTS: Once-weekly administration of LY significantly reduced (p < 0.01) fasting plasma glucose, 2-h post-test meal postprandial glucose and area under the curve (AUC) of glucose after test meals at doses ≥1 mg. These effects were seen after the first dose and were sustained through the weekly dosing cycle. Most doses produced statistically significant increases in insulin and C-peptide AUC when normalized for glucose AUC. Statistically significant reductions in HBA1c were observed for all dose groups except 0.3 mg. The most commonly reported adverse effects (AEs) were nausea (35 events), headache (20 events), vomiting (18 events) and diarrhoea (8 events). CONCLUSIONS: LY showed improvement in fasting and postprandial glycaemic parameters when administered once weekly in subjects with type 2 diabetes. The pharmacokinetics and safety profiles also support further investigation of this novel agent.

Height velocity in Argentinean girls with Turner's syndrome.

Height velocities from birth to maturity derived from 1,049 height increments measured over intervals 0.85-1.15 years were studied from a sample of 187 patients with Turner's syndrome (TS) diagnosed on the basis of karyotype. Length of follow up in each girl varied from 1.0 to 11.0 years. Cross-sectional analysis showed a relatively stable growth velocity during pubertal ages. However, longitudinal analysis of individual growth curves showed the existence of a small growth spurt in 37 out of 47 girls with available data during pubertal years. Mean peak height velocity (PHV) of this spurt was 5.7 cm/year, SD 1.34; mean age at PHV was 12.66 years, SD 1.70. Selected percentiles were calculated using the least mean squares (LMS) method. Results show that a small growth spurt in girls with TS may be more frequent than previously thought.

Effect of upper respiratory tract infection on AIR inhaled insulin pharmacokinetics and glucodynamics in healthy subjects.

The suitability of employing AIR Inhaled Insulin (AIR Insulin; AIR is a registered trademark of Alkermes) during acute upper respiratory tract infection (URI) has not been determined. Twenty-one healthy, non-diabetic subjects were enrolled in a single-sequence, two-period, euglycemic clamp study. Subjects received a single 12 U-equivalent dose of AIR Insulin before rhinovirus (RV16) inoculation and during symptomatic infection. Spirometry was used to evaluate pulmonary safety. AIR Insulin exposure (the area under the immunoreactive insulin (IRI) concentration vs time curve from time zero until the IRI concentrations returned to the predose baseline value (AUC(0-t'))) and glucodynamic response (total amount of glucose infused (G(tot))) were comparable before and during RV infection (AUC(0-t') 46,300 vs 52,600 pmol min/l, P=0.21; G(tot) 61,800 vs 68,700 mg, P=0.42, respectively). Variability of pharmacokinetic and pharmacodynamic parameters did not change during URI; either did the number or intensity of adverse events. No significant change in forced expiratory volume or forced vital capacity was observed following AIR Insulin administration or during URI. The AIR Insulin system provides similar pharmacokinetic and glucodynamic responses under conditions of an experimentally induced RV infection and is regarded as suitable for use in diabetic patients during URIs.

Joint detection of important biomarkers and optimal dose-response model using penalties.

We propose a method to jointly detect influential biomarkers and estimate how they change with dose. The assessment is made in dose-ranging trials collecting multiple outcomes for efficacy, safety, pharmacokinetics or pharmacodynamics. We regress all these outcomes versus a non-parametric transformation of the dose. The regression coefficients and the parameters from the dose-response model are simultaneously estimated using a penalized alternating least-squares method. We illustrate the technique with a phase I clinical trial and a metabonomic experiment in rats.

Indication for thresholds of chromosome non-disjunction versus chromosome lagging induced by spindle inhibitors in vitro in human lymphocytes.

Risk assessment from exposure to spindle inhibitors should take into account the possibility of threshold concentration-response curves for aneuploidy induction. We analysed concentration-dependent induction of chromosome non-disjunction by well known spindle poisons (colchicine, carbendazim, mebendazole and nocodazole) and a reference clastogen, methyl methanesulphonate (MMS) in vitro in human lymphocytes; and integrated these findings with earlier results of chromosome loss in micronuclei. Chromosome non-disjunction was estimated on cytokinesis-blocked lymphocytes after simultaneous fluorescent in situ hybridization labelling with two chromosome-specific centromeric probes (chromosomes 1 and 17). The frequencies of spontaneous non-disjunction showed important inter-individual variations and were surprisingly high (7.04-15.39%). Lower concentrations of aneugens did not induce a statistically significant increase of non-disjunction frequencies over the respective control levels, whereas higher concentrations clearly induced a concentration-dependent increase in the non-disjunction frequencies with the four aneugens tested. On the contrary, even at high concentrations, MMS induced a slight increase in the frequency of non-disjunction but without being statistically significant when compared with the control frequencies. We estimated the inflection points, the first statistically significant concentrations, the last non-statistically significant concentrations and the number of events from concentration-response curves of chromosome non-disjunction and chromosome loss. A threshold-type of concentration-response for non-disjunction is highly probable for colchicine and nocodazole. For carbendazim and mebendazole the inflection point fell above the first statistically significant concentrations. But since it is obvious from dose-response curves where the inflection point/threshold lies, it appears that the model might be picking up some irregularities (possibly due to experimental variability in the dose-response curve at concentrations greater than the threshold). For accurate estimation of the threshold, analysis of more concentrations or more cells might be needed. Our data strongly indicate that in cultured human lymphocytes chromosome non-disjunction is a major mechanism of aneuploidy induction by spindle inhibitors and since non-disjunction occurs at lower concentration than chromosome loss, the aneuploidy threshold should be estimated on the basis of non-disjunction rather than on micronuclei frequencies (chromosome loss).

The organisation of a national survey for evaluating child psychomotor development in Argentina.

A total of 211 selected paediatricians were invited to participate in a national survey designed to evaluate the age of attainment of developmental milestones in children aged 0-5 years. Following a pilot study and a cascade training design, 61.1% of the paediatricians successfully completed the data collection on 139 developmental items. In the pilot study, there were more missing (not performed) items in children over one year of age, thus confirming the impression that paediatricians are more familiar with evaluating development in infants. However, in the age range 1-5 years, there were significantly fewer missing items in the gross motor area than in the other areas. Following a training programme and data editing and cleaning, a final sample of 3573 healthy, normal children was obtained. The impact of the training process was significant, in the sense that 3.5% of the items in children older than one year were not performed by the paediatricians before training, but this percentage was reduced to 1.9% after training (P < 0.01). The sample formed 0.11% of the national population less than 6 years of age and included a sex ratio of 1.01 compared with a national ratio of 1.02. There were no significant differences in the geographical distribution of the sample in comparison with that of the national population. The social composition, assessed by maternal education level, was biased towards a better education level than the national population. Mean Z-scores for height and weight were not significantly different from zero, when calculated on the basis of the national growth standards. In addition to successfully obtaining a representative sample for the analysis of the age of attainment of developmental milestones in Argentinian children, the survey also accomplished an educational objective in the training of paediatricians in developmental paediatrics.

Lymphocyte subsets and cytokines in adenoviral infection in children.

To determine the distribution of major blood lymphocyte subsets we evaluated blood lymphocytes by flow cytometry in adenovirus-infected infants aged 30-730 d. In addition, interleukin-1-receptor antagonist, interleukin-10 and transforming growth factor-beta1 were measured in serum by enzyme-linked immunosorbent assay. According to clinical parameters, mechanical ventilation and outcome, infections were classified as moderate (n = 15), severe (n = 11) and fatal (n = 12). Controls were 13 healthy children. In severe and fatal infection, T cells (CD5+/CD19-), NK effectors (CD16+), CD4+ T subset and B1 subset of B lymphocytes (CD5+/CD19+) were all significantly decreased. CD8+ cells were decreased in severe but not fatal cases. There was no difference in serum values of interleukin-10; however, fatal cases had high interleukin 1-receptor antagonist values. Interestingly, patients with moderate infection showed significantly increased values of transforming growth factor-beta1. These results demonstrate that life-threatening adenoviral infection is associated with marked abnormalities in blood lymphocyte and cytokine profile.