重组人生长激素对老年男性慢性心力衰竭患者血脂代谢影响的研究

目的：探讨重组人生长激素在治疗老年男性慢性心力衰竭时对血脂代谢的影响。方法：将对87例老年慢性心力衰竭患者随机分别进行常规心力衰竭治疗组（CHF对照组）（n=46）和常规治疗基础上加用生长激素治疗组（CHF实验组）（n=41）及正常对照组（n=10）;均连续治疗3个月,观察治疗前后生长激素（GH）、（胰岛素样生长因子-1（IGF-1）、总胆固醇（1℃）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-c）、高密度脂蛋白胆固醇（HDL-C）等各项指标的变化。结果：治疗前,各组之间GH、IGF-1水平无明显差异。治疗后,CHF实验组患者GH（0．71±0．34／350．96±0．48）、IGF-1（95．64±21．11 vs 111．64±23．14）水平较治疗前明显升高,CHF对照组治疗前后GH（0．81±0．32 vs 0．79±0．29）、IGF-1（97．82±19．74 vs 99．65±20．11）水平无明显差异。治疗后CHF实验组与CHF对照组相比GH（0．96±0．48 vs 0．79±0．29）、IGF-1（111．64±23．14 vs 99．65±20．11）水平显著升高（P〈0．05）。治疗前,3组患者血脂各项指标无明显差异（P〉0．05）,治疗后,CHF实验组LDL-C（2．11±0．82 vs 1．76±0．51）、TC（3．78±1．34 vs 3．21±1．17）水平较治疗前有所下降（P〈0．05）,而HDL-C（1．10±0．31 vs 0．99±0．28）、TG（1．89±1．07 vs 1．66±0．95）水平较治疗前无显著差异（P〉0．05）。然而,CHF对照组治疗前、后相比,LDL-C、HDL-C、TC、TG水平无显著差异（P〉0．05）。结论：应用重组人生长激素治疗老年慢性心力衰竭,GH参与了血脂代谢,可降低LDL-C、TC水平,但对HDL-C、TG水平无明显影响。故在长期应用生长激素时需要关注血脂代谢,及时调整血脂治疗。     

RP-HPLC法测定重组人生长激素注射液中间甲酚含量

目的：建立测定重组人生长激素注射液中间甲酚含量的方法。方法：采用RP-HPLC法,色谱柱为ShiseidoC4（250mmx4.6mm,5um）,流动相为0.05MTris-HCL（pH7.5）-正丙醇（71：29）,流速0.5ml/min,检测波长为317nm,柱温为40℃。结果：间甲酚在0.2mg-0.8mg/ml（r=0.9996,n=5）浓度范围内与峰面积呈良好线性关系,最低检出线为0.1ng,平均回收率为100.5%（n=9）。结论：本方法准确,重现性好,可为重组人生长激素注射液质量评价提供较为可靠的分析方法。     

重组人生长激素对梗阻性黄疸大鼠sIgA、EGF的影响

目的：观察重组人生长激素对梗阻性黄疸大鼠sIgA、EGF的影响。方法：Wistar大鼠60只随机分4组（n=15）：假手术对照组（A组）、胆总管结扎组（B组）、胆总管结扎＋rhGH治疗1周组（C组）、胆总管结扎＋rhGH治疗2周组（D组）。除A组外,其余各组将胆总管结扎,致胆总管完全梗阻。A组和B组术后2周处死大鼠;C组于术后开始,在双后肢内侧轮流皮下注射rhGH 0.75U.kg^-1.d^-1,1周后处死;D组于术后开始,在双后肢内侧轮流皮下注射rhGH 0.75U.kg^-1.d^-1,2周后处死。各组均无菌操作,在麻醉成功后开腹直视下获取标本,测定TB、ALP、PA、IGF-I、sIgA、EGF等。结果：大鼠梗阻性黄疸时,B、C、D组血中PA、IGF-I及胃肠液中sIgA、EGF降低,血中TB、ALP升高,与A组比较均具有显著性差异（P〈0．05）;而给予外源性生长激素的c组、D组胃肠液中sIgA、EGF降低幅度明显低于B组（P〈0．05）,且梗阻性黄疸大鼠细菌移位率也明显低于B组。结论：外源性生长激素,能保护梗阻性黄疸大鼠的肝脏功能,以及肠道的机械屏障功能和免疫屏障功能,减少肠道细菌移位的发生。     

饥饿状态下草鱼生长激素的分泌

以两种规模草鱼为对象,研究了饥饿对其生长激素的影响。检测由背大动脉导管抽取的连续血样的结果表明;饥饿状态下草鱼（体重为0．5－1．0kg）生长激素分泌仍是间歇性的,但饥饿明显提高其总体生长激素平均值、基础生长激素平均值和其最大峰值。对于草鱼鱼种（体重为25．30g）,饥饿也明显提高其血液中生长激素水平,但草鱼种的肥满度系数和血糖浓度却。在体外灌流实验中,饥饿的草鱼种脑垂体碎片生长激素基础分泌值明显高于正常投喂的对照组。这些结果表明：饥饿状态下草鱼生长激素分泌增强。     

分泌型重组人生长激素工程菌发酵及其产物纯化

在 5L发酵罐中将工程菌pET-ompA3-hGH/BL21(DE3)进行补料式发酵 ,诱导表达分泌型重组人生长激素。通过对发酵培养基成分、补料成分、补料体积、补料时机和滴加流速的选择 ,分泌表达rhGH的量可达到 250mg/L ,占周质蛋白的 44%～ 54% ,发酵周期缩短为8h。用rhGH纯蛋白免疫动物制备的多克隆抗体制成的抗体亲和层析柱 ,一步纯化大肠杆菌周质中分泌表达的rhGH ,产物纯度达到96%以上 ,纯化产物在分子质量大小、免疫活性和二硫键的形成与天然生长激素相一致 。     

半胱胺对草鱼下丘脑-脑垂体组织共孵育中生长激素分泌的影响

采用静态孵育和放射免疫测定技术,研究了生长抑素抑制剂半胱胺盐酸盐对草鱼脑垂体组织单独孵育或下丘脑脑垂体组织共孵育中生长激素分泌的影响。结果表明：脑垂体组织单独孵育时,半胱胺盐酸盐(0．1、1和10mmol／L)对基础生长激素分泌无影响;而下丘脑脑垂体组织共孵育时,半胱胺盐酸盐(0．1、1和10mmol／L)对基础生长激素分泌有明显影响,且是剂量依存的。神经肽hGHRH、sGnRH—A和LHRH—A对CSH影响的下丘脑脑垂体组织共孵育中生长激素分泌均无协同作用。我们认为,半胱胺盐酸盐可在下丘脑水平调节生长激素释放,半胱胺盐酸盐调节草鱼离体生长激素分泌是由下丘脑途径介导的。     

恒河猴血清孕酮含量测定方法

目的建立恒河猴血清中孕酮含量测定方法。方法本文采用放射免疫测定技术。结果孕酮的回收率为94％,批内CV为5．1％～8．3％,批间CV为4．5％～7．7％,灵敏度为5～10Pg。说明该方法具有较高的灵敏度、特异性、准确性。分别测定了幼年组、成年组和老年组的雌性恒河猴的血清中的孕酮含量分别为：（0．20±0．04）ng／mL、（6．26±0．17）ng,mL和（0．35±0．06）ng/mL;成年雌性恒河猴月经周期孕酮的变化范围为：滤泡期为（1．10±0．12）ng／mL,排卵期（2．36±0．18）ng/mL,黄体期（6．17±0．15）ng/mL,妊娠期随着妊娠月份的增加,孕酮浓度也增加,最高可达50ng／mL。结论经实验验证,该方法灵敏、可靠、适用,可作为恒河猴血清中孕酮含量测定的一种方法。     

聚乙二醇修饰重组人生长激素的初步研究

目的 探讨聚乙二醇(MW20kD)修饰重组人生长激素(rhGH)的反应条件以及修饰产物的纯化方法。方法在不同条件下,将聚乙二醇活性酯与rhGH反应,以单个PEG-GH的比例为指标,用SDS-PACE和薄层扫描方法,确定其在反应产物中所占的比例;采用CM-Sepharose FF离子交换和Sephacry 1S-200分子筛凝胶层析法对修饰产物进行分离纯化。结果聚乙二醇修饰rhGH的反应条件为pH8．0、rhGH与聚乙二醇的比例1：2(mg：mg)、反应时间2．0h;反应产物经两步纯化,所得的单个PEG-GH纯度大于95％。结论 初步确定了聚乙二醇修饰rhGH的反应条件和修饰产物的纯化方法。     

重组人生长激素治疗特发性矮小患儿的疗效及生长速率预测模型的建立

摘要 目的：探讨重组人生长激素（rhGH）对特发性矮小（ISS）患儿的治疗效果,并建立rhGH治疗后生长速率（GV）的预测模型。方法：回顾性分析确诊为 ISS并应用rhGH治疗1年的130例患儿的疗效,以治疗12个月后的GV为因变量,采用多元逐步回归方法建立ISS患儿疗效的预测模型。结果：rhGH治疗6个月、12个月的身高、身高标准差分值（HtSDS）均逐渐升高（P<0.05）,治疗12个月的身高增长（△Ht）、GV 低于治疗 6个月（P<0.05）。治疗6个月、治疗12个月的GV 均与初始治疗时的生活年龄（CA）、骨龄（BA）、身高、体重及垂体高度呈负相关（P<0.05）。将治疗12个月GV 作为因变量,治疗前初始身高（X1）、治疗6个月GV（X2）被纳入方程建立预测模型：Y=7.631-0.035X1+0.567X2,R²=0.791,并通过内外部验证。结论：rhGH治疗对ISS患儿的身高增长具有良好效果,前6个月的效果更好。rhGH治疗后ISS患儿的GV与治疗前CA、BA、身高、体重及垂体高度呈负相关。治疗前的身高、治疗6个月的GV能够较好地预测治疗12个月的GV。     

生长激素/胰岛素样生长因子1与阿尔茨海默病

生长激素／胰岛素样生长因子-1（GH／IGF-1）轴的合成、分泌、调节及生物学活性与阿尔茨海默病（AD）有密切关系。生长激素（GH）的合成和分泌受生长激素释放激素（GHRH）正向调节。GH／IGF-1轴活性下降导致一系列生理功能变化。GH／IGF-1缺乏可引起衰老及神经退行性变（AD）而导致认知功能的下降,相应激素的补给可以抑制或逆转这种认知障碍。越来越多的证据表明：GH／IGF-1参与AD型痴呆病理过程,对AD有很好的治疗应用前景。本文就生长激素／胰岛素样生长因子1在AD发病中的机理和药理学研究做一综述。     

Association of Daily Growth Hormone Injection Adherence and Height Among Children With Growth Hormone Deficiency

ObjectiveRecombinant human growth hormone (somatropin) is recommended for children with growth hormone deficiency (GHD) to normalize adult height. Prior research has indicated an association between adherence to somatropin and height velocity. Further research is needed using real-world data to quantify this relationship; hence the objective of this study was to investigate the association between adherence to somatropin and change in height among children with GHD.MethodsThis retrospective cohort study included patients in the IQVIA PharMetrics Plus and Ambulatory Electronic Medical Records databases aged 3 to 15 years, with ≥1 GHD diagnosis code claim and newly initiated on somatropin between January 1, 2007 and November 30, 2019. Adherence was measured over the follow-up using the medication possession ratio (MPR); patients were classified as adherent (MPR ≥ 0.8) or nonadherent (MPR < 0.8).ResultsAmong 201 patients initiated on somatropin, 74.6% were male, mean age was 11.4 years, and the mean follow-up was 343.3 days. Approximately 76.6% of patients were adherent to somatropin over the follow-up period. Adjusted growth trajectories were similar between adherent and nonadherent patients pre-treatment initiation (P = .15). Growth trajectories post-initiation were significantly different (P = .001). On average, adherent patients gained an additional 1.8 cm over 1 year compared with nonadherent patients, adjusted for covariates.ConclusionGreater adherence to somatropin therapy is associated with improved height velocity. As suboptimal adherence to daily somatropin therapy is an issue for children with GHD, novel strategies to improve adherence may improve growth outcomes.     

Response to long-term growth hormone therapy in short children with reduced GH bioactivity

BACKGROUND/AIMS: The aim of the present study was to investigate whether short children with normal growth hormone (GH) immunoreactivity, but reduced bioactivity (bioinactive GH) could benefit from rhGH treatment as GH deficient (GHD) patients. Methods: We evaluated 12 pre-pubertal children (8 M, 4 F), with GH deficiency-like phenotype showing normal serum GH peak levels (>10 ng/ml), measured by immunofluorimetric assay (IFMA-GH), in contrast with a reduced GH bioactivity (bio-GH), evaluated using the Nb(2) cells. We also evaluated 15 age-matched GHD pre-pubertal children (11 M, 4 F) with serum GH peak <5 ng/ml. Both groups were treated with rhGH therapy at the dose of 0.23 mg/kg/week s.c. RESULTS: Serum bio-GH/IFMA-GH ratio at peak time for each patient during the provocative test was significantly lower in bioinactive GH than in GHD children (0.29 vs. 2.05, p = 0.00001). Recombinant human GH therapy induced a significant (p < 0.001) increase in growth rate in both groups during the first 2 years. In the third year of treatment, while growth rate in GHD children is maintained, in bioinactive GH patients it decreases remaining, however higher compared to the pre-treatment one. CONCLUSIONS: Short rhGH therapy given to selected bioinactive GH children improve growth rate and might result in greater final adult height.     

Growth hormone and neurofibromatosis

Data collected from 102 neurofibromatosis (NF) children with growth hormone (GH) deficiency (GHD) who were receiving GH replacement therapy were reviewed to assess the efficacy and safety of GH therapy in this condition. GH was administered at a mean dose of 0. 18 mg/kg/week. During the 1st year the median height velocity increased significantly from 4.2 cm/year before treatment to 7.1 cm/year, and the median height standard deviation score increased from -2.4 to -1.9. The response to therapy, however, was not as good as that observed in patients with idiopathic GHD. GH therapy did not influence the progression of any of the features of NF, including intracranial tumours, and was not associated with an excess of other adverse events. We conclude that GH treatment of NF patients with GHD is beneficial in terms of improved growth rate and is well tolerated.     

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.     

Final height in children with idiopathic growth hormone deficiency treated with a fixed dose of recombinant growth hormone

There is no consensus regarding the optimal dosing of recombinant human growth hormone (rhGH) for children with growth hormone deficiency (GHD). Our objective was to evaluate the final adult height (FAH) in children with idiopathic GHD treated with a fixed rhGH dose of 0.18 mg/kg/week. We reviewed all charts of patients with idiopathic GHD treated with rhGH since 1985 who reached FAH. Ninety-six patients were treated for an average of 5.4 years. The mean age was 11.9 years, the mean height -2.87 standard deviation score (SDS) and the mean FAH was -1.04 SDS. Females had a lower predicted adult height than males at the initiation of therapy (-2.0 vs. -1.01 SDS; p = 0.0087) but a higher FAH - predicted adult height (1.08 vs. 0.04 SDS; p = 0.0026). In multiple regression analysis, the FAH SDS was positively related to the midparental height SDS, the height SDS at GH initiation and growth velocity during the first year of therapy, and negatively correlated with peak GH and bone age at initiation (r(2) = 0.51; p < 0.005). Treatment of children with idiopathic GHD with a fixed dose of 0.18 mg/kg/week rhGH is sufficient to reach FAH within 2 SDS of the normal population range (84%) with an average FAH within -0.5 SDS of midparental height.     

Final height in children with idiopathic growth hormone deficiency treated with recombinant human growth hormone: the Belgian experience

BACKGROUND: The growth response to recombinant hGH (rhGH) treatment and final height of 61 Belgian children (32 boys) with idiopathic growth hormone deficiency (GHD) were studied. PATIENTS/METHODS: Two patient groups were compared: Group 1 with spontaneous puberty (n = 49), Group 2 with induced puberty (n = 12). The patients were treated with daily subcutaneous injections of rhGH in a dose of 0.5-0.7 IU/kg/week (0.17-0.23 mg/kg/week) from the mean +/- SD age of 11.9 +/- 3.1 years during 5.1 +/- 2.1 years. RESULTS: rhGH treatment induced a doubling of the height velocity during the first year and resulted in a normalisation of height in 53 (87%) patients. Final height was -0.7 +/- 1.1 SDS, being 170.4 +/- 7.2 cm in boys and 158.0 +/- 6.4 cm in girls. Corrected for mid-parental height, final height was 0.0 +/- 1.1 SDS. Ninety-two percent of the patients attained an adult height within the genetically determined target height range. Although height gain during puberty was smaller in the patients with induced puberty (boys: 17.1 +/- 7.0 cm vs. 27.5 +/- 6.6 cm (p < 0.005); girls: 9.6 +/- 7.4 cm vs. 22.2 +/- 6.1 cm (p < 0.005)), no differences in final height after adjustment for mid-parental height were found between patients with spontaneous or induced puberty. CONCLUSIONS: We conclude that patients with idiopathic GHD treated with rhGH administered as daily subcutaneous injections in a dose of 0.5-0.7 IU/kg/week reach their genetic growth potential, resulting in a normalisation of height in the majority of them, irrespective of spontaneous or induced puberty.     

重组人类生长激素对胃癌细胞的体外增殖研究

目的：通过体外实验,研究重组人类生长激素对胃癌细胞的增殖的影响。方法：实验分为空白组,重组人类生长激素组,奥沙利铂组和重组人类生长激素＋奥沙利铂组。用不同浓度的重组人类生长激素处理SGC．7901细胞,采用MTT法和流式细胞仪检测人胃癌细胞株的细胞抑制率,细胞周期和DNA抑制率。结果：体外实验结果表明,重组人类生长激素对SGC．7901细胞株增殖没有明显的促进作用,重组人类生长激素组和空白组以及重组人类生长激素＋奥沙利铂组和奥沙利铂组之间没有统计显著性（P〉0．05）,细胞抑制率和停止生长的细胞在G0-G1期明显增加（P〈0．01）,同时重组人类生长激素＋奥沙利铂组和空白组以及奥沙利铂组在S期,细胞数依次下降,DNA抑制率依次增加。重组人类生长激素＋奥沙利铂组与奥沙利铂组相比,细胞抑制率有明显上升趋势。结论：体外实验表明,重组人类生长激素并不加快人类胃癌细胞的增殖,与抗癌药物一同使用时,有增加治疗功效的作用。     

Effects of Growth Hormone (GH) Therapy Withdrawal on Glucose Metabolism in Not Confirmed GH Deficient Adolescents at Final Height

Context, objective

Growth hormone deficiency (GHD) is associated with insulin resistance and diabetes, in particular after treatment in children and adults with pre-existing metabolic risk factors. Our aims were. i) to evaluate the effect on glucose metabolism of rhGH treatment and withdrawal in not confirmed GHD adolescents at the achievement of adult height; ii) to investigate the impact of GH receptor gene genomic deletion of exon 3 (d3GHR).

Design, setting

We performed a longitudinal study (1 year) in a tertiary care center.

Methods

23 GHD adolescent were followed in the last year of rhGH treatment (T0), 6 (T6) and 12 (T12) months after rhGH withdrawal with fasting and post-OGTT evaluations. 40 healthy adolescents were used as controls. HOMA-IR, HOMA%β, insulinogenic (INS) and disposition (DI) indexes were calculated. GHR genotypes were determined by multiplex PCR.

Results

In the group as a whole, fasting insulin (p<0.05), HOMA-IR (p<0.05), insulin and glucose levels during OGTT (p<0.01) progressively decreased from T0 to T12 becoming similar to controls. During rhGH, a compensatory insulin secretion with a stable DI was recorded, and, then, HOMAβ and INS decreased at T6 and T12 (p<0.05). By evaluating the GHR genotype, nDel GHD showed a decrease from T0 to T12 in HOMA-IR, HOMAβ, INS (p<0.05) and DI. Del GHD showed a gradual increase in DI (p<0.05) and INS with a stable HOMA-IR and higher HDL-cholesterol (p<0.01).

Conclusions

In not confirmed GHD adolescents the fasting deterioration in glucose homeostasis during rhGH is efficaciously coupled with a compensatory insulin secretion and activity at OGTT. The presence of at least one d3GHR allele is associated with lower glucose levels and higher HOMA-β and DI after rhGH withdrawal. Screening for the d3GHR in the pediatric age may help physicians to follow and phenotype GHD patients also by a metabolic point of view.     

Growth response of Egyptian children with idiopathic short stature during four years of growth hormone therapy

BACKGROUND:

Multiple factors affect the growth response to recombinant human growth hormone (rhGH) in children with idiopathic short stature (ISS).

AIM:

To evaluate the growth responses of children with ISS treated with rhGH, aiming to identify the predictors of growth response.

MATERIALS AND METHODS:

We studied 120 cases, 90 males (75%), with a mean age of 13.8±2.7 years and 30 females (25%), with a mean age of 12.3±2.5 years. All patients received rhGH with a standard dose of 20 IU/m²/week. The calculated dose per week was divided into six days and given subcutaneous at night.

RESULTS:

A significant positive trend was detected in the delta changes of all anthropometric data. For the first year, the growth response was positively correlated to CA and BA delay and negatively correlated to height, weight and IGF-1 SDSs. For the second year, the growth response was correlated positively to first year growth velocity, BA, triceps skin fold thickness SDS and deviation from target height, and negatively correlated to weight, IGFBP3 SDS and target height SDS. For the third year, the growth response was positively correlated to five variables namely target height, 2^nd year growth velocity, IGF-1 SDS, weight SDS and triceps skin fold thickness SDS. For the fourth year, growth response was positively correlated to 2^nd and 3^rd year growth velocity, BA, deviation from target height and weight/ height SDS.

CONCLUSION:

Our study showed multiplicity of predictors that is responsible for response in ISS children treated with rhGH, and BA was an important predictor.