Efficacy of needle-free administration of recombinant human growth hormone in adults with growth hormone deficiency

AIM: Needle-free administration of recombinant human growth hormone (rhGH) is effective in the treatment of growth hormone deficiency (GHD) in children, but has not been studied in adult patients. Therefore, we evaluated the efficacy of needle-free administration of rhGH in adults with GHD. METHODS: Insulin-like growth factor-I (IGF-I) concentrations were compared in newly diagnosed patients with GHD (n = 21) and in patients previously treated by subcutaneous injection of rhGH (switchers, n = 34), at baseline, 12 months and 24 months. RESULTS: In the new patients, IGF-I standard deviation scores (SDS) increased from - 1.82 +/- 0.46 to + 0.75 +/- 0.33 at 12 months and to + 0.65 +/- 0.41 at 24 months (P < or = 0.001 vs. baseline). In switchers, IGF-I SDS remained unchanged with values of + 0.98 +/- 0.32 at baseline, + 0.87 +/- 0.23 at 12 months and + 0.73 +/- 0.29 at 24 months (P = 0.696 vs. baseline). In new patients, the rhGH dose was 0.46 +/- 0.03 mg day(-1) at 12 months and 0.47 +/- 0.03 mg day(-1) at 24 months. In switchers, the rhGH dose was 0.53 +/- 0.04 mg day(-1) at baseline (s.c. injection), 0.52 +/- 0.03 mg day(-1) at 12 months and 0.48 +/- 0.03 mg day(-1) at 24 months (NS between the different time points). There was no difference in the dose of rhGH at 12 and 24 months between the two groups. Side-effects were generally minor and consisted of local tissue reactions. CONCLUSION: Administration of rhGH by needle-free, transdermal injection is effective in maintaining IGF-I concentrations in the normal range for age in adults with GHD, and is as effective as traditional subcutaneous injection of rhGH.     

Clinical evaluation of recombinant human growth hormone injection in children with growth hormone deficiency

Recombinant human growth hormone (rhGH) has been widely used in the clinical treatment of growth hormone deficiency. To simplify the injection process and increase drug compliance, application of the GH injection has become a new treatment plan in recent years. The purpose of the current study was to evaluate the efficacy and safety of rhGH injection for the treatment of growth hormone deficiency (GHD) in children in China. In a nationwide, noncomparative, prospective, randomized, open trial, 31 children with confirmed complete GHD received subcutaneous injection of rhGH at 0.25 mg/kg·wk (0.107 IU/kg·d). The injection was given daily and the total weekly amount was separated into 6–7 injections. The patients were followed up at 3-month intervals and the treatment duration was 12 months. The height (HT), annual growth velocity (GV), mean height standard deviation score (HT SDS), blood serum insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP-3), and bone maturity before and after treatment were compared, and the safety of the treatment was analyzed. The mean HT, GV, and HT SDS were increased from 109.0±14 cm, 2.7±0.9 cm/yr, and −4.62 ±1.46 at baseline to 121.8±13.4 cm, 12.9±3.3 cm/yr, and −2.47±1.86 after 12 months of treatment, respectively (P<0.001). At the same time, blood IGF-I and IGFBP- 3 were increased significantly [41.27±64.43 μg/L vs 159.21±167.92 μg/L and 1540.00±1325.11 mg/L vs 3533.93±1413.82 mg/L, respectively (P<0.001)]. The bone age assessments performed 6 and 12 months after the treatment showed that no advanced bone maturation was noted. No serious adverse events occurred during the treatment, and the drug-related adverse events were mainly decreased thyroid function. We conclude that rhGH injection is a safe and effective drug for treatment of growth hormone deficiency in children.     

Effect of dihydroergokryptine administration on serum prolactin and growth hormone levels in normal,hyperprolactinaemic and acromegalic subjects: Evidence of potent and long-lasting pituitary dopamine receptor stimulation

Summary The endocrine effects of a relatively potent dopaminergic agent, dihydroergokryptine, have been studied in normal subjects, and in hyperprolactinaemic and acromegalic patients. A single 6 mg oral dose of the drug caused a marked, long lasting fall in prolactin (PRL) plasma levels in healthy subjects, in hyperprolactinaemic patients and in normoprolactinaemic acromegalics. Growth hormone (GH) levels decreased in l-DOPA — responder, acromegalic patients, but dihydroergokryptine did not affect GH levels in normal volunteers or in l-DOPA non — responder, acromegalic patients. The PRL-and GH- lowering activity of 6 mg dihydroergokriptine was significantly greater than that of 6 mg dihydroergocristine, and was similar to that of an oral dose of 500 mg l-DOPA.     

Tesamorelin,a human growth hormone releasing factor analogue

Background: The combination of clinical effectiveness with a variety of adverse side effects from the use of recombinant human growth hormone (rhGH) in therapy for growth hormone (GH)-deficient disorders has led to the development of human growth hormone releasing factor (GFR) analogues, which may be better tolerated. Tesamorelin, a synthetic GFR, has been developed as a potential treatment for a variety of conditions that may be associated with a relative deficiency of GH including HIV-related lipodystrophy. Objective: This article reviews the development of tesamorelin and its purported role in HIV-related lipodystrophy and other potential indications. Methods: Relevant articles and abstracts were obtained from searches of the medical and chemical literature databases and the references from published articles. Results/conclusion: A multicenter, randomized, placebo-controlled, Phase III clinical trial suggested that tesamorelin might be a beneficial treatment strategy for HIV-related lipodystrophy with a good safety profile and a positive effect on reducing visceral fat. Other potential indications for tesamorelin appear less promising from the current data.     

半乳糖化重组人生长激素和重组人生长激素在小鼠体内的药物动力学

目的：比较半乳糖化重组人生长激素和重组人生长激素在小鼠体内的药物动力学特征。方法：用＾１２５Ｉ标记Ｇａｌ－ｒｈＧＨ和ｒｈＧＨ、通过小鼠尾静脉ｉｖ，测定血和肝中相对放射性随时间的变化，以３Ｐ８７药物动力学程序进行模型拟合和参数求算。结果：＾１２５Ｉ－ｒｈＧＨ－Ｇａｌ在血中的相对放射性呈现双峰，其体内药行动力学特征与＾１２５Ｉ－ｒｈＣＨ明显不同，进一步证实了Ｇａｌ－ｒｈＧＨ的肝靶向性。     

重组人生长激素治疗血液透析营养不良患者的疗效观察

目的探讨重组人生长激素治疗维持性血液透析患者营养不良的疗效。方法选择我院中心32例营养不良维持性血液透析患者进行分组比较,治疗组（B组）给予重组人生长激素,通过测定血清白蛋白、干体质量、上臂肌围等的变化进行分析。结果随防3个月后,两组患者营养指标均有改善,治疗组与对照组比较,营养状况改善更明显（P〈0.05）。结论重组人生长激素能改善维持性血液透析患者营养不良的状态。     

特发性生长激素缺乏性矮小症在重组人生长激素治疗1年后身体构成的变化

目的:探讨青春期前特发性人生长激素缺乏症(IGHD)用基因重组人生长激素(rhGH)治疗后其身体构成的改变。方法:17例年龄为(14．6±4．5)岁,骨龄(12．1±0．8)岁的IGHD青少年(男14例,女3例),在rhGH治疗前生长速度每年(2．9±0．7)cm,患者每周0．5 u·kg-1,分5次于临睡前皮下注射rhGH,共1年。测定患者治疗前和治疗后1,3,6,9和12个月身高、体重、体内脂肪百分含量(F％)、去脂肪量(FFM)、左右手握力、血胰岛素样生长因子-1(IGF-1)和血胰岛素样生长因子结合蛋白-3(IGFBP-3)水平,并以2002年中国北方177例正常青少年值作为对照。结果:治疗前IGHD患者的身高、体重、FFM及血IGF-1和IGFBP-3水平均显著低于正常青少年(P<0．05),F％明显高于正常青少年(P<0．05),但体重指数(BMI)值无明显差异。用rhGH治疗1个月及随后治疗中,患者F％均显著低于治疗前(P<0．05),与正常青少年无统计学差异。经rhGH治疗6个月,17例IGHD患者的身高、生长速度、FFM及血IGF-1和IGFBP-3水平均明显增加(均P<0．05),其改变值均与F％的下降值相关(P均<0．01)。治疗1年后,所有患者的握力均明显增加。结论:IGHD青少年在使用rhGH后,身高、FFM及握力均显著增加,F％减少,提示患者骨骼和肌内组织的增加及脂肪含量的降低,即身体的构成发生了明显的改变。     

肽类激素兴奋剂对人体的危害

兴奋剂是国际体育组织规定的禁用药物和方法的总称，可分为蛋白同化制剂、肽类激素、β2受体激动剂、利尿剂、麻醉剂等不同种类。肽类激素是一类较新的兴奋剂，包括促红细胞生成素、生长激素及胰岛索样生长因子-1、促性腺激素、胰岛素、促皮质激素5大类。肽类激素属于人体内源性物质，很难被检测到，但滥用误用会对人体健康造成损害，如促红细胞生成素可引起过敏反应，生长激素可造成肢端肥大症，胰岛索样生长因子-1可引起急性低磷血症，促性腺激素可造成男性性早熟，胰岛素可造成视物模糊，促皮质激素可造成女性闭经等。     

The salivary exosomal microRNA as a potential biomarker in patients with periodontitis and oral cancers

Periodontitis and oral cancers are the most common oral diseases in the human population. The early diagnosis of oral diseases allows the efficient therapy of the patient. During oral diseases, resident cells in the affected tissue secrete exosomal microRNAs (miRNAs) into saliva. As these miRNAs have a crucial role in the pathogenesis of oral diseases, they have been suggested as non-invasive and validated biomarkers in predicting periodontitis severity and cancer progression. Several attempts have been performed to evaluate the expression of salivary exosomal miRNAs in patients with periodontitis and oral cancers. Some miRNAs are differentially expressed in the saliva of the affected patients when compared to healthy individuals. These miRNAs are reviewed in this narrative review. Collectively, it seems that salivary exosomal microRNAs could be used as a diagnostic biomarker in oral diseases. However, further studies are required to validate them.     

Procollagen type III amino-terminal propeptide and insulin-like growth factor I as biomarkers of growth hormone administration

The acceptance in 2012 by the World Anti-Doping Agency (WADA) of the biomarker test for human growth hormone (hGH) based on procollagen type III amino-terminal propeptide (P-III-NP) and insulin-like growth factor I (IGF-I) was perhaps the first time that such a method has been used for forensic purposes. Developing a biomarker test to anti-doping standards, where the strict liability principle applies, is discussed. An alternative WADA-accepted approach is based on the measurement of different hGH isoforms, a method that suffers from the very short half-life of hGH limiting the detection period. Modification or withdrawal of the immunoassays, on which the biomarker measurements largely depend, has necessitated revalidation of the assays, remeasurement of samples and adjustment of the decision limits above which an athlete will be assumed to have administered hGH. When a liquid chromatography coupled mass spectrometry (LC–MS) method became a reality for the measurement of IGF-I, more consistency of results was assured. Measurement of P-III-NP is still dependent on immunoassays although work is underway to develop an LC–MS method. The promised long-term detection time for the biomarker assay does not appear to have been realised in practice, and this is perhaps partly the result of decision limits being set too high. Nevertheless, more robust assays are needed before a further adjustment of the decision limit is warranted. In the meantime, WADA is considering using P-III-NP and IGF-I as components of a biomarker passport system recording data from an individual athlete, rather than the population. Using this approach, smaller perturbations in the growth hormone (GH) score would mandate an investigation and possible action for hGH administration.     

基因重组人生长激素治疗青春期前特发性生长激素缺乏症临床试验

目的:评价基因重组人生长激素(rhGH)治疗青春期前特发性生长激素缺乏症(IGHD)患儿6个月的疗效和安全性。方法:对49例IGHD患儿进行rhGH治疗,每晚睡前皮下注射0．5IU·kg~(-1),每周分5次注射,共26周。评价治疗前后身高、生长速度、身高标准差计数(SDS)等指标。结果:在rhGH治疗期间,46例患儿生长速度由每年(2．5±1．0)cm提高到(11．5±2．5)cm(P＜0．005)。身高SDS由治疗前(-4．2±1．8)增为(-3．7±1．8)。同时患儿13和26周血清胰岛素样生长因子(IGF-1)和IGF结合蛋白(IGFBP,)水平均较治疗前明显升高(P＜0．05)。其体重与骨龄无明显变化。治疗后共有15．7%患儿出现甲状腺功能降低,抗hGH抗体阳性率为21．7%,但所有这些现象均未影响患者体格的线性增长。在治疗期间所有患者肝肾功能、血尿常规和代谢性指标(如血糖和血脂水平)等均保持在正常范围。结论:rhGH是治疗IGHD安全有效的药物。     

The role of growth hormone-receptor antagonism in relation to acromegaly

Acromegaly is a rare but disabling condition associated with reduced life expectancy. It is caused almost invariably by a growth hormone-secreting pituitary adenoma. Transsphenoidal surgery and/or radiotherapy are still considered to be the treatment of choice, but despite recent advances in both these forms of treatment, the overall surgical cure rate remains ～ 60%, and radiotherapy is characterised by delayed effect and a high incidence of hypopituitarism. Medical therapy in the form of dopamine agonists and somatostatin analogues has traditionally been used as an adjunct to surgery and/or radiotherapy, but is increasingly being used as first line therapy in the treatment of acromegaly. Recently, a third form of medical therapy, the growth hormone receptor antagonist, pegvisomant, has been licensed for use in acromegaly. This article examines the design, properties, clinical efficacy and safety of pegvisomant.     

Clinical applications of recombinant human growth hormone in adults

The main function of growth hormone (GH) is to promote linear growth during childhood; however, GH secretion persists throughout life after cessation of skeletal growth. This hormone has important physiological functions apart from growth stimulation. Many aspects of the physiological and pharmacological actions of GH have been recently clarified. Accordingly, in the last years, especially since the introduction of recombinant human GH (rhGH), GH therapeutical applications have increased. In the last years, the main clinical application of rhGH has been to stimulate growth of growth-retarded GH deficient (GHD) children. More recently, rhGH therapy has been approved for other conditions associated with short stature, including Turner syndrome and end stage renal disease. In adults, the only therapeutic indications approved are the adult GHD syndrome and the AIDS-associated wasting. This review outlines the present knowledge of the physiological effects, clinical applications, therapeutic perspectives, side effects, precautions and contraindications of rhGH therapy in adults.     

乳糖化人生长激素在小鼠体内的组织分布和药代动力学

目的　研究乳糖化人生长激素 (hGH L)在小鼠体内的组织分布和药代动力学特征。方法　用放射性核素体内示踪技术研究体内分布 ,用放射免疫分析 (RIA)技术研究药代动力学。并对比研究人生长激素 (hGH)。结果　12 5I hGH L具有明显的趋肝性 ,肝最大摄取率为 6 8 83% ,约为12 5I hGH的 2倍。hGH L的血药时曲线下面积 (AUC为32 6 86 9)和在血清的平均驻留时间 (MRT为 2 1 37min)均小于hGH (AUC为 36 913 0 8,MRT为 2 4 98min) (P <0 0 0 5 ) ;而靶器官肝脏的hGH L分布半衰期T12 α( 1 84min)、清除半衰期T12 β( 11 0 9min)小于hGH (T12 α2 11min ,T12 β75 6 5min) (P <0 0 0 5 ) ,其AUC( 176 2 1 9) >hGH( 12 148 2 ) (P <0 0 0 5 )。结论　hGH L可望成为提高hGH治疗儿童生长激素缺乏症的新药     

Applying metabolomics to detect growth hormone administration in athletes: Proof of concept

Growth hormone (GH), an endogenous peptide regulating anabolism and lipolysis in humans, is known to be abused by athletes to improve their performance. Despite the development of two distinct screening methods, few positive cases have been reported by the antidoping authorities, probably due to the quick turnover of GH and the masking effects of age, ethnicity, and sex. Apart from growth regulation, GH is known to affect several metabolic pathways in humans including ketosis, amino‐acid uptake, and protein breakdown. It is reasonable to imagine observing its markers of effects through the leading tool on metabolism study, metabolomics. In this proof‐of‐concept study, a cohort of well‐trained volunteers was split in two equal groups and administered with micro‐doses of EPO or EPO + GH every second day for 2 weeks. Urine and plasma samples were collected before, during, and after treatment and analyzed using metabolomics and lipidomics approaches. The results show that, by applying a direct discriminant analysis on the treated groups, it is possible to distinguish the treatments, and to use this difference to classify them correctly. High intragroup variability is observed, due to the subject‐specific effect of the hormones. Through time 0 centering the data, a longitudinally tracking of the group was performed and a higher difference was observed between the groups, including a perfect classification of the samples before and after the treatments.     

重组人生长激素治疗肝硬变低蛋白血症腹水的临床研究

目的　探讨重组人生长激素对肝硬变低蛋白血症、腹水的疗效。方法　选择肝硬变腹水病人33例 ,随机分为重组人生长激素 (rhGH)治疗组 16例 ,对照组 17例。治疗组每晚睡前皮下注射rhGH 4U ,10d为 1个疗程 ;对照组每周补白蛋白 2 0g ,10d为 1个疗程。分别在治疗前、后检测两组的血浆白蛋白、空腹血糖、血脂并监测肾功能 ;观察 2 4h尿量及腹水的消退情况。结果　治疗后治疗组血浆白蛋白明显增加 ,腹水消退明显 ,与对照组相比差异有显著意义 (P均 <0 0 5 )。结论　重组人生长激素有明显促进肝硬变病人血清白蛋白合成的作用 ,具有临床应用价值。     

Properties of a cleaved two-chain form of recombinant human growth hormone

Escherichia coli cells transformed with plasmids engineered for the expression of recombinant human growth hormone as a secreted product also produced a proteolytically cleaved form of rhGH. This variant is isolated at a high resolution anion exchange chromatography stage during the manufacturing process. The higher isoelectric point of this form is demonstrated by isoelectric focusing and chromatofocusing and the two-chain nature by tryptic mapping, N- and C-terminal sequence analyses, and sodium dodecyl sulfate polyacrylamide gel electrophoresis. These data indicate that the single site of cleavage is between Thr-142 and Tyr-143, in contrast to the two-chain variant isolated from human pituitary glands, which has a clip after residue Phe-139. The recombinant two-chain form was further characterized by reversed-phase high performance liquid chromatography at both acidic and basic pHs. The assay utilizing bicarbonate-containing mobile phases was determined to be the most efficient and sensitive method. The bioactivity of this two-chain form was measured by the in vivo rat weight gain assay and by the in vitro Nb2 cell bioassay. Its immunological similarity to intact one-chain rhGH was demonstrated with an enzyme-linked immunosorbent assay.     

Serum microRNA 125b as a diagnostic or prognostic biomarker for advanced NSCLC patients receiving cisplatin-based chemotherapy

Aim:

To investigate the expression profile of microRNAs in inoperable advanced non-small cell lung cancer (NSCLC) patients receiving chemotherapy and the potential relevance of microRNAs to clinicopathological characteristics and prognosis.

Methods:

Serum samples were taken from 260 inoperable advanced NSCLC patients and 260 healthy individuals. All the patients received cisplatin-based chemotherapy, including NP/NC regimens, GP/GC regimens, and TP/TC regimens. The serum levels of microRNAs (miR-125b, miR-10b, miR-34a and miR-155) were determined by quantitative real-time PCR.

Results:

Serum levels of the 4 microRNAs examined in NSCLC patients were significantly increased as compared with healthy individuals. The levels of miR-125b and miR-155 were changed in a similar pattern: the patients with stage IV disease had the highest one, while the patients with stage III A and stage III B disease showed similar increased levels. The levels of miR-10b and miR-34a in the patients with different stages were increased to similar extent. The level of miR-125b in poorly differentiated cancer was significantly higher than those in well and moderately differentiated cancers, while the levels of miR-10b, miR-34a, and miR-155 did not significantly differ with cancer differentiation. Among the 4 microRNAs examined, only miR-125b was significantly associated with therapeutic response, exhibiting higher expression levels in non-responsive patients. Furthermore, the high level of miR-125b was significantly correlated with poor patient survival. A multivariate Cox regression analysis showed that the expression level of miR-125b was an independent prognostic marker in NSCLC patients.

Conclusion:

Our results suggest that miR-125b is a potential diagnostic or prognostic biomarker for NSCLC. This finding has important implications for development of targeted therapeutics to overcome chemotherapeutic resistance in NSCLC.