Investigating the Bioavailability and Insulin-like Growth Factor-I Release of Two Different Strengths of Somapacitan: A Randomised, Double-Blind Crossover Trial.

STUDY DESIGN AND OBJECTIVE: Randomised, double-blind, crossover trial to confirm bioequivalence of somapacitan, a long-acting growth hormone (GH), in 5 mg/1.5 mL and 10 mg/1.5 mL strengths in equimolar doses. METHODS: Healthy participants were randomised (1:1:1) to subcutaneous somapacitan treatment in one dosing period with 5 mg/1.5 mL and two periods with 10 mg/1.5 mL. Eligibility criteria included age 18-45 years and body mass index 18.5-24.9 kg/m2. Exclusion criteria included history of GH deficiency, previous GH treatment, weight > 100.0 kg and participation in any clinical trial of an investigational medicinal product within 45 days or five times the half-life of the previous investigational product before screening. Area under the curve from time 0 until last quantifiable observation (AUC0-t), maximum serum concentration (Cmax), time to Cmax and terminal half-life of somapacitan and safety were assessed. RESULTS: In total, 33 participants were randomised. For AUC0-t, estimated treatment ratio (ETR) (5 mg/1.5 mL versus 10 mg/1.5 mL) was 0.95 (90% confidence interval [CI] 0.89-1.01). Point estimate and 90% CIs were within the acceptance range (0.80-1.25). For Cmax, ETR was 0.77 (90% CI 0.68-0.89). Point estimate and 90% CIs were outside the acceptance range (0.80-1.25). Mean insulin-like growth factor-I (IGF-I) and IGF-I standard deviation score concentration-time curves for each strength were almost identical. No new safety issues were identified. CONCLUSIONS: Bioequivalence criterion for somapacitan 5 mg/1.5 mL and 10 mg/1.5 mL was met for AUC0-t but not for Cmax. The two strengths had equivalent IGF-I responses. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03905850 (3 April 2019).

Somapacitan is a long-acting growth hormone used to treat people with growth hormone deficiency. Somapacitan is injected under the skin with an injection pen. The dose is based on a person's body weight and how they respond to treatment. We compared two strengths of injection pen, containing either 5 or 10 mg of somapacitan per 1.5 mL. For both strengths, participants were given the same dose. We wanted to understand whether the body absorbs these different strengths into the bloodstream in the same way. We also measured levels of insulin-like growth factor-I (IGF-I), a hormone formed when growth hormone is present in the blood, to see the effect of different strengths of somapacitan on the body. In our study, 33 healthy adults received one round of injection using the somapacitan 5 mg pen and two rounds using the somapacitan 10 mg pen, all at least 3 weeks apart. We found no differences in the amount of somapacitan being absorbed into the bloodstream, nor how fast it was absorbed. The peak amount of somapacitan in the bloodstream was higher in people using the 10 mg pen. There were no differences in IGF-I levels following use of either injection pen. Overall, our results show both strengths of somapacitan lead to similar responses in the body. Having different strength options could allow doctors to adjust the dose of somapacitan more easily, depending on a patient's response to treatment.

The growzen™ buddy smartphone app to improve adherence in patients receiving recombinant human growth hormone therapy: a retrospective observational study in Argentina.

Introduction: This study in Argentina evaluated the impact of the growzen™ buddy smartphone app on adherence to recombinant human growth hormone (r-hGH) treatment. Methods: The adherence data, invitation dates with a link to the app, app activation dates, and height measurements entered were extracted from the growzen™ digital health ecosystem. Patients with 12 months of adherence data, aged ≥2 years at treatment start, and aged <19 years were selected both before and after app implementation. Mean adherence was classified as optimal (≥85%) versus suboptimal (<85%). Adherence before and after implementation and the pre-post effect on adherence were assessed. Results: Data for 830 patients were available. Prior to app implementation, the proportion of patients with optimal adherence was 68% (n = 348/515). Following the app implementation, out of 315 patients, 302 (96%) received an invitation with a link to the app, 225 (71%) activated their account, and 127 (40%) entered height data in the first year. There was a significant early increase in the proportion of patients with optimal adherence following implementation: 82% (n = 258/315), p < 0.001. After implementation, the proportion of patients with optimal adherence included 80% (n = 78/98) of those with an active account who did not enter height measurements and 89% (n = 113/127) of those who did. There was a significant and positive pre-post app effect on adherence (p < 0.01) in patients with an active account. Discussion: Our results show that using the growzen™ buddy app has a rapid and positive impact on adherence to r-hGH treatment, and patients who were more engaged with the app demonstrated better adherence.

Healthcare professionals' perspectives towards the digitalisation of paediatric growth hormone therapies: expert panels in Italy and Korea.

Introduction: To analyse the perspectives of healthcare professionals (HCPs) regarding the acceptance of digital health solutions for growth hormone (GH) deficiency care. This study identified factors impacting HCPs' intent to use and recommend digital solutions supporting recombinant-human growth hormone (r-hGH) therapy in Italy and Korea with a use case of connected drug delivery system (Aluetta® with Smartdot™) integrated in a platform for GH treatment support (the Growzen™ digital health ecosystem). Methods: Participatory workshops were conducted in Rome, Italy, and Seoul, Korea, to collect the perspectives of 22 HCPs on various predefined topics. HCPs were divided into two teams, each moderated by a facilitator. The workshops progressed in five phases: introduction of the project and experts, capturing views on the current context of digitalisation, perceived usefulness and ease of use of Aluetta® with Smartdot™, exploration of the perception of health technology evolution, and combined team recommendations. Data shared by HCPs on technology acceptance were independently analysed using thematic analysis, and relevant findings were shared and validated with experts. Results: HCPs from both Italy and Korea perceived Aluetta® with Smartdot™ and the Growzen™ based digital health ecosystem as user-friendly, intuitive, and easy-to-use solutions. These solutions can result in increased adherence, a cost-effective healthcare system, and medication self-management. Although technology adoption and readiness may vary across countries, it was agreed that using digital solutions tailored to the needs of users may help in data-driven clinical decisions and strengthen HCP-patient relationships. Conclusion: HCPs' perspectives on the digitalisation in paediatric GH therapies suggested that digital solutions enable automatic, real-time injection data transmission to support adherence monitoring and evidence-based therapy, strengthen HCP-patient relationships, and empower patients throughout the GH treatment process.

Short Adult Height After Rapid-tempo Puberty: When is it too Late to Treat?

A rarely reported phenomenon of rapid-tempo puberty in which the physical changes of puberty and testosterone levels increase very rapidly has not been reported outside apart from in two reviews. The resulting rapid advancement of skeletal age causes early completion of growth with shorter adult stature than expected. This appears to be genetic given its occurrence in the present report in two families, one with three brothers, one with two. We also describe potential treatments and found for the youngest that early initiation of standard therapy preserved or reclaimed adult height (AH) potential. The foreshortened AH in this situation involves rapidly advancing puberty resulting from high circulating testosterone levels leading to rapid advance in skeletal age. This was recognized earlier among younger brothers and treatment with gonadotropin-releasing analogues, growth hormone (GH) and/or aromatase inhibitor therapy (AIT) was tried. Two brothers in family A and family B were treated. Case 5 started treatment early enough so his AH was within target height (mid-parental height) range. Cases 2, 3, 4 were tried on GH and/or AIT with outcomes suggesting benefit. The prevalence and mechanism of rapid-tempo puberty requires further study. Furthermore, as illustrated by two of the current cases, this phenomenon may have a heightened prevalence, or at least may occur, in children previously diagnosed with constitutional delay of growth, underscoring the need to be cautious in assurance of a normal AH outcomes in this population, based on data from a single assessment.

Atosiban interacts with growth hormones as adjuvants in frozen-thawed embryo transfer cycles.

Objective: To investigate the interaction between atosiban and growth hormone (GH) as adjuvants in frozen-thawed embryo transfer (FET) cycles. Method: A total of 11627 patients who underwent FET at Xiamen University Affiliated Chenggong Hospital between January 2018 to December 2022 were retrospectively analyzed. Among them, 482 patients received atosiban and 275 patients received GH. The interactions were estimated by comparing the odds ratio (OR) for pregnancy comparing patients with or without atosiban adjuvant in cohorts stratified according to the presence of GH use in either the overall cohort or a propensity score (PS) matched cohort. An interaction term (atosiban × GH) was introduced to a multivariate model to calculate the ratio of OR (ORR) adjusted for confounders. Results: For all patients receiving atosiban administration, no obvious effect on pregnancy was observed in comparison with either matched or unmatched controls. However, when the patients were stratified according to GH administration, atosiban showed a significant association with clinical pregnancy in comparison with either matched or unmatched controls among patients with GH treatment with rate ratios (RR) of 1.32 (95%CI: 1.05,1.67) and 1.35 (95%CI: 1,1.82), respectively. On the other hand, however, the association was absent among patients without GH treatment. The adjusted ORRs in both matched and unmatched cohorts were 2.44 (95%CI: 1.07,5.84) and 1.95 (95%CI: 1.05, 3.49) respectively. Conclusion: The combination use of atosiban and GH in FET cycles is potentially beneficial to the pregnancy. However, indications for the use of atosiban and GH may need further assessment.

Efficacy of Human Recombinant Growth Hormone in Females of a Non-Obese Hyperglycemic Mouse Model after Birth with Low Birth Weight.

We examined whether the administration of growth hormone (GH) improves insulin resistance in females of a non-obese hyperglycemic mouse model after birth with low birth weight (LBW), given that GH is known to increase muscle mass. The intrauterine Ischemia group underwent uterine artery occlusion for 15 min on day 16.5 of gestation. At 4 weeks of age, female mice in the Ischemia group were divided into the GH-treated (Ischemia-GH) and non-GH-treated (Ischemia) groups. At 8 weeks of age, the glucose metabolism, muscle pathology, and metabolome of liver were assessed. The insulin resistance index improved in the Ischemia-GH group compared with the Ischemia group (p = 0.034). The percentage of type 1 muscle fibers was higher in the Ischemia-GH group than the Ischemia group (p < 0.001); the muscle fiber type was altered by GH. In the liver, oxidative stress factors were reduced, and ATP production was increased in the Ischemia-GH group compared to the Ischemia group (p = 0.014), indicating the improved mitochondrial function of liver. GH administration is effective in improving insulin resistance by increasing the content of type 1 muscle fibers and improving mitochondrial function of liver in our non-obese hyperglycemic mouse model after birth with LBW.

Post hoc subgroup analysis of Asian children with paediatric GHD from the global phase 3 efficacy and safety study of once-weekly somatrogon vs. once-daily somatropin.

OBJECTIVES: Somatrogon is a long-acting recombinant human growth hormone used to treat patients with paediatric growth hormone deficiency (pGHD). This global phase 3 study compared the efficacy and safety of once-weekly somatrogon with once-daily somatropin in children with GHD. METHODS: Prepubertal patients were randomized 1:1 to once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. The primary endpoint was height velocity (HV) at month 12; secondary endpoints included HV at month 6 and change in height standard deviation score (SDS) at months 6 and 12 and insulin-like growth factor 1 (IGF-1) SDS. RESULTS: This post hoc subgroup analysis focused specifically on Asian children (somatrogon: n=24 and mean age=7.76 years; somatropin: n=21 and mean age=8.10 years) across eight countries. Mean HV at month 12 was 10.95 cm/year (somatrogon) and 9.58 cm/year (somatropin); the treatment difference of 1.38 cm/year favoured somatrogon. The lower bound of the two-sided 95 % CI of the treatment difference (somatrogon-somatropin) was -0.20, similar to the overall study population (-0.24). Compared with the somatropin group, the somatrogon group had numerically higher HV at month 6 (8.31 vs. 11.23 cm/year); a similar trend was observed for height SDS and IGF-1 SDS at months 6 and 12. Safety and tolerability were similar between treatment groups; adverse events occurred in 83 % of somatrogon-treated children and 76 % of somatropin-treated children. CONCLUSIONS: This subgroup analysis demonstrated that somatrogon efficacy and safety in Asian children were consistent with the overall study population, where once-weekly somatrogon was non-inferior to once-daily somatropin. Clinicaltrials.gov: NCT02968004.

Effects of growth hormone therapy on the onset and progression of pubertal development in girls with idiopathic short stature.

OBJECTIVE: The aim of this study was to explore the impact of growth hormone (GH) therapy on the onset and progression of puberty in girls with idiopathic short stature. METHODS: This study included 541 girls aged between 4.5 and 10.6 years who were receiving GH treatment, monitored over a 22-year follow-up period. Of these, 126 girls have been followed up to the onset of menarche. The participants were divided into two groups: a ISS control group (n = 66) and a group receiving daily GH treatment at a dose of 0.15 iu/kg (n = 60). We assessed the pubertal development and GH usage of these girls every three months. RESULTS: (1) There was no significant difference in the onset of puberty between the growth hormone (GH) treatment group and the control group; however, the average duration of puberty was longer in the treatment group compared to the control group. (2) During puberty, there were no significant differences in height growth between the treated and untreated groups. (3) The duration of GH treatment showed a significant negative correlation with the age at onset of gonadal development and the age at menarche in females within the treatment group. CONCLUSION: GH treatment does not seem to accelerate the onset of puberty but may extend its duration, without significantly impacting height growth during puberty. Additionally, longer GH treatment duration is linked to earlier gonadal development and menarche in females.

Does growth hormone supplementation of in vitro fertilization/intracytoplasmic sperm injection improve cumulative live birth rates in women with poor embryonic development in the previous cycle?

BACKGROUND: Growth hormone (GH) has been proposed as an adjunct in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles, especially in women with poor ovarian response. However, it is unclear whether GH supplementation is effective in women with poor embryonic development in the previous IVF cycle. The aim of this study was to evaluate the effectiveness of GH supplementation in IVF/ICSI cycles in women with poor embryonic development in the previous cycle. METHODS: This is a retrospective cohort study from a public fertility center in China, in which we performed propensity score-matching (PSM) for female age and AFC in a ratio of 1:1. We compared the cumulative live birth rate per started cycle, as well as a series of secondary outcomes. We included 3,043 women with poor embryonic development in the previous IVF/ICSI cycle, of which 1,326 had GH as adjuvant therapy and 1,717 had not. After PSM, there were 694 women in each group. RESULTS: After PSM, multivariate analyses showed the cumulative live birth rate to be significantly higher in the GH group than the control group [N = 694, 34.7% vs. N = 694, 27.5%, risk ratio (RR): 1.4 (95%CI: 1.1-1.8)]. Endometrial thickness, number of oocytes retrieved, number of embryos available, and number of good-quality embryos were significantly higher in the GH group compared to controls. Pregnancy outcomes in terms of birth weight, gestational age, fetal sex, preterm birth rate, and type of delivery were comparable. When we evaluated the impact of GH on different categories of female age, the observed benefit in the GH group did not appear to be significant. When we assessed the effect of GH in different AFC categories, the effect of GH was strongest in women with an AFC5-6 (32.2% versus 19.5%; RR 2.0; 95% CI 1.2-3.3). CONCLUSIONS: Women with poor embryonic quality in the previous IVF/ICSI cycles have higher rates of cumulative live birth with GH supplementation.

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Recombinant human growth hormone (rhGH) is an effective therapeutic drug for improving short stature. Currently, rhGH can be used for various causes of short stature, including growth hormone deficiency, and the expansion of its clinical application has raised concerns about its safety. Based on existing evidence, when rhGH is used in a standardized manner for physiological replacement therapy, its safety profile is favorable. In clinical practice, attention should be focused on short-term safety during rhGH treatment, with the combination of literature evidence and clinical experience. There is still no definitive conclusion on the long-term safety due to insufficient duration of rhGH treatment. This paper reviews the possible adverse events that may occur during rhGH treatment and their risk control measures, aiming to help clinical physicians understand the overall safety of rhGH treatment and improve its clinical standardization.

Growth hormone therapy does not impact the development of intracranial hypertension in children with Chiari malformation.

OBJECTIVES: Patients with Chiari malformation (CM) are prone to a variety of neurological sequelae, including benign intracranial hypertension (BIH). In these patients, BIH is attributed to impaired cerebrospinal fluid (CSF) flow due to anatomical abnormalities of the posterior fossa. Occasionally, patients with CM may require growth hormone therapy (GHT), which can increase the production of CSF. It is thought that patients with CM who undergo GHT are at high risk of BIH-associated symptoms (BIHAS). We describe the incidence of neurological symptoms in 34 patients with CM before and during GHT. METHODS: The database of a pediatric endocrinology center was queried for patients with CM who received GHT from 2010-22. Records were reviewed for adverse events. Demographic and radiological data were collected and analyzed. Patients with neoplastic disease, active inflammation, or acute trauma were excluded. CM diagnoses were independently assigned by a neuroradiology department. Patients were grouped based on the presence and nature of symptoms before and during GHT. Relationships between starting dose/BMI and occurrence of BIHAS/all GHT-associated symptoms were evaluated. RESULTS: GHT was not associated with new-onset or worsening of preexisting BIHAS in 33 out of 34 patients with CM. Five complex patients continued to have preexisting BIHAS, which did not worsen. Of the four patients who developed new-onset BIHAS during GHT, three patients' symptoms were attributed to other medical conditions. No patient permanently discontinued GHT due to BIHAS. CONCLUSIONS: Growth hormone therapy is likely a safe treatment in patients with Chiari malformation and is unlikely to cause BIHAS.

Transdermal Delivery of Recombinant Human Growth Hormone by Liposomal Gel for Skin Photoaging Therapy.

Human growth hormone (hGH) has emerged as a promising therapeutic agent to prevent and treat skin photoaging. However, the success of hGH therapy largely lies in the availability of an optimal delivery system that enables the efficient delivery of hGH to the dermal layer of the skin. Here, we report a delivery system of hyaluronic acid/liposome-gel-encapsulated hGH (HA/HL-Gel) that can transdermally deliver hGH into the skin for hGH-based photoaging therapy through the upregulation of collagen type I (collagen-I). Specifically, hGH-liposomes were prepared by ethanol injection and then modified with HA to achieve specific targeting. The best formulation of HA/hGH-liposomes (HA/HL) had a high encapsulation efficiency (about 20%), with a size of 180 ± 1.2 nm. The optimized HA/HL was further incorporated into the carbomer gel to form an HA/HL-Gel. The biological activity of HA/HL on human dermal fibroblasts (HDFs) was confirmed by the elevated expression level of collagen-I through the enhanced local formation of insulin-like growth factor-1 (IGF-1) in the photoaging model. Moreover, HA/HL-Gel reduced ultraviolet (UV)-induced erythema and wrinkle formation. Meanwhile, immunohistochemical staining further showed higher levels of collagen-I in the HA/HL-Gel group compared to other groups tested. Taken together, these results demonstrate that HA/HL-Gel treatment could significantly ameliorate skin photoaging and thus may be used as a clinical potential for antiaging therapy.

Adding Letrozole to Growth Hormone and Gonadotropin-Releasing Hormone Analog Increases Height in Girls With Short Stature: A Hospital Record-Based Retrospective Study.

OBJECTIVE: There have been rare data on letrozole for height improvement in girls. This study aimed to clarify the efficacy and safety of combination therapy with recombinant human growth hormone (rhGH), GnRHa, and letrozole in improving the height of girls with short stature and advanced bone age. METHODS: This was a hospital record-based retrospective study. Follow-up was conducted on girls with short stature who received treatment with rhGH, GnRHa, and letrozole in our hospital. The treatment group included a total of 29 participants. Before treatment, the mean age of the patients was 11.17 years, and the mean treatment duration was 17.31 months. The control group consisted of 29 short-statured girls who received rhGH/GnRHa treatment, with the mean age and treatment duration of 12.43 years and 16.59 months, respectively. RESULTS: The predicted adult heights (PAHs) before and after treatment were 155.38 and 161.32 cm (P < .001). The ΔPAH in the treatment group was 4 cm higher than that in the control group (5.85 vs 1.82 cm, P < .001). Significant differences were noted in the height standard deviation scores of bone age (P < .001) and chronological age (P = .003) before and after treatment. There was an increasing body mass index during therapy (P = .039). The height gain was 8.71 ± 4.46 cm, and the growth rate was 6.78 ± 3.84 cm per year. CONCLUSION: Combined treatment with GH, GnRHa, and letrozole can enhance the adult height and PAH in short-statured girls, and no significant side effects have been reported.

Diagnosis and treatment of growth hormone deficiency in children on the ketogenic diet: A case series.

The ketogenic diet (KD) can have a negative impact on the linear growth and body composition of children. The aims of this study were to review two centers' experience with children who developed height deceleration on the KD and determine if the height deceleration was secondary to growth hormone deficiency (GHD), and if growth hormone therapy (GHT) would be effective and safe (not altering ketosis or seizure frequency). Retrospective chart reviews were performed on patients with KD referred to Endocrinology between 2013 and 2018. Seventeen children were identified. Data reviewed included: demographics, growth velocity, KD ratio, protein/calorie intake, lab results, GH dosage, Tanner stage, and seizure frequency, and endocrine recommendations. Descriptive statistics were performed. Of the 17 children referred to the Endocrine Division, seven children were growth hormone deficient and began GHT. Data were provided for six patients (2 males, 4 females; age 2-7 years at the start of KD) on the KD for >6 years and on GHT for >4 years. Growth for all patients stabilized or increased. IGF-1 z-scores normalized. GHT did not affect seizure frequency or ketosis. GHT in those with GHD can be an appropriate option allowing better growth while still maintaining ketogenic therapy and seizure control. PLAIN LANGUAGE SUMMARY: The KD can be an effective treatment for difficult-to-control epilepsy and some disorders of carbohydrate metabolism. The KD can adversely affect the linear growth (height) of children. This case series reviewed six patients who had slow linear growth. It was found that all six children had growth hormone deficiency, grew better with growth hormone treatments, and that their seizures and ketone levels were not affected.

Pediatric growth hormone deficiency: Understanding the patient and caregiver perspectives.

Childhood growth hormone deficiency (GHD) is a rare disorder associated with significant burden on both patients and caregivers. Although previous reports have detailed aspects of the burden experienced by patients and their caregivers, there is a paucity of first-hand information on the patient and caregiver journeys from their respective voices. To address this need, an advisory board meeting was conducted on September 30, 2022, with 4 pediatric patients with GHD and their caregivers to discuss their experiences prior to GHD diagnosis, during the diagnostic process, and during ongoing treatment with recombinant growth hormone. Feedback from patients and caregivers was reviewed by pediatric endocrinologists, who provided their own perspectives on the patient and caregiver journeys based on the information reported. Despite the small sample size, important insights were obtained: patients and caregivers reported remarkable growth benefits achieved with treatment, which provided strong motivation to remain adherent to daily injection regimens. Patient and caregiver accounts reflected wide variability between families in time from suspicion to diagnosis and in treatment challenges faced, ranging from practical issues such as handling and administration of medication to broader concerns about treatment access and continuity, as well as key knowledge gaps among patients, caregivers, and clinicians. Recommendations are provided to enhance the patient and caregiver journeys, including increasing development and availability of educational materials, providing opportunities for patient advocacy by clinicians and health care providers, and encouraging institutional improvements to ensure that patients continue to receive uninterrupted treatment during their critical period of growth.

Treatment of acromegaly with oral octreotide.

Acromegaly is a rare disease caused by a growth hormone excess, usually due to a secreting pituitary adenoma. Somatostatin receptor ligands (SRL) are the mainstay of medical therapy for patients with acromegaly who fail to achieve biochemical control post-operatively or are not eligible for surgical treatment. SRLs are typically administered as monthly injections and have shown to be effective in maintaining biochemical and radiological control of acromegaly. However, these injections may cause local adverse events and are associated with increased psychological burden in some patients. Oral octreotide provides a new alternative for patients responding to injectable SRLs. This new formulation has shown to have similar safety and efficacy profiles compared to injectable SRLs and may be a preferable option for some patients with acromegaly. The aim of this review is to provide an overview of the role of oral octreotide in the management of acromegaly.

Oral SSTR5 Antagonist SCO-240 for Growth Hormone Stimulation: A Phase I Single-Dose Study in Healthy Individuals.

Somatostatin inhibits endocrine and exocrine secretion in various tissues by acting on five somatostatin receptor subtypes (SSTR1-5). The clinical effects of SSTR5 antagonism remain unknown. Herein, we evaluated the effects of SCO-240, an oral SSTR5 antagonist, in healthy individuals. This randomized, single-center, double-blind, placebo-controlled, phase I study included healthy Japanese and White individuals. The effects of ascending single oral doses of SCO-240 were evaluated in healthy individuals. The main outcome measures were safety, tolerability, pharmacokinetics, and pharmacodynamics (gallbladder contractions and levels of serum insulin and plasma glucagon-like peptide-1 (GLP-1)). The levels of pituitary hormones were evaluated in our exploratory analysis. The results indicated that SCO-240 was safe and well-tolerated at all tested doses. Oral SCO-240 was readily absorbed, with its systemic exposure increasing in a dose-dependent manner. The median time to maximum concentration and mean terminal half-life of SCO-240 were 3-4 and 10.2-12.6 hours, respectively, in the ascending dose section. No clinically meaningful changes in SCO-240 pharmacokinetic profiles were observed between fed and fasted or between Japanese and White individuals. No increase in gallbladder contractions or levels of insulin and GLP-1 were detected. SCO-240 induced robust growth hormone (GH) secretion without altering the levels of other pituitary hormones. In conclusion, the study is the first to demonstrate that SSTR5 antagonism stimulates GH secretion in humans. SCO-240 was safe and well-tolerated and exhibited once-daily oral dosing potential. The robust effects of SCO-240 on GH secretion suggest that it may be a treatment option for GH-related disorders.

Subperiosteal delivery of transforming growth factor beta 1 and human growth hormone from mineralized PCL films.

The ability to locally deliver bioactive molecules to distinct regions of the skeleton may provide a novel means by which to improve fracture healing, treat neoplasms or infections, or modulate growth. In this study, we constructed single-sided mineral-coated poly-ε-caprolactone membranes capable of binding and releasing transforming growth factor beta 1 (TGF-ß1) and human growth hormone (hGH). After demonstrating biological activity in vitro and characterization of their release, these thin bioabsorbable membranes were surgically implanted using an immature rabbit model. Membranes were circumferentially wrapped under the periosteum, thus placed in direct contact with the proximal metaphysis to assess its bioactivity in vivo. The direct effects on the metaphyseal bone, bone marrow, and overlying periosteum were assessed using radiography and histology. Effects of membrane placement at the tibial growth plate were assessed via physeal heights, tibial growth rates (pulsed fluorochrome labeling), and tibial lengths. Subperiosteal placement of the mineralized membranes induced greater local chondrogenesis in the plain mineral and TGF-ß1 samples than the hGH. More exuberant and circumferential ossification was seen in the TGF-ß1 treated tibiae. The TGF-ß1 membranes also induced hypocellularity of the bone marrow with characteristics of gelatinous degeneration not seen in the other groups. While the proximal tibial growth plates were taller in the hGH treated than TGF-ß1, no differences in growth rates or overall tibial lengths were found. In conclusion, these data demonstrate the feasibility of using bioabsorbable mineral coated membranes to deliver biologically active compounds subperiosteally in a sustained fashion to affect cells at the insertion site, bone marrow, and even growth plate.