Efficacy and Safety of Sustained-Release Recombinant Human Growth Hormone in Korean Adults with Growth Hormone Deficiency

Purpose

The administration of recombinant human growth hormone in adults with growth hormone deficiency has been known to improve metabolic impairment and quality of life. Patients, however, have to tolerate daily injections of growth hormone. The efficacy, safety, and compliance of weekly administered sustained-release recombinant human growth hormone (SR-rhGH, Declage™) supplement in patients with growth hormone deficiency were evaluated.

Materials and Methods

This trial is 12-week prospective, single-arm, open-label trial. Men and women aged ≥20 years with diagnosed growth hormone deficiency (caused by pituitary tumor, trauma and other pituitary diseases) were eligible for this study. Each subject was given 2 mg (6 IU) of SR-rhGH once a week, subcutaneously for 12 weeks. Efficacy and safety at baseline and within 30 days after the 12th injection were assessed and compared. Score of Assessment of Growth Hormone Deficiency in Adults (AGHDA score) for quality of life and serum IGF-1 level.

Results

The IGF-1 level of 108.67±74.03 ng/mL was increased to 129.01±68.37 ng/mL (p=0.0111) and the AGHDA QoL score was decreased from 9.80±6.51 to 7.55±5.76 (p<0.0001) at week 12 compared with those at baseline. Adverse events included pain, swelling, erythema, and warmth sensation at the administration site, but many adverse events gradually disappeared during the investigation.

Conclusion

Weekly administered SR-rhGH for 12 weeks effectively increased IGF-1 level and improved the quality of life in patients with GH deficiency without serious adverse events.     

Potential of Recombinant Human Growth Hormone in HIV-Associated Adipose Redistribution Syndrome

HIV infection recently has been complicated by the emergence of a rare metabolic dysmorphic disorder characterised by fat atrophy, redistribution and accumulation in the setting of hyperlipidaemia and, on occasion, hyperglycaemia. The disorder, sometimes referred to as HIV-associated Adipose Redistribution Syndrome (HARS), has a prevalence rate of about 50 to 60% and seems temporally related to the advent of highly active antiretroviral therapy, especially the usage of protease inhibitors. Various studies also implicate the nucleoside analogues stavudine, didanosine and lamivudine in the pathogenesis of HARS, especially fat atrophy. It is uncertain whether the changes described in HARS represent a single syndrome or a group of related syndromes. Reports have noted differences between morphologic and metabolic changes. More recently, it has been suggested that fat atrophy and fat accumulation may also be separate entities. There are several potential pathogenic theories for HARS that implicate both protease inhibitors and nucleoside analogues as causative agents. However, long term HIV infection rather than any specific agent or class of agent may be the source. Recombinant human growth hormone (rhGH) is a mammalian cell-derived product, which has been useful in a variety of human disorders ranging from pituitary dwarfism to septic shock. It has anabolic, immunological and metabolic properties that restore normal functioning to many aberrant disease pathways. The lipolytic properties of rhGH have been especially beneficial in the diminution of localised fat accumulation in the dorsocervical area (buffalo humps) and truncal region. This has been observed in various reports where rhGH has been administered at doses of 5 to 6 mg/day in patients with HARS for periods ranging from 3 months to >2 years. Relapses after discontinuation of rhGH occurred in most patients. Adverse effects included carpal tunnel syndrome, facial swelling, arthralgias and myalgias and worsening or onset of hyperglycaemia. The small uncontrolled studies conducted to date suggest that the most notable effect of rhGH treatment is the reduction of truncal adiposity and buffalo humps and that the agent has little effect on restoring the adiposity of the appendicular muscles, buttocks or face. Although most patients with HARS have associated hyperlipidaemia, rhGH has no notable effect on serum cholesterol and triglyceride levels. However, blood glucose levels can increase and pre-existent diabetes mellitus may worsen. A short term confirmatory placebo-controlled trial in patients with HARS is urgently needed, as are comparative trials using other anabolic agents such as oxandrolone and testosterone.     

两种治疗肝硬化低蛋白血症方案的成本—效果分析

目的 比较应用重组人生长激素（rhGH)和人血清白蛋白（HSA）治疗肝硬化低蛋白血症的疗效、不良反应及成本－效果对比。方法 运用药物经济学成本－效果分析方法,对rhGH和HSA治疗肝硬化低蛋白血症的疗效及成本进行评价。结果 rhGH和HSA治疗肝硬化低蛋白血症,治疗后第4周有效率分别为75．0％、83．3％,成本效果比分别为68．4、51．0。治疗后第8周有效率分别为87．5％、54．2％,成本效果比分别为55．0、78．5。结论 rhGH能有效治疗肝硬化低蛋白血症,能明显提高白蛋白含量并有较长的疗效,从远期看,成本效果比优于HSA。     

两种治疗肝硬化低蛋白血症方案的成本-效果分析

目的比较应用重组人生长激素(rhGH) 和人血清白蛋白(HSA)治疗肝硬化低蛋白血症的疗效、不良反应及成本-效果对比.方法运用药物经济学成本-效果分析方法,对rhGH和HSA治疗肝硬化低蛋白血症的疗效及成本进行评价.结果 rhGH和HSA治疗肝硬化低蛋白血症,治疗后第4周有效率分别为75.0%、83.3%,成本效果比分别为68.4、51.0;治疗后第8周有效率分别为87.5%、54.2%,成本效果比分别为55.0、78.5.结论 rhGH能有效治疗肝硬化低蛋白血症,能明显提高白蛋白含量并有较长的疗效,从远期看,成本效果比优于HSA.     

Effects of 4 Weeks Recombinant Human Growth Hormone Administration on Insulin Resistance of Skeletal Muscle in Rats

Purpose

Effect of recombinant human growth hormone (rhGH) administration on lipid storage, and its subsequent effect on insulin sensitivity have not yet been adequately examined. Thus, we investigated the effects of rhGH treatment on muscle triglyceride (TG) and ceramide content, and insulin sensitivity after 4 weeks of rhGH administration in rats.

Materials and Methods

Fourteen rats were randomly assigned to two groups: rhGH injection group (GH, n = 7) and saline injection group (CON, n = 7). GH received rhGH by subcutaneous injections (130 µg·kg^-1·day^-1, 6 days·week^-1) for 4 weeks, while CON received saline injections that were equivalent in volume to GH group. Intramuscular TG and ceramide content and hepatic TG content were measured. To determine insulin sesitivity, oral glucose tolerance test (OGTT) and muscle incubation for glucose transport rate were performed in rats, and used as indicators of insulin sensitivity. We also examined plasm lipid profiles.

Results

After 4 weeks of rhGH treatment, the GH group had higher muscle and liver TG contents than the CON (p < 0.05). Ceramide content in GH was significantly greater than that in CON (p < 0.05). GH also had higher plasma levels of FFA (p < 0.05), glucose and insulin responses during OGTT (p < 0.05), and lower glucose transport rates in submaximal insulin concentration (p < 0.05) as compared with CON. Results indicate that rhGH treatment is associated with insulin resistance in rats.

Conclusion

rhGH treatment elevated muscle TG and ceramide content, and hepatic TG content. Thus, elevation of these compounde by rhGH treatment could contribute to the development of insulin resistance in rats.     

The Autodecomposition of Radiolabeled Human Growth Hormone

Abstract

Human growth hormone (hGH) was radiolabeled with ¹²⁵I, using a gentle lactoperoxidase technique. The stability and decomposition products of this tracer were studied by frequent periodic analysis by Sephadex G-100 chromatography on a long column. Monomeric ¹²⁵I-hGH showed an exponential decline, with a half-life of 61 days. The main radioactive degradation product was iodide, which appeared with a fractional appearance rate of 0.01136 per day. Secondary degradation products were a series of radioactive oligomers of hGH, which appeared with an overall fractional rate of 0.00525 per day. The kinetic data obtained should provide guidelines for the shelf- life and repurification schedule of radioiodinated polypeptides.     

Effect of Recombinant Human Growth Hormone and Rosiglitazone for HIV-Associated Abdominal Fat Accumulation on Adiponectin and other Markers of Inflammation

Background/Objective: In a previous report of HIV-infected patients with fat redistribution, we found that recombinant human growth hormone (rhGH) therapy reduced visceral adipose tissue (VAT) but increased insulin resistance, and that the addition of rosiglitazone reversed the negative effects of rhGH on insulin sensitivity. In this study, we sought to determine the effects of rhGH and rosiglitazone therapy on an array of inflammatory and fibrinolytic markers.

Methods: 72 patients with HIV-associated abdominal obesity and insulin resistance were randomized to treatment with rhGH, rosiglitazone, the combination of rhGH and rosiglitazone, or placebo for 12 weeks. Subjects with plasma and serum samples available at weeks 0 (n = 63) and 12 (n = 46–48) were assessed for adiponectin, C-reactive protein, homocysteine, interleukin-1, interleukin-6, tumor necrosis factor alpha, interferon gamma, fibrinogen, plasminogen activator inhibitor-1 antigen, and tissue plasminogen activator antigen.

Results: Treatment with both rosiglitazone alone and the combination of rosiglitazone and rhGH for 12 weeks resulted in significant increases in adiponectin levels from baseline. Adiponectin levels did not change significantly in the rhGH arm alone . There were no significant changes in the other biomarkers among the different treatment groups.

Discussion: In this study of HIV-infected patients with altered fat distribution, treatment with rosiglitazone had beneficial effects on adiponectin concentrations, an effect that was also seen with a combination of rosiglitazone and rhGH. RhGH administration alone, however, did not demonstrate any significant impact on adiponectin levels despite reductions in VAT.     

人血清生长激素化学发光免疫分析方法的建立

建立链霉亲和素-生物素双抗体夹心化学发光免疫分析法(CLIA)测量人血清生长激素(GH),并进行临床应用检测.以链霉亲和素包被微孔板,生物素化一株GH单克隆抗体(McAb),辣根过氧化物酶标记另一株McAb,校准品与国家标准品进行溯源,建立GH CLIA法,进行性能参数测试,与国外试剂盒比对.结果表明本法线性范围为2....     

重组人血管内皮抑制素对荷瘤裸小鼠的治疗作用

观察了重组人血管内皮抑制素 (YH - 16 )对人肝癌Be174 0 2 细胞系、人宫颈癌Hela细胞系和人胃癌SGC790 1细胞系在裸小鼠体内的抑制作用。试验采用每日尾静脉注射给药 ,YH - 16的剂量分别为 1.5、0 .75、0 .4mg/kg ,共给药 14次。结果表明YH - 16对上述三种人癌细胞系有明显抑制作用 ,其抑制率Be174 0 2 为 45 .6 7、43.0 8和 40 .0 0 % ;Hela为 40 .70、30 .15和2 4.12 % ;SGC790 1为 5 1.89、44 .34和 35 .85 %。YH— 16各给药组动物健康状况良好 ,无明显毒副反应     

A Highly Sensitive Radioimmunoassay for Human Growth Hormone Using a Monoclonal Antibody

Biozzi-strain mice were immunized with a highly purified preparation of 20K wriant of hGH. Spleen-cells were fused with SP2/0Ag14 myeloma cells. Clone productions were screened for specificity toward 20K and 22K hGH and for the affinity constant of antibody-antigen reaction. For the selected monoclonal antibody, Ka was 1.02.10¹¹ L/M using 22K hGH as both tracer and reference preparation. No cross reactivity was found with PRL and other pituitary hormones; hPL reactivity was 0.002 percent that of hGH. According to these antibody characteristics, a highly sensitive RIA system was developed and used for specific GH measurement in human serum. Using logit-log co-ordinates, the slope of the standard curve was -1.099 and the minimum detected dose was 0.5 uIU/ml.

Excellent correlation (r=0.9575) was found between assay data in this system and those of a conventional RIA method using specific polyclonal rabbit antiserum.

The International Reference preparation (66/217) could adequately be used to calibrate the monoclonal antibody system since the in house internal 22K GH standard and international one were equally well recognized by the monoclonal antibody.     

Recombinant Human Thrombin

? Recombinant human thrombin (rhThrombin) is a serine protease coagulant, manufactured in vitro using recombinant DNA technology, which shares an identical amino acid sequence and similar structure with the native human protein. It is indicated for topical use as an aid to hemostasis in patients undergoing surgery. ? Topical rhThrombin 1000 U/mL was no less effective than bovine thrombin (bThrombin) 1000 U/mL as a hemostatic agent in a randomized, double-blind, multicenter, phase III trial in patients undergoing various surgical procedures (n = 401). Hemostasis, achieved within 10 minutes, occurred in 95.4% of rhThrombin versus 95.1% of bThrombin recipients (primary endpoint) in the overall surgical cohort. Moreover, hemostasis occurred rapidly, with more than 70% of recipients of rhThrombin or bThrombin achieving hemostasis within 3 minutes. ? In a post hoc, subgroup analysis of this phase III trial, rhThrombin was also effective in patients undergoing vascular surgery, with hemostasis occurring within 10 minutes at >90% of all vascular anastomotic sites. ? Significantly fewer patients undergoing various surgical procedures were seropositive for antibodies against rhThrombin than bThrombin 1 month after topical hemostatic treatment in the phase III trial. ? In a noncomparative, multicenter, phase IIIb trial (n = 200), 1 month after vascular or spinal surgery where topical rhThrombin was used as a hemostat, the incidence of patients with evidence of anti-rhThrombin antibody formation was zero and did not differ between those classified as seropositive or seronegative for preexisting anti-bThrombin antibodies at baseline (primary endpoint). ? rhThrombin was generally well tolerated during the treatment and 1-month follow-up periods in adult surgical patients, with a tolerability profile similar to that of bThrombin.     

Recombinant Human Mullerian Inhibiting Substance Inhibits Epidermal Growth Factor Receptor Tyrosine Kinase

Abstract

Autophosphorylation of the epidermal growth factor (EGF) receptor in A-431 cells and plasma membrane fractions was inhibited by partially purified recombinant human Mullerian Inhibiting Substance (MIS). Immunoprecipitation of the EFG receptor using anti-EGF receptor or anti-phosphotyrosine antibodies, and phosphoamino acid analysis of this receptor, demonstrated that MIS specifically inhibited EGF-induced tyrosine phosphorylation. Inhibition of EGF receptor autophosphorylation by MIS in membrane preparations was not affected by increasing concentrations of EGF, manganese or [γ-(32)P] ATP. Thus, it is unlikely that MIS competes for EGF binding sites or sequesters substrate. Immunoabsorption of MIS with anti-human MIS antibody blocked the MIS inhibition of EGF receptor autophosphorylation, indicating that the inhibition was due to MIS. Our data suggest that MIS regulates the activity of the EGF receptor tyrosine kinase in A-431 cells.     

外用重组人碱性成纤维细胞生长因子 在牙周炎中的应用效果

目的 探究外用重组人碱性成纤维细胞生长因子（rh FGF）在牙周炎治疗中的应用效果。方法 选取2018年1月~2019年1月在我院就诊的牙周炎患者100例,随机分为对照组和观察组,每组50例。对照组采用基础疗法进行治疗,观察组在基础疗法的基础上给予外用重组人碱性成纤维细胞生长因子进行治疗。比较两组治疗后不同时间点的龈沟出血指数（SBI）、牙周探诊深度（PD）、临床附着丧失（CAL）、炎症因子和治疗有效率。结果 两组治疗3周、6周的SBI、PD和CAL与治疗前比较均有所改善,治疗6周的改善程度高于治疗3周,差异具有统计学意义（P＜0.05）;观察组治疗3周、6周的SBI、PD和CAL均优于对照组,差异具有统计学意义（P＜0.05）。两组治疗3周、6周的IL-1β、IL-8和IL-17与治疗前比较均降低,治疗6周的IL-1β、IL-8和IL-17均低于治疗3周,差异具有统计学意义（P＜0.05）;观察组治疗3周、6周的IL-1β、IL-8和IL-17均低于对照组,差异具有统计学意义（P＜0.05）。观察组治疗总有效率高于对照组（90.00% vs 62.00%）,差异具有统计学意义（P＜0.05）。结论 rh FGF治疗牙周炎患者,能够改善龈沟出血指数,减少牙周探诊深度、临床附着丧失,减低炎性因子,提高牙周组织的愈合速度。     

ELISA for Determination of Human Growth Hormone: Recognition of Helix 4 Epitopes

Human growth hormone (hGH) signal transduction initiates with areceptor dimerization in which one molecule binds to the receptorthrough sites 1 and 2. A sandwich enzyme-linked immunosorbentassay was developed for quantifying hGH molecules that presenthelix 4 from binding site 1. For this, horse anti-rhGH antibodieswere eluted by an immunoaffinity column constituted bysepharose-rhGH. These antibodies were purified through a secondcolumn with synthetic peptide correspondent to hGH helix4, immobilized to sepharose, and used as capture antibodies.Those that did not recognize synthetic peptide were used as amarker antibody. The working range was of 1.95 to 31.25ng/mLof hGH. The intra-assay coefficient of variation (CV) was between4.53% and 6.33%, while the interassay CV was between 6.00% and8.27%. The recovery range was between 96.0% to 103.8%. Therewas no cross-reactivity with human prolactin. These features showthat our assay is an efficient method for the determination of hGH.     

生长激素释放激素和胰高血糖素对成人及生长激素缺乏患者生长激素分泌的影响

本文报告正常成人和成年生长激素缺乏(GHD)患者血清生长激素(GH)对GH释放激素(GHRH)和胰高血糖素(G1u)的反应。肌注G1u后血糖失升高后降低,血糖下降是兴奋GH分泌的因素。联合注射G1u/GHRH后的血清GH峰值部GH反应曲线下面积等于单独注射G1u和GHRH的和。二例对GHRH有GH分泌反应的GHD患者,对单独注射G1u无GH分泌反应。他们的GH分泌对联合注射G1u/GHRH与单独注射GHRH的反应相同。作者认为注射G1u引起的血糖下降可能是通过抑制下丘脑释放生长抑素从而引起GH的分泌。     

Recombinant Human Insulin Analogues

The recent introduction of recombinant DNA technology has made possible the manufacture of insulin analogues with altered pharmacokinetic properties. Such analogues include insulins with single or multiple amino acid substitution(s) in the A or B chains of human insulin. The modification of the amino acid sequence results in a lower tendency towards aggregation of the insulin analogues when compared with human insulin. In particular, the subcutaneous injection of rapid-acting insulin analogues generates a peak that is superimposable on the peripheral plasma insulin profile of healthy individuals after a meal, without the need for a time interval between the injection and the meal. However, long term multicentre trials with rapid-acting insulin analogues have not shown an improvement in glycated haemoglobin (HbA(1c)) values despite an improvement in post-meal (2 hour) glycaemic control. This result is probably due to the shorter action of insulin analogues compared with human regular insulin, causing higher glycaemic values at 4 hours after insulin administration despite lower values at 2 hours. Thus, the simple substitution of rapid-acting analogues for regular insulin can lead to a potential deterioration of metabolic control, causing hyperketonaemia in patients without residual C-peptide secretion. Such patients should receive supplemental intermediate insulin at bedtime and also, at low dosages and on the basis of glucose values, at any time the interval between meals is longer than 4 hours.     

Analysis of Major Isoforms of Human Growth Hormone before and after Intensive Physical Exercise

We developed a semiquantitative method for the analysis of main growth hormone isoforms. The use of immunoaffinity sorbents, two-dimensional electrophoresis, and immunoblotting allows detection of more than 90% circulating growth hormone. It was demonstrated that the proportion of growth hormone isoforms in human serum before and after strenuous exercise remained unchanged. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 146, No. 10, pp. 446–450, October, 2008     

Growth Hormone Deficiency in Adults

Although growth hormone has been in clinical use for almost 40 years to promote linear growth in children with growth hormone deficiency, replacement therapy in adults was previously not deemed clinically indicated. However, intensive research over the past decade has led to important advances in our medical knowledge and improvements in the care for patients with growth hormone deficiency. Well-controlled clinical trials have demonstrated beneficial effects of replacement therapy with recombinant human prion-free growth hormone (rhGH; somatropin). The most important restoration parameters include reduction of cardiovascular risk factors and improved lipid profile, normalised body composition, improved exercise capacity and bone mass, as well as enhanced psychological well-being. Some important issues regarding growth hormone deficiency and long term somatropin treatment are unresolved, such as diagnostic criteria and the potential for malignancy and impaired glucose tolerance. Furthermore, the effect on hard end-points such as life expectancy or vertebral fracture rate is unknown, but is expected to emerge from physician-managed, multinational databases. Consequently, at this point somatropin therapy should be given in conjunction with clinical trials.     

131I标记重组人表皮生长因子在裸鼠体内的辐射生物学效应研究

研究131I标记的重组人表皮生长因子(131I-rhEGF)对荷人乳腺癌裸鼠的辐射生物学效应。通过131I-rhEGF在小鼠体内的分布实验找寻131I-rhEGF的主要浓聚组织,再通过生化检查和活组织病理检查检测131I-rhEGF对荷人乳腺癌裸鼠主要浓聚131I-rhEGF的组织的辐射损伤。131I-rhEGF在小鼠体内的分布实验显示,131I-rhEGF主要浓聚在肾、肝、脾、血。生化检查和活组织病理检查结果显示,注射131I-rhEGF2次(每次注射量相当于50kg人体注射14.58GBq,间隔为14d)对荷人乳腺癌裸鼠的肿瘤有较强的杀伤作用,而对肾、肝、脾和造血组织均无辐射损伤。因此,131I-rhEGF在受体介导放射性靶向治疗乳腺癌的过程中对正常组织是安全的药物。     

Fibroblast Growth Factor-2 Augments Recombinant Human Bone Morphogenetic Protein-2-Induced Osteoinductive Activity

The osteoinductive activity induced by recombinant human BMP-2 (rhBMP-2) blunts proportionately as the recipient ages. In order to compensate for this bluntness administration of fibroblast growth factor-2 (FGF-2) has been considered. The aim of this study was to determine whether FGF-2 administration augments osteoinductive activity caused by rhBMP-2 and to evaluate the effect of aging on bone formation induced by coadministration of rhBMP-2 and FGF-2. Sixty-four Wistar strain male rats of 8-week-old (prepubertal) and 16-week-old (postpubertal) received bone defects bilaterally in the parietal bone and the defects were filled by a polylactic acid polyglycolic acid copolymer/gelatin sponge (PGS) impregnated with rhBMP-2 plus 0 ng, 25 ng, and 250 ng FGF-2 (n=10 in each). At 2 weeks after grafting, the new bone volume seemed to be larger in the rhBMP-2+FGF-2 groups than in the rhBMP-2 alone group. At 4 weeks, the new bone formation was linked to the adjacent original bone. In the prepubertal rats, all newly formed bone was similarly calcified. In the postpubertal rats, only the rhBMP-2+25 ng FGF-2 group showed this higher degree of calcification. At 2 weeks, alkaline phosphatase (ALP) activity in the rhBMP-2+25 ng FGF-2 group was significantly (p<0.05) larger than that in the rhBMP-2 group in both prepubertal and postpubertal rats. This result shows that low-dose administration of FGF-2 enhanced the degree of calcification and ALP activity in the rhBMP-2 grafting site especially in the postpubertal rats. Therefore, FGF-2 would be a candidate to compensate for the reduction of osteoinductive activity of rhBMP-2 with aging.