Anti-stress effects of human placenta extract: possible involvement of the oxidative stress system in rats.

BACKGROUND: Human placenta hydrolysate (hPH) has been utilized to improve menopausal, fatigue, liver function. Its high concentration of bioactive substances is known to produce including antioxidant, anti-inflammatory and anti-nociceptive activities. However, its mechanisms of stress-induced depression remain unknown. METHODS: The present study examined the effect of hPH on stress-induced depressive behaviors and biochemical parameters in rats. hPH (0.02 ml, 0.2 ml or 1 ml/rat) was injected intravenously 30 min before the daily stress session in male Sprague-Dawley rats exposed to repeated immobilization stress (4 h/day for 7 days). The depressive-like behaviors of all groups were measured by elevated plus maze (EPM) and forced swimming test (FST). After the behavior tests, brain samples of all groups were collected for the analysis of glutathione peroxidase (GPx) and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) staining. RESULTS: Treatment with hPH produced a significant decrease of immobility time in the FST compared to the controls. Additionally, hPH treatment elicited a slightly decreasing trend in anxiety behavior on the EPM. Furthermore, hPH increased the level of GPx protein in the hippocampus, and decreased the expression of NADPH-d in the paraventricular nucleus (PVN). CONCLUSION: This study demonstrated that hPH has anti-stress effects via the regulation of nitric oxide (NO) synthase and antioxidant activity in the brain. These results suggest that hPH may be useful in the treatment of stress-related diseases such as chronic fatigue syndrome.

Comparative study of idursulfase beta and idursulfase in vitro and in vivo.

Hunter syndrome is an X-linked lysosomal storage disease caused by a deficiency in the enzyme iduronate-2-sulfatase (IDS), leading to the accumulation of glycosaminoglycans (GAGs). Two recombinant enzymes, idursulfase and idursulfase beta are currently available for enzyme replacement therapy for Hunter syndrome. These two enzymes exhibited some differences in various clinical parameters in a recent clinical trial. Regarding the similarities and differences of these enzymes, previous research has characterized their biochemical and physicochemical properties. We compared the in vitro and in vivo efficacy of the two enzymes on patient fibroblasts and mouse model. Two enzymes were taken up into the cell and degraded GAGs accumulated in fibroblasts. In vivo studies of two enzymes revealed similar organ distribution and decreased urinary GAGs excretion. Especially, idursulfase beta exhibited enhanced in vitro efficacy for the lower concentration of treatment, in vivo efficacy in the degradation of tissue GAGs and improvement of bones, and revealed lower anti-drug antibody formation. A biochemical analysis showed that both enzymes show largely a similar glycosylation pattern, but the several peaks were different and quantity of aggregates of idursulfase beta was lower.

12-month effects of once-weekly sustained-release growth hormone treatment in adults with GH deficiency.

The weekly sustained-release recombinant human GH formulation LB03002, showed beneficial effects in GH-deficient (GHD) adults in a previous 26-week double-blind study. Prior studies of long-acting GH preparations in adults have only been conducted for 6 or 8 months, so the effects of longer-term use are unknown; this is important to address, as replacement is given for many years in GHD adults. This open-label, 26-week study extension evaluated longer-term safety and efficacy of LB03002 over 52 weeks in adults with GHD who had previously been randomized to GH, and provides additional safety and efficacy data over 26 weeks in the cohort who had previously been randomized to placebo. Of 147 adults with GHD who completed a preceding study, 136 patients continued in this open-label study to receive LB03002 over an additional 26 weeks. This represented a continuation of long-acting GH for 26 weeks in the cohort who took this medication in the prior study (LB03002 Throughout group), and describes the first use of long-acting GH in the cohort that was randomized to placebo in the prior study (Switched to LB03002 group). The LB03002 dose was adjusted according to serum insulin-like growth factor-I (IGF-I) levels. LB03002 treatment demonstrated mean significant decreases from baseline in fat mass (FM) for both 26 (Switched group, P = 0.001) and 52 weeks (Throughout group, P = 0.002) of 1.11 (1.95) kg and 1.06 (3.16) kg, respectively. Prolonged GH treatment was effective in sustaining the increase in lean body mass (LBM), serum IGF-I and IGFBP-3 levels achieved during the first 26 weeks. Long-term treatment with the sustained-release weekly GH preparation over both 26 and 52 weeks in adults with GHD demonstrated a sustained reduction of FM with a favorable safety profile. This study extends prior knowledge about long-acting GH because it reports the most prolonged treatment of adults with any long-acting GH preparation, thereby confirming the value and safety of such agents for long-term GH replacement.

A randomized, double-blind study to assess the efficacy and safety of valtropin, a biosimilar growth hormone, in children with growth hormone deficiency.

Valtropin is a recombinant human GH (rhGH) manufactured using a novel yeast expression system, classed as a 'biosimilar'. Valtropin was compared with Humatrope in children with GH deficiency (GHD). Treatment-naive, prepubertal children with GHD were randomized to Valtropin (n = 98) or Humatrope (n = 49) for 1 year. Standing height was measured 3-monthly and height velocity (HV) calculated. Serum IGF-I, IGFBP-3 and GH antibodies were determined centrally. HV at 1 year was 11.3 +/- 3.0 cm/year with Valtropin and 10.5 +/- 2.8 cm/year with Humatrope. Treatment difference was 0.09 cm/year with 95% confidence limits of -0.71, 0.90, within the preset non-inferiority limit of -2.0 cm/year. Height standard deviation (SD) scores were increased in both treatment arms with no acceleration of bone maturation. IGF-I and IGFBP-3 were increased comparably for both treatments. Adverse events showed no clinically relevant differences between treatment groups. Anti-GH antibodies were detected in 3 (3.1%) Valtropin and 1 (2.0%) Humatrope patients and the growth pattern was indistinguishable from the rest of the cohort. The 1-year efficacy and safety profile of Valtropin, a new biosimilar rhGH, are equivalent to the comparator rhGH, Humatrope. Valtropin can be used for the treatment of children with GHD and longer term data will fully establish its efficacy and safety profile.

Effect of granulocyte macrophage-colony stimulating factor (GM-CSF) on 5-FU-induced ulcerative mucositis in hamster buccal pouches.

The present study was performed to investigate the protective effects of granulocyte macrophage-colony stimulating factor (GM-CSF) against ulcerative mucositis in hamster buccal pouch. GM-CSF was topically administered to the buccal pouches of hamsters with two different doses of 5 and 20 microg/ml. The treatment of GM-CSF led to rapid healing effects in gross and histopathological findings. It decreased expression of pro-inflammatory cytokine mRNA levels in the mucosal tissue of buccal pouches. Also GM-CSF-treated animals showed high numbers of Ki-67 positive cells in basal cell layer. These results suggest that GM-CSF provided excellent healing effects to ulcerative mucositis in the buccal pouch of hamster.

Human placental extract exerts hair growth-promoting effects through the GSK-3ß signaling pathway in human dermal papilla cells.

Human placental extract (HPE) is widely used in Korea to relieve fatigue. However, its effects on human dermal papilla cells (hDPCs) remain unknown. In the present study, in an effort to develop novel therapies to promote hair growth, we screened HPE. We demonstrate that HPE has hair growth­promoting activities and induces ß­catenin expression through the inhibition of glycogen synthase kinase­3ß (GSK­3ß) by phosphorylation in hDPCs. Treatment with HPE significantly increased the viability of the hDPCs in a concentration­dependent manner, as shown by bromodeoxyuridine (BrdU) assay. HPE also significantly increased the alkaline phosphatase (ALP) expression levels. The increased ß­catenin levels and the inhibition of GSK­3ß (Ser9) by phosphorylation suggested that HPE promoted the hair-inductive capacity of hDPCs. We compared the effects of treatment with HPE alone and treatment with HPE in conjunction with minoxidil (MXD). We found that HPE plus MXD effectively inhibited GSK­3ß by phosphorylation (Ser9) in the hDPCs. Moreover, we demonstrated that HPE was effective in inducing root hair elongation in rat vibrissa hair follicles, and that treatment with HPE led to a delay in catagen progression. Overall, our findings suggest that HPE promotes hair growth and may thus provide the basis of a novel therapeutic strategy for the clinical treatment of hair loss.

Efficacy of short-term growth hormone treatment in prepubertal children with idiopathic short stature.

PURPOSE: It has been reported that daily recombinant human growth hormone (GH) treatment showed beneficial effects on growth in prepubertal children with idiopathic short stature (ISS). The present study aimed to validate the GH (Eutropin®) effect on growth promotion and safety after short-term GH treatment. MATERIALS AND METHODS: This study was an open-label, multicenter, interventional study conducted at nine university hospitals in Korea between 2008 and 2009. Thirty six prepubertal children with ISS were enrolled in this study to receive 6-month GH treatment. Yearly growth rate, height standard deviation score (SDS), and adverse events were investigated during treatment. RESULTS: After 26 weeks of GH treatment, the height velocity significantly increased by 6.36±3.36 cm/year (p<0.001). The lower end of one-sided 95% confidence interval was 5.22 cm/year, far greater than the predefined effect size. The gain in height SDS at week 26 was 0.57±0.27 (p<0.0001). Bone age significantly increased after GH treatment, however, bone maturation rate (bone age for chronological age) showed limited advancement. This 26-week GH treatment was effective in increasing serum levels of insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 from baseline (p<0.0001). Eutropin was well tolerated and there were no withdrawals due to adverse events. No clinically significant changes in laboratory values were observed. CONCLUSION: This 6-month daily GH treatment in children with ISS demonstrated increased height velocity, improved height SDS, and increased IGF-I and IGFBP-3 levels with a favorable safety profile.

24-month use of once-weekly GH, LB03002, in prepubertal children with GH deficiency.

BACKGROUND: Sustained-release GH formulations may provide a strategy for improving treatment compliance and persistence in GH-deficient patients. OBJECTIVE: The aim of the study was to examine efficacy and safety of LB03002, a sustained-release GH formulation for once-weekly administration. DESIGN: We conducted a phase III, 12-month, multinational, randomized, open-label, comparator-controlled trial with a 12-month uncontrolled extension. PATIENTS: Prepubertal GH treatment-naive GH-deficient children (mean age, 7.8 y) participated in the study. INTERVENTION: We administered once-weekly LB03002 (n=91) or daily GH (n=87) for 1 year, followed by once-weekly LB03002 for all patients for another year (LB03002 throughout, n=87; switched to LB03002, n=80). OUTCOME MEASURES: Height, height velocity (HV), IGF-1, GH antibodies, and adverse events were determined throughout. Primary analysis was noninferiority of LB03002 vs daily GH at 1 year by analysis of covariance. RESULTS: Mean±SD HV during year 1 was 11.63±2.60 cm/y with LB03002, and 11.97±3.09 cm/y with daily GH, with increases from baseline of 8.94±2.91 and 9.04±3.19 cm/y, respectively. The least square mean HV difference for LB03002 - daily GH was -0.43 cm/y (99% confidence interval, -1.45 to 0.60 cm/y). Mean HV also remained above baseline in year 2 (8.33±1.92 cm/y in the LB03002 throughout group, and 7.28±2.34 cm/y in the switched to LB03002 group). Injection site reactions occurred more frequently in LB03002-treated patients but were considered mild to moderate in >90% of cases. CONCLUSIONS: Growth response with once-weekly LB03002 in GH-deficient children is comparable to that with daily GH, achieving expected growth rates for 24 months. Once-weekly LB03002 is a strong candidate for long-term GH replacement in GH-deficient children.

Efficacy and safety of LB03002, a once-weekly sustained-release human GH for 12-month treatment in Korean children with GH deficiency.

PURPOSE: The purpose of this study was to investigate the efficacy and safety of LB03002, a sustained-release human GH (SR-hGH), compared with that of daily rhGH for 12 months in children with GH deficiency (GHD). METHODS: A total of 73 children with GHD were screened and 63 eligible subjects were randomized in a 1:1 ratio of LB03002 (SR-hGH) to daily rhGH treatment group. LB03002 was administered once weekly at a dose of 0.5 mg/kg while daily rhGH was administered for 6 consecutive days with equally divided doses to make a total of 0.21 mg/kg per week. Treatments were given for 12 months by s.c. injections. Injection site reactions and adverse events were investigated throughout the study period. RESULTS: The mean (S.D.) height velocity (HV) SHOWED a clinically significant increase after the 6-month treatment: 3.00 (1.15) cm/year at screening to 9.78 (1.98) cm/year at 6 months in the LB03002 group; 2.39 (1.63) cm/year at screening to 10.56 (2.65) cm/year at 6 months in the daily rhGH group. The increased HV at 12 months was still maintained in both the groups: 9.06 (1.63) cm/year at 12 months in the LB03002 group; 9.72 (2.32) cm/year at 12 months in the daily rhGH group. Most of the adverse drug reactions were mild and tolerable. No subjects were withdrawn due to adverse events. CONCLUSION: Weekly injection of LB03002 at a dose of 0.5 mg/kg per week was confirmed to have comparable efficacy to daily injection of rhGH at a dose of 0.21 mg/kg per week. Both formulations were well tolerated.

Three-year efficacy and safety of LB03002, a once-weekly sustained-release growth hormone (GH) preparation, in prepubertal children with GH deficiency (GHD).

BACKGROUND: GH treatment currently requires daily sc injections, resulting in suboptimal compliance. A GH regimen with fewer injections may offer patients and caregivers a less arduous option. LB03002 is a novel sustained-release GH formulation for once-weekly dosing. PATIENTS AND METHODS: GH-deficient, GH-naive prepubertal children were randomized to four groups who received 0.2 mg/kg/wk LB03002 for 12 months, followed by 0.5 mg/kg/wk for another 24 months (n=13); 0.5 mg/kg/wk LB03002 for 36 months (n=13); 0.7 mg/kg/wk LB03002 for 12 months, followed by 0.5 mg/kg/wk for another 24 months (n=13); or daily GH 0.03 mg/kg/d for 24 months, switched to 0.5 mg/kg/wk LB03002 for 12 months (n = 12). RESULTS: Height velocity increased in all groups; the increase was less for the 0.2 mg/kg/wk LB03002 group at 12 (P = 0.008) and 24 months (P = 0.030), with no statistically significant differences at any time for the 0.5 mg/kg/wk and 0.7 mg/kg/wk LB03002 groups, vs. daily GH. Height sd score gain at 12 months was significantly (P = 0.023) less for the 0.2 mg/kg/wk group (1.05 ± 0.38) than daily GH (1.47 ± 0.29), but with no statistically significant difference for the 0.5 mg/kg/wk (1.37 ± 0.39) and 0.7 mg/kg/wk (1.50 ± 0.44) LB03002 groups vs. daily GH. There were no significant differences in height sd score gain between any groups at 24 and 36 months. Bone maturation did not differ for any LB03002 dose compared with daily GH. Serum IGF-I concentrations increased as expected, with no long-term differences between groups. Mean fasting glucose and glycosylated hemoglobin concentrations did not exceed normal ranges for any treatment group at any time. CONCLUSION: LB03002 at doses of 0.5 mg/kg/wk and 0.7 mg/kg/wk was shown to be effective and safe with once-weekly dosing in GH-deficient children, and 0.5 mg/kg/wk LB03002 was chosen as the optimal dose for long-term assessment.

Effects of once-weekly sustained-release growth hormone: a double-blind, placebo-controlled study in adult growth hormone deficiency.

BACKGROUND: A sustained-release recombinant human GH formulation, LB03002, has been recently developed, with pharmacokinetics and pharmacodynamic activity appropriate for once-weekly administration. LB03002 is a long-acting GH that is administered once a week by s.c. injection. OBJECTIVE: This study evaluated efficacy and safety of LB03002 in adult patients with GH deficiency. PATIENTS AND METHODS: A total of 152 patients were randomized to receive LB03002 or placebo once weekly for 26 wk. Changes in body composition were evaluated from DXA (dual-energy x-ray absorptiometry). IGF-I was assessed at each study visit. Safety was assessed from adverse events, glucose homeostasis, and antibody development. RESULTS: IGF-I increased significantly (P < 0.001) with LB03002 and remained unchanged with placebo. Mean fat mass (FM) decreased by 1.052 kg [95% confidence interval (CI) = -1.614 to -0.491] in the LB03002 group vs. an increase of 0.570 kg (95% CI = -0.205-1.345) in the placebo group; treatment difference was 1.622 kg (95% CI = -2.527 to -0.717; P < 0.001). FM change was mainly due to decreased trunk fat. Least square mean treatment difference was 1.032 kg (95% CI = -1.560 to -0.515; P < 0.001). LBM (lean body mass) was significantly increased with LB03002 vs. placebo (least square mean difference was 1.393 kg; 95% CI = 0.614-2.171; P < 0.001). No concerning safety issues arose during the study. CONCLUSIONS: Weekly GH replacement with the sustained-release preparation LB03002 in adults significantly reduced FM over 6 months and was well tolerated.

Pharmacokinetic and pharmacodynamic profile of a new sustained-release GH formulation, LB03002, in children with GH deficiency.

OBJECTIVE: LB03002 is a novel, sustained-release recombinant human GH, developed for once-a-week s.c. injection. To evaluate the suitability for long-term GH replacement therapy in children with GH deficiency (GHD), the present study assessed the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of LB03002 at three doses. STUDY DESIGN AND PATIENTS: The randomised, comparator-controlled, assessor-blinded, phase II study assessed 37 (24 boys, 13 girls) pre-pubertal, GH-naïve children with GHD, in 11 European centres, for PK and PD analyses. GH, IGF1 and IGFBP3 concentrations were measured following the last daily GH dose and the first and 13th once-a-week administration of LB03002 at doses of 0.2, 0.5 or 0.7 mg/kg. RESULTS: GH C(max) values after the three doses of LB03002 were increased up to fourfold, with a clear dose proportionality. For each LB03002 dose, GH area under the concentration versus time curve did not increase from the first to 13th (month 3) administration, indicating no accumulation of circulating GH. IGF1 C(max) showed a progressive increase during LB03002 administration. Conversely, IGFBP3 showed a rapid increase in C(max). IGF1 SDS were fully normalised after 3 months of treatment, whereas IGFBP3 SDS were already in the normal range for all the three LB03002 dosages after 1 week. CONCLUSIONS: At the doses used, LB03002 has a suitable profile for long-term treatment to promote growth in children with GHD. The quantitative changes in IGF1 and IGFBP3 indicate adequate stimulation of the IGF system by LB03002 and the pattern of increase is comparable with that seen in GHD children in a standard IGF1 generation test using daily GH.