Pharmacological treatment for pubertal progression in boys with delayed or slow progression of puberty: A small-scale randomized study with testosterone enanthate and testosterone undecanoate treatment.

Context: The use of testosterone enanthate (TE), 50-75 mg intramuscularly (i.m.)/month, for the treatment of boys with delayed puberty or slow progression to induce puberty is the standard of care (SoC) in Sweden. This treatment is empirical and has not been scientifically evaluated. Replacement therapy in hypogonadal boys/young men in Sweden after induction is mainly performed with testosterone undecanoate (TU), 1,000 mg/3 months. TE is only available on license. TE was deregistered in Sweden in 2006. Therefore, this study was initiated to compare the two products. Objective: To clinically evaluate pubertal progression with six injections of TE, 75 mg i.m./month (1/3-1/5 of adult dose), compared with two injections of TU, 250 mg i.m./3 months (1/4 of adult dose). Trial design: In the Pubertal Replacement in Boys Study (PRIBS), boys aged 14-16 years in West Sweden with pubertal delay were randomized in a parallel study to TE or TU for pubertal progression. Inclusion criteria were morning testosterone levels of 0.5-3 nmol/L and testicular volume ≤6 ml. Between June 2014 and Nov 2019, 27 boys were included. Methods: The primary outcome was testicular enlargement ≥8 ml after 12 months. TU treatment was considered clinically similar if the number of boys with testicular enlargement ≥8 ml was 80%-125% of the number of boys with TE. Fisher's exact chi-square test was used for this analysis. Results: Both treatments were well tolerated. Twelve of 14 (86%) TU-treated boys reached the primary outcome and 12/12 in the TE group. Fisher's exact chi-square testing indicated a one-sided p-value of 0.28 (the two-sided p-value was 0.483). The TU treatment was considered not clinically different from SoC. A post-hoc study showed 25% power. Therefore, no evidence-based conclusion can be drawn from the results even if the clinical data support a similar effect of the treatments. Conclusion: The present small-scale study supports that both TE and TU had similar effects in terms of pubertal progression. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/home, identifier NCT05417035; https://www.clinicaltrialsregister.eu/ctrsearch/search, identifier EUDRACTEudraCT nr 2012-002337-11.

Efficacy and safety of dapagliflozin in children and young adults with type 2 diabetes: a prospective, multicentre, randomised, parallel group, phase 3 study.

BACKGROUND: Since there are few treatment options for young people with type 2 diabetes, we aimed to assess the efficacy and safety of dapagliflozin as add-on therapy in children, adolescents, and young adults with type 2 diabetes receiving metformin, insulin, or both. METHODS: This multicentre, placebo-controlled, double-blind, randomised phase 3 study was undertaken at 30 centres in five countries (Hungary, Israel, Mexico, Russia, and the USA). Participants aged 10-24 years with type 2 diabetes and HbA1c concentration of 6·5-11% (48-97 mmol/mol) were randomly assigned 1:1 to oral dapagliflozin 10 mg or placebo during a 24 week double-blind period, which was then followed by a 28 week open-label safety extension in which all participants received dapagliflozin. Participants and study personnel were masked and participants were randomly assigned treatment (placebo or study drug) using an interactive web and voice response system. The primary outcome was between-group differences in change in HbA1c concentration from baseline to 24 weeks (intention-to-treat analysis). A prespecified sensitivity analysis of the primary outcome was also assessed in the per-protocol population, which included only protocol-compliant participants. This trial is registered with ClinicalTrials.gov, NCT02725593. FINDINGS: Between June 22, 2016, and March 15, 2019, 72 participants (19 [26%] of whom were aged 18-24 years) were randomly assigned (39 to dapagliflozin and 33 to placebo). Mean age was 16·1 (SD 3·3) years. In the intention-to-treat analysis, after 24 weeks, mean change in HbA1c concentration was -0·25% (95% CI -0·85 to 0·34; -2·7 [-9·3 to 3·7] mmol/mol) for dapagliflozin and 0·50% (-0·18 to 1·17; 5·5 [-2·0 to 12·8] mmol/mol) for placebo. The between-group difference was -0·75% (95% CI -1·65 to 0·15; -8·2 [-18·0 to 1·6] mmol/mol; p=0·10). In a sensitivity analysis in the per-protocol population (34 in the dapagliflozin group and 26 in the placebo group) after 24 weeks, mean change was -0·51% (-1·07 to 0·05; -5·6 [-11·7 to 0·5] mmol/mol) for dapagliflozin and 0·62% (-0·04 to 1·27; 6·8 [-0·4 to 13·9] mmol/mol) for placebo. The between-group difference was -1·13% (-1·99 to -0·26; -12·4 [-21·8 to -2·8] mmol/mol; p=0·012). Adverse events occurred in 27 (69%) dapagliflozin-assigned participants and 19 (58%) placebo-assigned participants over 24 weeks, and in 29 (74%) participants who received dapagliflozin over 52 weeks. Hypoglycaemia occurred in 11 (28%) dapagliflozin-assigned and six (18%) placebo-assigned participants who received dapagliflozin over 24 weeks and in 13 participants (33%) who received dapagliflozin over 52 weeks; none were considered as serious adverse events. No adverse events of diabetic ketoacidosis occurred. INTERPRETATION: The primary outcome of change in HbA1c concentration was not significant in the intention-to-treat analysis of children, adolescents, and young adults with type 2 diabetes receiving dapagliflozin in addition to standard-of-care treatment. A prespecified sensitivity analysis of protocol-compliant participants showed a significant difference in HbA1c concentration between groups. No new safety signals were identified and there was a low risk of severe hypoglycaemia. FUNDING: AstraZeneca.

Correction to: How is the Pharmaceutical Industry Structured to Optimize Pediatric Drug Development? Existing Pediatric Structure Models and Proposed Recommendations for Structural Enhancement.

The article How is the Pharmaceutical Industry Structured to Optimize Pediatric Drug Development? Existing Pediatric Structure Models and Proposed Recommendations for Structural Enhancement, written by Thomas Severin et al. was originally published electronically on the publisher's internet portal on February 6, 2020 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on April 22, 2020 to © The Author(s) 2020 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License https://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

How is the Pharmaceutical Industry Structured to Optimize Pediatric Drug Development? Existing Pediatric Structure Models and Proposed Recommendations for Structural Enhancement.

BACKGROUND: Pediatric regulations enacted in both Europe and the USA have disrupted the pharmaceutical industry, challenging business and drug development processes, and organizational structures. Over the last decade, with science and innovation evolving, industry has moved from a reactive to a proactive mode, investing in building appropriate structures and capabilities as part of their business strategy to better tackle the challenges and opportunities of pediatric drug development. METHODS: The EFGCP Children's Medicines Working Party and the IQ Pediatric working group have joined their efforts to survey their member company representatives to understand how pharmaceutical companies are organized to fulfill their regulatory obligations and optimize their pediatric drug development programs. RESULTS: Key success factors and recommendations for a fit-for-purpose Pediatric Expert Group (PEG) were identified. CONCLUSION: Pediatric structures and expert groups were shown to be important to support optimization of the development of pediatric medicines.

Prevalence of Premature Thelarche at 18 Months of Age: A Population- and Hospital-Based Study of Prevalence and Incidence in Girls Born at Northern Älvsborg County Hospital in Sweden.

OBJECTIVE: The aim of this work was to investigate the prevalence of premature thelarche (PT) in 18-month-old girls, and the incidence of clinically evaluated PT for girls aged 18-36 months. METHODS: In the prevalence substudy, a prospective population-based cohort of 3,140 girls born at Northern Älvsborg county hospital (NÄL) in Trollhättan, Sweden, was followed for 2 years. Girls with breast development at the 18-month health check were referred to one pediatric center in NÄL for evaluation. All girls with PT were included and followed for clinical outcome and 17ß-estradiol. The prospective incidence substudy covered 8 years in a 10-year period and included all girls aged 18-36 months born at NÄL who were clinically evaluated for PT. RESULTS: The prevalence of PT at 18 months in our cohort was 1.6/1,000. The 5 girls with PT no longer showed symptoms at the follow-up 3-6 months later. The incidence was 1.1/1,000 for girls aged 18-36 months and 1.0/1,000 for girls aged 18-30 months who were clinically evaluated for their PT. CONCLUSION: This is the first prospective population-based study of PT and it shows a prevalence of PT at age 18 months of 1.6/1,000. The incidence of clinically evaluated PT was 1.1/1,000. Our result is in line with other studies reporting the incidence of PT from medical records (0.4-40/1,000). The outcome of PT in our study, as in the other studies, is that the great majority of girls show only benign symptoms.

17ß-Estradiol and Gonadotropin Levels for the Diagnosis of the Benign Form of Breast Development in Girls Aged up to 4 Years in Real-Life Clinical Practice.

BACKGROUND: Early onset of breast development in a young girl is usually a benign and isolated prepubertal condition, i.e., premature thelarche (PT), but can sometimes be progressive and the first sign of pubertal precocity (PP). Serum 17ß-estradiol (17ß-E2) level is a possible marker to differentiate between benign and pathological forms of breast development. We defined an upper serum 17ß-E2 level for benign, "classic" PT for girls aged 9-48 months. METHODS: Serum 17ß-E2 was analysed with a highly sensitive extraction radioimmunoassay (RIA). Gonadotropins, Tanner breast stage, growth, other investigations, and clinical outcome were assessed in 125 girls with breast development, in a population-based study in West Sweden. RESULTS: A total of 125 of 128 girls had a benign form of breast development with a mean serum 17ß-E2 level of 15.2 pmol/L and a mean + 2 SD of 31 pmol/L, which was regarded as the upper limit for benign PT; 3 girls with PP had 17ß-E2 levels above 70 pmol/L. CONCLUSION: This is the first study to define an upper serum 17ß-E2 level associated with benign PT. Girls aged 9-48 months with PT and Tanner breast stage 2 have 17ß-E2 levels below 32 pmol/L using extraction RIA. LH below the detection limit (0.1 IU/L) and measurable FSH support benign PT.

First Morning Voided Urinary Gonadotropin Measurements as an Alternative to the GnRH Test.

AIMS: We studied whether first morning voided (FMV) urinary gonadotropin measurements could be used as a noninvasive alternative to the GnRH test in the assessment of the hypothalamic-pituitary-gonadal function in children. METHODS: In a single-center study, we compared FMV urinary gonadotropin concentrations with basal and GnRH-stimulated serum gonadotropin levels in 274 children and adolescents (78 girls, 196 boys) aged 5-17 years referred for growth and pubertal disorders. The concordance between FMV urinary gonadotropin concentrations and GnRH test results was assessed. RESULTS: FMV urinary LH (U-LH), urinary FSH (U-FSH) and their ratios correlated well with the corresponding basal and GnRH-stimulated serum parameters (r ≥ 0.66, p < 0.001). Receiver operating characteristic curve analyses using urinary and serum LH and FSH concentrations showed that FMV U-LH and U-LH/U-FSH performed equally well as the GnRH test in the differentiation of early puberty (Tanner stage 2) from prepuberty (Tanner stage 1) (area under the curve 0.768-0.890 vs. 0.712-0.858). FMV U-LH and U-LH/U-FSH performed equally well as basal serum LH in predicting a pubertal GnRH test result (area under the curve 0.90-0.93). CONCLUSION: FMV U-LH determination can be used for the evaluation of pubertal development and its disorders, reducing the need for invasive GnRH stimulation tests.

Sex Steroid Replacement Therapy in Female Hypogonadism from Childhood to Young Adulthood.

The overall goal of pubertal sex hormone replacement therapy (HRT) in girls is not only about development of secondary sexual characteristics, but also to establish an adult endocrine and metabolic milieu, as well as adult cognitive function. Estradiol (E2) is the first choice for HRT compared to ethinyl estradiol (EE2). E2 is the most potent endogenous estrogen in the circulation, with established levels during spontaneous puberty. Transdermal E2, compared to oral administration, is the first choice to start pubertal HRT. Transdermal application avoids liver exposure to supraphysiologic estrogen concentrations and provides a more physiologic mechanism for hormone delivery. By cutting E2 matrix patches in doses of 0.05-0.07 µg/kg or administrate E2 gel in doses of 0.1 mg/day, serum concentrations of E2 seen in early spontaneous puberty can be obtained. Patches can be removed in the morning and thereby mimic the normal circadian rhythm. For those clinics with access to sensitive E2 determinations methods (extraction followed by radioimmunoassay or mass spectrometry) monitoring the attained E2 serum levels is recommended in order to optimally mimic the levels seen in early puberty as well as growth velocity, breast and uterus development. Mid- and late pubertal HRT is obtained by increased doses of E2, adding cyclic oral or transdermal progestin, as well as testosterone gel over the pubic area if indicated.

Sensitive RIA measures testosterone concentrations in prepubertal and pubertal children comparable to tandem mass spectrometry.

BACKGROUND: Immunoassays have been criticized for poor accuracy at low testosterone concentrations. Mass spectrometry (MS) has been proposed as the only reliable method for testosterone determination. The aim of this study was to compare a sensitive testosterone radioimmunoassay (RIA) with results from different MS. METHODS: We compared testosterone concentrations determined by a sensitive testosterone RIA, lower limit of detection 0.03 nmol/L and limit of quantitation 0.1 nmol/L, with four tandem MS that were included in an international external quality assessment program for laboratory medicine. We also compared the morning concentrations of testosterone in girls and boys at different pubertal stages, using results from the RIA, with reported values determined by LC-MS/MS, developed for androgen determination in children. RESULTS: The mean (SD), concentrations were similar between RIA and MS: 1.5 (0.3) and 1.4 (0.4) in the child/women range (0.8-2.6 nmol/L) and 16.0 (3.7) and 17.8 (4.5) nmol/L for the adult male range (10.1-30.0 nmol/L), respectively. The ratio between RIA and MS versus results from mean values of the four MS methods was 1.0 (0.18); 1.1 (0.18) for child/women concentrations and 0.9 (0.13) for male testosterone concentrations. Furthermore, compared to the pediatric reference values determined by LC-MS/MS, the sensitive testosterone RIA delivered similar testosterone values across the different pubertal stages. CONCLUSIONS: The comparison between different tandem MS methods and a sensitive testosterone RIA illustrates that there are immunoassays that deliver clinically useful information in prepubertal and pubertal children.

Physiological estrogen replacement therapy for puberty induction in girls: a clinical observational study.

BACKGROUND/AIM: The goal of estrogen replacement therapy (ERT) in girls with hypogonadism is to achieve the endocrine milieu similar to natural puberty, where transdermal administration is the most physiological route. The aim of the study was to evaluate guidelines for the induction of puberty with transdermal estradiol (E2) patches in a large outpatient setting. METHODS: In a retrospective study, serum E2 levels from 18 clinics were analyzed at the Göteborg Pediatric Growth Research Center laboratory, as part of the initiation of ERT in girls with hypogonadism. Exclusion criteria were pubertas tarda and pubertal arrest. Eighty-eight observations (50 with Turner syndrome, TS) were included. Serum E2 levels were determined by extraction + radioimmunoassay (detection limit 4 pmol/l) and analyzed in relation to the dose of Evorel(®) (25 µg/24 h, containing 1.60 mg estradiol hemihydrate; Janssen-Cilag Pharmaceutica N.V., Beerse, Belgium). RESULTS: There was a linear relationship between serum E2 and the weight-based dose, with r = 0.56, p < 0.0001 for all observations and r = 0.59, p < 0.0001 for the TS study group. Linear regression analysis for doses of 0.05-0.07 µg/kg resulted in serum levels of 17-23 pmol/l (TS 17-24 pmol/l) and doses of 0.08-0.12 µg/kg in 26-39 pmol/l (TS 27-39 pmol/l). CONCLUSIONS: For the initiation of ERT with nocturnally administered E2 patches, we recommend reduced starting doses of 0.05-0.07 µg/kg, with the goal of mimicking E2 levels during gonadarche. In older girls, when breast development is of high priority, the starting dose can still be 0.08-0.12 µg/kg.

Comparison of methods for evaluation of the suppressive effects of prednisolone on the HPA axis and bone turnover: changes in s-DHEAS are as sensitive as the ACTH test.

OBJECTIVE: Different hypothalamic-pituitary-adrenal (HPA) axis function tests are used for diagnosing disease and evaluating suppressive effects of corticosteroid treatment. Our objectives were to evaluate sensitivity and precision of different HPA axis tests to be able to select one that combines good performance with good practicability, suitable for investigation of new corticosteroids in clinical trials. METHODS: In this descriptive, double-blind, parallel-group study, 60 healthy male volunteers were treated with once-daily morning doses of prednisolone for 2 weeks. The volunteers were randomized to 1 of 5 treatment groups (prednisolone 2.5, 5, 7.5, 10, or 15 mg). We compared the plasma-cortisol (p-cortisol) 24-hour average concentration (Cav) with morning (08:00 hours) p-cortisol, daytime p-cortisol Cav, and 24-hour urinary cortisol excretion. Adrenocorticotrophic hormone (ACTH) stimulation tests and the metyrapone test were also performed. Furthermore, we analyzed levels of serum dehydroepiandrosterone sulfate (s-DHEAS), insulin, and markers of bone turnover. RESULTS: Dose-related effects were shown, but the magnitude of effects and sensitivities varied greatly between the tests. P-cortisol measurements over the course of 24 hours were used as the reference method. Low- and standard-dose ACTH tests and morning s-DHEAS levels had similar sensitivity. Urinary cortisol excretion and the metyrapone stimulation test had low sensitivity. The effects of prednisolone on markers of bone turnover were, in general, less than those on the HPA axis. Only osteocalcin, procollagen Type 1 C-peptide and procollagen Type 3 N-peptide were significantly affected. Treatment with prednisolone was well tolerated. CONCLUSION: Changes in s-DHEAS and the low-dose ACTH test combine good sensitivity and precision for evaluation of the suppressive effect of exogenous corticosteroids on the HPA axis, and they are easy to perform.

Pubertal growth and serum testosterone and estradiol levels in boys.

BACKGROUND/AIMS: To study serum testosterone and estradiol in healthy boys in relation to growth during puberty up to peak height velocity (PHV). METHODS: Growth velocity was analyzed through testosterone (n = 41) and 17ß-estradiol (n = 37) 24-hour profiles in a dose-response model. Participants were 26 healthy boys admitted for short or tall stature or participating as healthy volunteers at the Queen Silvia Children's Hospital. Other inclusion criteria included the following: gestational age 37-42 weeks, birth weight and length >-2 standard deviation score (SDS) and prepubertal height and weight within ± 3 SDS. Testosterone was measured using a modified radioimmunoassay (RIA) with a detection limit of 0.03 nmol/l. Estradiol was determined using an ultrasensitive extraction RIA with a detection limit 4 pmol/l. A sixth-grade polynomial was fitted to each child's growth data, giving growth velocity and age at PHV. RESULTS: Growth velocity increased by 50% from prepubertal growth to PHV at a morning testosterone level of 3.1 nmol/l (95% confidence interval 2.4-4.2), EC50. The corresponding EC50 of 17ß-estradiol was 6.5 pmol/l (3.2-13). Boys approaching PHV (<4% remaining) had morning testosterone levels >10 nmol/l and 17ß-estradiol >9 pmol/l. CONCLUSION: Observed early puberty/initial mid puberty morning testosterone levels of 2.4-4.2 nmol/l are associated with a 50% increase in growth velocity from prepubertal growth to PHV in healthy boys.

Age at adiposity rebound is associated with fat mass in young adult males-the GOOD study.

OBJECTIVE: Age at adiposity rebound (AR) is associated with obesity and Type 2 Diabetes in adults. The aim of the present study was to investigate the role of age at AR in adult fat mass, fat distribution and pubertal timing for a Swedish cohort. PATIENTS AND METHODS: This is a retrospective cohort study. Detailed growth charts were retrieved for the men participating in the population-based GOOD (Gothenburg Osteoporosis and Obesity Determinants) study (n=573). Body composition was analysed using dual X-ray absorptiometry and computed tomography at 18-20 years of age. Age and BMI at AR were calculated using pediatric growth charts and AR was defined as the lowest BMI between 3 and 9 years of age. RESULTS: Subjects were divided into early (age at AR below 5.4 years of age), middle (age at AR 5.4 to 6.8 years of age) and late (age at AR after 6.8 years of age) age at AR tertiles. Subjects in the early age at AR tertile had higher young adult BMI (+8%), whole body fat mass (+34%) and amount of subcutaneous adipose tissue (+61%) than the subjects in the middle and late tertiles (p<0.01). The early age at AR tertile had an increased risk of obesity (Odds Ratio 4.1 [95% CI 1.2-13.9]) compared with the middle and late tertiles. In addition, the early age at AR tertile had Peak Height Velocity (PHV) 7 months earlier than the late tertile. CONCLUSIONS: Early age at AR was associated with young adult obesity as a consequence of a high amount of subcutaneous adipose tissue in men. In addition we made the novel observation that early age at AR was associated with an early puberty in men.

Estradiol and pubertal growth in girls.

AIM: The objective of this study was to determine estradiol levels and assess their relationship to pubertal growth in girls. METHODS: Thirty-seven 24-hour profiles of serum 17ß-estradiol were retrospectively analyzed in relation to growth in 27 healthy girls admitted for short/tall stature (n = 20) or recruited as healthy volunteers at Göteborg Pediatric Growth Research Center (GP-GRC). INCLUSION CRITERIA: Birth weight and length above -2 SDS, gestational age 37-42 weeks, prepubertal height and weight within ± SDS and normal growth hormone secretion. Serum estradiol was determined by a validated ultrasensitive extraction radioimmunoassay (detection limit 4 pmol/l). A sixth-grade polynomial was fitted to each girl's growth data. Growth velocity and age at peak height velocity (PHV) was calculated. RESULTS: A dose-response model was used to find the morning 17ß-estradiol level at which half of the maximal pubertal growth up to PHV had occurred, EC(50), which was 20 pmol/l with a 95% confidence interval of 13-31. When 17ß-estradiol exceeds early pubertal levels (Tanner breast stage 2, 10-51 pmol/l), less than 25% of the potential pubertal growth velocity up to PHV remains. CONCLUSIONS: Morning 17ß-estradiol in the low early pubertal range (13-31 pmol/l) is associated with increasing growth velocity.

Tolerability, pharmacokinetics, and pharmacodynamics of the glucokinase activator AZD1656, after single ascending doses in healthy subjects during euglycemic clamp.

OBJECTIVES: AZD1656 is a novel glucokinase activator with a postulated dual mechanism of action by activating glucokinase in both the pancreas and the liver, and with the potential to deliver effective glucose-lowering in Type 2 diabetes mellitus. Here, we present the tolerability, pharmacokinetics and pharmacodynamics of AZD1656 in two single-blind, randomized, placebo-controlled studies, one with Western and the other with Japanese healthy adult male subjects. METHODS: Both studies evaluated oral single ascending doses of AZD1656 of up to 180 mg, administered during euglycemic clamp conditions to explore a wide dose range without risking hypoglycemia. Safety, pharmacokinetics and effects on serum insulin and glucose infusion rate were assessed. A population pharmacokinetics analysis was also conducted. RESULTS: AZD1656 was well tolerated in single doses up to 180 mg in both populations. AZD1656 was rapidly absorbed, and a dose-proportional increase in total exposure was observed for AZD1656 and the equipotent metabolite, AZD5658. Taking differences in body weight into account, there were no differences in pharmacokinetic parameters between Western and Japanese subjects. A dose-dependent blood glucose lowering effect was indirectly demonstrated by the increased glucose infusion rate required to maintain euglycemia, which was of similar magnitude in both populations. Dose-dependent increases in insulin secretion were also observed. CONCLUSIONS: No safety concerns were raised. AZD1656 displayed uncomplicated pharmacokinetics and dose-dependent pharmacodynamics effects were observed. The results suggest no ethnic differences in AZD1656 tolerability, pharmacokinetics or pharmacodynamics.

The glucokinase activator AZD6370 decreases fasting and postprandial glucose in type 2 diabetes mellitus patients with effects influenced by dosing regimen and food.

AIMS: To investigate the pharmacodynamics, pharmacokinetics and safety of the glucokinase activator AZD6370 after 1 day of administration under fed and fasted conditions in patients with type 2 diabetes mellitus (T2DM). METHODS: This was a two-part study. In Part A, patients received a single oral dose of AZD6370 (20, 60 or 180 mg) or placebo in the fasted or fed states (both n=8). In Part B, patients (n=8) received placebo and a total dose of AZD6370 180 mg given in one, two or four divided doses. Plasma glucose, insulin and C-peptide changes versus placebo were assessed. RESULTS: AZD6370 provided dose-dependent reductions in plasma glucose of up to 30% versus placebo in both fasted and fed patients (p<0.001 at 60 and 180 mg doses). Insulin secretion increased with dose, but absolute increases were relatively small in the fasted versus fed state (0-4 h). Dosing AZD6370 twice or four-times over 1 day gave a smoother 24-h glucose profile than single-dose. AZD6370 was rapidly absorbed. Pharmacokinetics of AZD6370 were dose-independent and unaffected by food. AZD6370 was generally well tolerated. CONCLUSIONS: AZD6370 produced dose-dependent glucose reductions and increased glucose-stimulated insulin secretion in patients with T2DM.

Longitudinal assessment of bone mineral density in children and adolescents with inflammatory bowel disease.

OBJECTIVES: Low bone mineral density (BMD) is recognized as a potential problem in children with inflammatory bowel disease (IBD). We aimed to describe the longitudinal development of BMD in a population of Swedish pediatric patients with IBD. METHODS: A total of 144 patients with IBD (93 males; 83 with ulcerative colitis [UC], 45 with Crohn disease [CD]) were examined with dual-energy x-ray absorptiometry at baseline. At follow-up 2 years later, 126 of the initial 144 patients were reexamined. BMD values are expressed as z scores. RESULTS: Children with UC and CD had significantly lower mean BMD z scores for the lumbar spine (LS) at baseline and after 2 years. The reduction in BMD was equally pronounced in patients with UC and CD, and neither group improved their z score during the follow-up period. Furthermore, significantly lower mean BMD z scores for the LS were found at baseline in boys (-1.1 SD, ±2.7 SD, P < 0.001), but not in girls (-0.0 SD, ±3.0 SD). This finding remained unchanged at follow-up. Subanalyses of the different age groups at baseline showed the lowest BMD values in the group of patients ages 17 to 19 years in boys (mean z score for the LS 1.59 SD, ±3.1 SD) and in girls (mean z score for the LS -3.40 SD, ±3.1 SD); however, at follow-up, these patients had improved their BMD significantly (mean change z score for the LS 1.00 SD, 95% CI 0.40-1.60; 1.90 SD, 95% CI 0.60-3.20). CONCLUSIONS: In this longitudinal study, the entire group of pediatric patients with IBD showed permanent decreases in their BMD z scores for the LS; however, our data indicate that afflicted children have the potential to improve their BMD by the time they reach early adulthood.

Glucokinase activators AZD6370 and AZD1656 do not affect the central counterregulatory response to hypoglycemia in healthy males.

CONTEXT: Glucokinase is expressed in the hypothalamus, but effects of glucokinase activators (GKAs) on counterregulatory responses to hypoglycemia are unknown. OBJECTIVE: Two separate studies assessed the counterregulatory hormone responses to hypoglycemia induced by the GKAs, AZD6370 and AZD1656, compared with insulin infusion. DESIGN AND SETTING: Both studies were randomized, open, two-way crossover studies, conducted in separate clinical research centers. PARTICIPANTS: Both studies involved 12 healthy adult male volunteers. INTERVENTIONS: Each subject received two treatments in randomized order, separated by a washout. In the AZD6370 study, overnight-fasted subjects received either a single oral AZD6370 dose (300 mg) or insulin infusion (0.8 mU/kg · min). In the AZD1656 study, overnight-fasted subjects received either a single oral dose of AZD1656 (80 mg) plus supporting insulin (1 mU/kg · min) or insulin alone (1 mU/kg · min). Insulin was added to support AZD1656 because AZD1656 alone did not produce the desired hypoglycemia. Plasma glucose was lowered during a stepwise hypoglycemic clamp with a glycemic nadir of 2.7 mmol/liter for 30 min. MAIN OUTCOME MEASURES: Epinephrine, norepinephrine, GH, cortisol, and glucagon plasma levels were assessed. RESULTS: No safety issues were raised. AZD6370 and AZD1656 had no effect on counterregulatory responses for norepinephrine, GH, or cortisol, but epinephrine increased slightly with AZD1656. Glucagon responses were reduced by approximately 30% with both GKAs vs. insulin. CONCLUSIONS: These data suggest the central nervous system-mediated counterregulatory response during GKA-induced hypoglycemia was preserved, whereas the glucagon response was attenuated; the latter was possibly mediated by a local pancreatic effect (intraislet hyperinsulinemia) rather than by impairment of the central nervous system-mediated response.

Pubertal timing predicts leg length and childhood body mass index predicts sitting height in young adult men.

OBJECTIVE: To investigate the impact of pubertal timing and childhood body mass index (BMI), both within normal range, on adult anthropometrics. STUDY DESIGN: Detailed growth charts were retrieved for the men participating in the population-based Gothenburg Osteoporosis and Obesity Determinants study. Age at peak height velocity and childhood BMI were calculated (n = 527), and anthropometric measurements were performed. RESULTS: Analysis of variance analysis of tertiles according to age at peak height velocity demonstrated that the early peak height velocity tertile had a lower adult height (180.9 ± 6.8 cm) compared with the middle tertile group (182.7 ± 6.9 cm, P < .05), and this difference was attributable to shorter leg length. No difference was seen for sitting height. In contrast, analysis of tertiles according to childhood BMI demonstrated low sitting height in the low BMI tertile (93.7 ± 3.3 cm for low, 94.6 ± 3.3, for middle, and 94.8 ± 3.3 cm for high childhood BMI tertiles, P < .05 and P < .01, respectively), but childhood BMI did not affect adult height and leg length. CONCLUSION: We demonstrate that subjects with early pubertal timing have reduced adult height and leg length, and subjects with low childhood BMI have reduced adult sitting height. Thus childhood body composition and pubertal timing have different impact on trunk growth and growth of long bones.