Potent agonists of growth hormone-releasing hormone

Analogs of the 29 amino acid sequence of growth hormone-releasing hormone (GH-RH) with agmatine (Agm) in position 29 have been synthesized by the solid phase method, purified, and tested in vitro and in vivo. The majority of the analogs contained desaminotyrosine (Dat) in position 1, but a few of them had Tyr¹, or N-MeTyr¹. Some peptides contained one or more additional l - or d -amino acid substitutions in positions 2, 12, 15, 21, 27, and/or 28. Compared to the natural sequence of GH-RH(1-29)NH₂, [Dat′,Ala¹⁵]GH-RH(1-28)Agm (MZ-3-191) and [d -Ala²,Ala¹⁵]GH-RH(l-28)Agm (MZ-3-201) were 8.2 and 7.1 times more potent in vitro, respectively. These two peptides contained Met²⁷. Their Nle²⁷ analogs, [Dat^I,Ala¹⁵,Nle²⁷]GH-RH(1-28)Agm(MZ-2-51), prepared previously (9), and [^D-Ala²,Ala¹⁵,Nle²⁸]GH-RH(l-28)Agm(MZ-3-195) showed relative in vitro potencies of 10.5 and 2.4, respectively. These data indicate that replacement of Met²⁷ by Nle²⁷ enhanced the GH-releasing activity of the analog when the molecule contained Dat¹-Ala² residues at the N-terminus, but peptides containing Tyr¹-D-Ala² in addition to Nle²⁷ showed decreased potencies. Replacement of Ser²⁸ with Asp in multi-substituted analogs of GH-RH(l-28)Agm resulted in a decrease in in vitro potencies compared to the parent compound. Thus, the Ser²⁸-containing MZ-2-51, and [Dat¹,Ala¹⁵,d -Lys²¹,Nle²⁷]GH-RH(l-28)Agm, its Asp²⁸ homolog (MZ-3-149), possessed relative activities of 10.5 and 5.6, respectively. In vivo after the iv injection, the analogs [Dat¹,Ala¹⁵,Nle²⁷,Asp²⁸]GH-RH(l-28)Agm (MZ-3-149), [Dat¹, Ala¹⁵]GH-RH(l-28)Agm, (MZ-3-191) and [d -Ala²,Ala^,5]GH-RH(l-28)Agm (MZ-3-201) showed a potency equivalent to 7.6, 4.9 and 3.3 times that of GH-RH(1-29)NH₂, respectively, at 5 min and 20.3, 4.3 and 1.7 times higher, respectively, at 15 min. After sc administration, analogs MZ-3-149, MZ-3-191, and MZ-3-201 were shown to be 63.7, 55.2 and 56.8 times more potent than the parent hormone at 15 min and 57.6, 60.6, and 42.6 times more active, respectively, at 30 min. In addition, MZ-3-149 had prolonged GH-releasing activity as compared to the standard, and proved to be more potent than MZ-2-51, the most active member of our previous series (8, 9). Our studies indicate that very potent GH-RH analogs can result from the combination of agmatine in position 29 with other substitutions.     

Comparison of GH-stimulation by GH-RH(1-29)NH2 and an agmatine29 GH-RH analog,after intravenous,subcutaneous and intranasal administration and after pulmonary inhalation in rats

Many studies have shown that human GH-RH(1-29)NH₂ possesses full intrinsic activity of GH-RH(1-44)NH₂in vitro and in vivo. This investigation was performed to evaluate the efficacy of GH-RH(1-29)NH₂ given by different routes of administration in stimulating GH release in rats. In each case GH-RH(1-29)NH₂ was administered intravenously, subcutaneously, intranasally and by pulmonary inhalation at two different doses to groups of seven male rats. At a dose of 150 μg/kg GH-RH(1-29)NH₂, the magnitude of GH response was significantly higher for the pulmonary inhalation group (355 ± 33.2 ng GH/mL) than for the subcutaneous group (246 ± 36ng GH/mL) or for the intranasal group (175 ± 30ng GH/mL). The group injected intravenously with GH-RH(1-29)NH₂ at a dose of 2.5 μg/kg showed the highest response, GH levels reaching 877.2 ± 115 ng/mL. A similar pattern of responses was obtained for the superactive GH-RH(1-29) agmatine²⁹ analog, MZ–3-149, at doses that were 50 times lower. Our results indicate a high bioavailability of GH-RH(1-29)NH₂ or analog MZ-3-149 administered by a convenient pulmonary inhalation route. The GH-releasing effect of GH-RH(1-29)NH₂ or analog MZ-3-149 delivered by pulmonary inhalation is superior to subcutaneous and intranasal administration.     

Pegylated peptides V. Carboxy-terminal PEGylated analogs of growth hormone-releasing factor (GRF) display enhanced duration of biological activity in vivo

In the present study, human growth hormone-releasing factor (hGRF) and analogs were successfully pegylated at the carboxy-terminus using a novel solid- and solution-phase strategy. Following synthesis, these pegylated hGRF analogs were evaluated for in vitro and in vivo biological activity. Specifically, hGRF(1-29)-NH2, [Ala¹⁵-hGRF(1-29)-NH₂, [desNH₂ 2Tyr1, o-Ala2, Ala15-hGRF(1-29)-NH2 and [His1, Val2, Gin8, Ala15, Leu27-hGRF(1-32)-OH were each C-terminally extended using a Gly-Gly-Cys-NH2 spacer (previously demonstrated not to alter intrinsic biological activity), and then monopegylated via coupling to an activated dithiopyridyl-PEG reagent. PEG moieties of 750, 2000, 5000 or 10000 molecular weight (MW) were examined to determine the effect of polymer weight on activity. Initial biological evaluations in vitro revealed that all C-terminally pegylated hGRF analogs retained high growth hormone (GH)-releasing potencies, regardless of the MW of PEG polymer employed. Two of these pegylated hGRF analogs, [desN₂Tyr, D-Ala², Ala¹⁵-hGRF(1-29)-Gly-Gly-Cys(NH₂)-S-Nle- PEG₅₀₀₀ and [His, Val², Gin⁸, Ala¹⁵, Leu²⁷-hGRF(1-32)-Gly-Cys(NH2)-S-Nle-PEG5000, were subsequently evaluated in both pig and mouse models and found to be highly potent (in vivo potency range = 12-55-fold that of native hGRF). Relative to their non-pegylated counterparts, these two pegylated hGRF analogs exhibited enhanced duration of activity. © Munksgaard 1997.     

Synthesis and biological evaluation of mouse growth hormone-releasing factor

The recently described mouse growth hormone-releasing factor (mGRF) was synthesized by the solid phase procedure, purified by 2 stages of preparative high performance liquid chromatography and fully characterized. The biologic activity of the 42-amino acid peptide (H-His-Val-Asp-Ala-Ile-Phe-Thr-Thr-Asn-Tyr-Arg-Lys-Leu-Leu-Ser-Gln-Leu-Tyr-Ala-Arg-Lys-Val-Ile-Gln-Asp-Ile-Met-Asn-Lys-Gln-Gly-Glu-Arg-Ile-Gln-Glu-Gln-Arg-Ala-Arg-Leu-Ser-OH) was assessed in primary cultures of both mouse and rat anterior pituitary cells and compared to synthetic rat (rGRF) and human (hGRF) growth hormone-releasing factors. mGRF was equipotent to rGRF in mouse somatotrophs but slightly less potent in rat somatotrophs, while hGRF was 3-5 times less potent in both rodent species.     

Agonists of luteinizing hormone-releasing hormone in prostate cancer

Introduction: Androgen deprivation therapy (ADT) has been the first-line standard of care for treating patients with hormone-sensitive advanced prostate cancer (PCa) for many decades. The agonists of luteinizing hormone-releasing hormone (LHRH), also called gonadotropin-releasing hormone, are still the most frequently used form of medical ADT.

Areas covered: This article reviews the available data and most recent information concerning the use of LHRH agonists in advanced PCa. This article also reviews the discovery and development of LHRH agonists and summarizes the clinical evidence for their efficacy in PCa.

Expert opinion: The introduction and application of agonists of LHRH has modernized and improved the treatment of advanced PCa. The life-saving benefits of LHRH agonists are well established, yet underestimated. Despite their efficacy, agonists of LHRH have several disadvantages or drawbacks including disease flare. The approach to ADT has been recently further refined with the development of the LHRH antagonist degarelix. Degarelix, a highly clinically effective third-generation LHRH antagonist, is currently available in most countries for therapy of advanced PCa. This new drug offers attractive alternatives to LHRH agonists for treatment of advanced PCa. A therapy for castration-resistant PCa based on a targeted cytotoxic analog of LHRH, AEZS-108, is also emerging.     

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.     

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.     

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。     

Synthesis of human pancreatic growth hormone-releasing factor and two omission analogs by segment-coupling method in aqueous solution

The human growth hormone-releasing factor (GRF) peptides [GlyS¹⁵]-GRF-(1–15) (IV), trifluoroacetyl-GRF-(20–44) (VI), trifluoroacetyl-GRF-(18–44) (VIII), and trifluoroacetyl-GRF-(16–44) (X) were synthesized by the solid-phase method. Each of the peptides was reacted with citraconic anhydride and the trifluoroacetyl group was removed by reaction with 10% hydrazine in water. The citraconylated GRF-(1–15) peptide was coupled to the (20–44), (18–44) or (16–44) peptides by reaction with silver nitrate/N-hydroxysuccinimide to give GRF-(1–15)-(20–44) (XII), GRF-(1–15)-(18–44) (XIII), or GRF-(1–44), respectively. GRF-(1–44) was shown to stimulate the release of rat growth hormone from rat pituitary cells with an ED₅₀= 8.8 times 10^-11 M. Peptides XII and XIII were inactive, either as agonists or as antagonists of the action of GRF-(1–44).     

Conformational analysis of cyclo(2,9)-Ac-QCRSVEGSCG-OH from the C-terminal loop of human growth hormone

A 10 amino acid residue cyclic peptide, cyclo(2,9)-Ac-Glnl-Cys2-Arg3-Ser4-Val5-Glu6-Gly7-Ser8-Cys9-Glyl0, from the C-terminal region of human growth hormone (hGH) was synthesized and studied by 2D proton NMR and molecular dynamics (MD) simulations. The solubility of the peptide was low in water; hence, NMR studies were done in two solvent mixtures, water and deuterated dimethyl sulfoxide. NOE-constrained molecular dynamics and MD simulations resulted in major and minor conformers in solution. The major conformer has a type I β-turn at Glnl-Cys2-Arg3-Ser4 and a loop structure around Glu6-Gly7-Ser8. Comparison of the conformation of this peptide with the peptide fragment 181-190 in the intact hGH protein X-ray crystal structure indicated that the synthetic peptide retains some structural similarity to the intact protein. Since the C-terminal region is important in binding the hGH protein to its receptor, the conformation of the synthetic peptide could be useful in understanding the binding mechanism. © Munksgaard 1997.     

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     

Degradation of growth hormone releasing factor analogs in neutral aqueous solution is related to deamidation of asparagine residues

The incubation of a solution of the human growth hormone releasing factor analog, [Leu²⁷] hGRF(1-32)NH₂ at pH 7.4 and 37°, resulted in extensive degradation of the sample. The major degradation products were identified as the peptides [β-Asp⁸, Leu²⁷] hGRF(l-32)NH₂ and [α-Asp⁸, Leu²⁷] hGRF(1-32)NH₂, produced by deamidation of the Asn⁸ residue. When tested as growth hormone (GH) secretagogues in cultured bovine anterior pituitary cells, [β-Asp⁸, Leu²⁷] hGRF(l-32)NH₂ was estimated to be 400-500 times less potent than the parent Asn⁸ peptide, while [2-Asp⁸, Leu²⁷] hGRF(l-32)NH₂ was calculated to be 25 times less potent than the parent Asn⁸ peptide. Three additional analogs of [Leu²⁷] hGRF(1-32)NH₂ containing either Ser or Asn at positions 8 and 28 were prepared and evaluated for their GH releasing activity and stability in aqueous phosphate buffer (pH 7.4, 37°). Based on disappearance kinetics, [Leu²⁷] hGRF(1-32)NH₂ had a half-life of 202 h while the other analogs had the following half-lives: [Leu²⁷, Asn²⁸] hGRF(1-32)NH_: (150h); [Ser⁸, Leu²⁷, Asn²⁸] hGRF(l-32)NH₂ (746h); and [Ser⁸, Leu²⁷] hGRF(1-32)NH₂ (1550 h). After 14 days, incubated samples of the Asn⁸ analogs lost GH releasing potency, while the Ser⁸ analogs retained full potency. The potential for loss of biological activity brought about by deamidation of other engineered peptides and proteins should be considered in their design.     

Synthesis and in vitro antioxidant activity of some new fused pyridine analogs

A new series of pyrano[3,2-c]pyridines, pyrazolo[4,3-c]pyridines, and pyrido[4,3-d]pyrimidines were synthesized and screened for their in vitro antioxidant activity. Compounds 13, 14, 15, 23, 29, 30, and 31 exhibited the most active oxygen free-radical scavenger activity with percentage inhibitions of 99.4, 99.6, 99.8, 97.3, 99.0, 99.3, and 99.5%; respectively, which is comparable to the curcumin potency. Most of the tested compounds proved to be safe towards peripheral multinuclear neutrophils (PMNs). The detailed synthesis and antioxidant activity data are reported.     

New analogs of human growth hormone-releasing hormone (1-29) with high and prolonged antagonistic activity

Based on our previous results, in conjunction with various structural considerations, 19 new analogs of the GHRH antagonist [PhAc-Tyr¹,D-Arg²,Phe(pCl)⁶,Abu¹⁵,Nle²⁷,Agm²⁹]hGHRH(1-29) (MZ-5-156) were synthesized by the solid-phase method. These compounds were designed to develop further analogs of this class with increased receptor-binding affinity. All analogs had Abu¹⁵ and Nle²⁷ modifications and were acylated with phenylacetic acid at the N-terminus. Most of the analogs had d -Arg² and Phe(pCl)⁶ substituents and Agm²⁹ or Arg²⁹-NH₂ at the C-terminus. Additional single substitutions consisted of the incorporation of d - or l -Tic¹, d -Tic², Tic⁶ or Phe(pNO₂)⁶ and Arg²⁹-NH₂. The Arg²⁹-NH₂ analog of MZ-5-156 (KT-48) was further modified by single substitutions using Pal¹; d -Tpi²; d - or l -Phe⁴; Phe(pX)⁶×= F, Cl, I; Tyr⁷; Aib⁸; Tyr(Me)¹⁰ or Phe(pCl)¹⁰. Four peptides had multiple substitutions. All the analogs were evaluated for their ability to inhibit GH release induced by hGHRH(1-29)NH₂in vitro and some were also tested in vivo. Peptides [PhAc-Tyr¹,D-Arg²,Phe(pI)⁶,Abu¹⁵,Nle²⁷]hGHRH(1-29)NH₂ (KT-30), [PhAc-Tyr¹,D-Arg²,Phe(pCl)⁶,Aib⁸,Abu¹⁵,Nle²⁷]hGHRH(1-29)NH₂ (KT-50) and [PhAc-Tyr¹,D-Arg²,Phe(pCl)⁶,Tyr(Me)¹⁰,Abu¹⁵,Nle²⁷]hGHRH(1-29)NH₂ (KT-40) with Phe(pI)⁶, Aib⁸ or Tyr(Me)¹⁰modifications, respectively, showed high and prolonged inhibitory effect in superfused rat pituitary system. Analog KT-50 also exhibited a strong and long-term inhibitory activity in vivo in rats. Most of the new analogs showed high binding affinities to rat pituitary GHRH receptors.     

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。     

Synthesis and assay of tyrosinated analogs of a crustacean pigment-dispersing neuropeptide hormone

In an effort to obtain biologically active tyrosine analogs of the octadecapeptide pigment-dispersing hormone (β-PDH) of the fiddler crab Uca pugilator, we have synthesized [Tyr¹⁵]- and [Nle¹⁸]-β-PDH, as well as eight tyrosine analogs of [Nle¹⁵]-β-PDH by the solid-phase method. Each analog was purified to homogeneity by gel filtration, ion-exchange chromatography, and partition chromatography. When tested for melanophore pigment-dispersing activity in destalked Uca, [Nle¹⁵, Tyr¹⁶]-β-PDH and [Nle¹⁵]-β-PDH were found to be 31-fold and 16-fold more potent, respectively, than β-PDH. Somewhat reduced potency was displayed by [N-Tyr,Nle¹⁵]-β-PDH (81%) and [Nle¹⁵, Tyr¹⁷]-β-PDH (26%). All other analogs, including [Nle¹⁵, Tyr¹⁹]-β-PDH and the four derivatives of [Nle¹⁵]-β-PDH obtained through substitution for nonpolar amino acid residues at positions 4, 5, 8, and 11 in the primary structure, showed marked decrease in biological activity (0.01 to 2% potency).     

Synthesis and conformation of constrained peptides with hypoglycaemic activity derived from human growth hormone

The α-aminosuccinimide (Asu¹¹) octapeptide analogue of human growth hormone hGH[6-13] (Leu⁶-Ser-Arg-Leu-Phe-Asu-Asn-Ala¹³) has been reported [Robson et al. (1990) Biol. Chem. Hoppe Seyler 371 , 423-431] to have hypoglycaemic activity whilst the corresponding peptide with Asp at position 11 is inactive. In order to determine whether this change in activity is caused by conformational and/or stereo-electronic effects, the incorporation of two different isomeric γ-lactam structures at position 11 has been investigated. One lactam structure (i) is of the type developed by Freidinger and coworkers [Freidinger et al. (1982) J. Org. Chem. 47 , 102-107], whilst the isomeric γ-lactam structure (ii) represents a new type of constrained synthon for use in peptide synthesis. The chiral type-ii γ-lactam was synthesized via a suitably protected desoxo-dipeptide prepared in several ways from L-aspartic acid. The solution conformations of the [Asu¹¹]- and the [γ-lactam¹¹]-containing hGH[6-13] peptide analogues were investigated with the aid of two-dimensional NMR (COSY and NOESY) spectroscopy. Conformational similarities were found for these hGH[6-13] peptide analogues. For example, for all peptide analogues studied, weak NOEs were evident between the Phelo ring protons and protons of the amino acid residues at the C-terminus. Overall, however, the NOESY NMR spectra of the [Asu¹¹]- and the [γ-lactam¹¹]-containing peptides related to hGH[6-13] suggest the presence of an extended structure in solution with a possible weak type II′β-turn at position 11. The extent of conformational constraint introduced into these hGH[6-13] peptide analogues by substitution of the Asu¹¹ residue with either isomeric γ-lactam structure was reflected as differences in their hypoglycaemic activity. In particular, the hGH[6-13] peptide analogue derived from the new chiral type-ii γ-lactam exhibits both lower activity in intravenous insulin tolerance tests in vivo and weaker NOEs than the isomeric hGH[6-13] peptide analogue derived from the type (i) γ-lactam structure. The relative change in blood glucose levels from 20 to 90 min for the racemic (R,S)-form of the type-ii γ-lactam compared to the control values was approximately half that of the (S)-stereoisomer. © Munksgaard 1994.     

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。     

观察严重烧伤患者应用重组人生长激素时机不同对糖代谢的影响

目的观察严重烧伤患者应用重组人生长激素（rhGH）时机不同对糖代谢的影响。方法选择住院严重烧伤患者65例，随机分为rhGH治疗1组（GH1组）、rhGH治疗2组（GH2组）和对照组。GH1组，从烧伤后48h开始，肌内注射rhGH0．3IU／（kg·d），连续14d；GH2组，从烧伤后第7天开始行rhGH治疗，余同GH1组。对GH1组、GH2组，分别首次用药前及用药后3、7、14、21d检测血糖浓度。与GH1组和GH2组上述指标检测各时相点相对应，检测对照组血糖浓度。结果GH1和GH2两组血糖水平在14d用药期间均明显高于对照组（P〈0．01）；但两组之间用药前及用药后同期相比，血糖差异无统计学意义（P〉0．05）。结论rhGH应用于严重烧伤患者，虽然有明显升高血糖的作用，但其升高程度与应用rhGH时机早晚无明显时效关系。     

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。