The enantiomer of octreotate binds to all five somatostatin receptors with almost equal micromolar affinity--a comparison with SANDOSTATIN

Octreotate (1b) is the octreotide (SANDOSTATIN; 1a) analogue, carrying a C-terminal CO(2)H (Thr) instead of the CH(2)OH (threoninol) group. In pursuit of our interest in unnatural peptides, we have now synthesized (by the solid-phase Fmoc method) the enantiomeric form 2 of octreotate and determined its affinity for the five human somatostatin (SRIF) receptors (hsst(1-5)). The binding was found to be 9.1, 4.1, 1.0, 1.4, and 4.2 microM, respectively. This almost equal one-digit micromolar affinity of ent-octreotate (2) to all five receptors contrasts with the behavior of most other somatostatin mimics including SANDOSTATIN (octreotide; 1a) and [Tyr(3)]-octreotate (1c), which have affinities for the various receptors differing up to and above 10(4)-fold. Thus, the structure of the new compound does not prevent binding, albeit more weakly than its pseudo-enantiomer octreotide, and there is hardly any selectivity of the peptide-protein interaction (PPI) for any one of the five SRIF G-protein coupled receptors (GPCRs). Since the detailed structure(s) of these membrane-embedded receptors is unknown (no X-ray structure!), the result described here may be useful for modeling structures by comparing the affinities of the numerous known somatostatin mimics.     

加贝酯联合奥曲肽对急性胰腺炎患者胃肠功能、免疫功能及炎性因子水平的影响

目的:探讨加贝酯联合奥曲肽对急性胰腺炎(AP)患者胃肠功能、血清炎性因子及免疫功能的影响。方法:选取2014年1月到2018年6月在我院接受治疗的AP患者100例,采用随机数字表法将所有患者分为对照组和观察组各50例。对照组给予注射用醋酸奥曲肽治疗,观察组在对照组的基础上给予注射用甲磺酸加贝酯治疗。对比两组患者治疗后临床疗效、胃肠功能恢复情况、血清炎性因子水平及免疫球蛋白lgG、lgM、lgA的变化情况。结果:治疗后观察组总有效率为83.24%,高于对照组的67.03%(P0.05)。治疗后观察组排气恢复时间、排便恢复时间、肠鸣音消失时间、腹胀缓解时间、腹痛缓解时间均显著短于对照组(P0.05)。治疗后两组肿瘤坏死因子-α(TNF-α)、C反应蛋白(CRP)、白细胞介素-6(IL-6)及白细胞介素-8(IL-8)水平较治疗前均明显下降(P0.05),且治疗后观察组的TNF-α、CRP、IL-6及IL-8水平低于对照组(P0.05)。治疗后两组的lgG、lgM、lgA水平均较治疗前均明显升高(P0.05),治疗后观察组的lgG、lgM水平高于对照组(P0.05)。结论:加贝酯联合奥曲肽治疗AP不仅能够有效抑制患者的炎症反应,改善其免疫功能,还能够促进患者胃肠功能恢复,提高临床疗效。     

奥曲肽辅助十二指肠镜治疗急性水肿型胆源性胰腺炎疗效及对炎症反应的影响

目的:探讨奥曲肽辅助十二指肠镜治疗急性水肿型胆源性胰腺炎疗效及对炎症反应的影响。方法:选择急性水肿型胆源性胰腺炎患者100例,随机分为研究组与对照组各50例,两组患者均给予禁食、抗感染、营养支持、酶抑制剂治疗,对照组同期给予十二指肠镜治疗,研究组同期给予奥曲肽辅助十二指肠镜治疗,比较两组腹痛缓解时间,白细胞(WBC)、体温恢复正常时间,治疗前(T0)、治疗3d(T1)、治疗7d(T2)血、尿淀粉酶水平与炎症因子CRP、IL-6、TNF-α水平的变化。结果:(1)研究组腹痛缓解时间、WBC、体温恢复正常时间均较对照组明显缩短(P0.05);(2)两组患者T1、T2血、尿淀粉酶水平均较T0明显降低,且T2血、尿淀粉酶水平低于T1(P0.05),研究组T1、T2血、尿淀粉酶水平均低于对照组(P0.05);(3)两组T1、T2血清CRP、IL-6、TNF-α水平均较T0明显降低,且T2低于T1(P0.05),研究组T1、T2时血清CRP、IL-6、TNF-α水平均低于对照组(P0.05)。结论:奥曲肽辅助十二指肠镜治疗急性水肿型胆源性胰腺炎可提高早期治疗效果,减轻炎症反应。     

Synthesis and in vitro evaluation of [18F]fluoroethyl triazole labelled [Tyr3]octreotate analogues using click chemistry

A novel class of alkyne linked [Tyr³]octreotate analogues have been labelled by a copper catalysed azide-alkyne cycloaddition reaction (CuAAC) to form a 1,4-substituted triazole using the reagent [¹⁸F]2-fluoroethyl azide. An unexpected variability in reactivity during the CuAAC reaction was observed for each alkyne analogue which has been investigated. Two lead alkyne linked [Tyr³]octreotate analogues, G-TOCA (3a) and βAG-TOCA (5a) have been identified to be highly reactive in the click reaction showing complete conversion to the [¹⁸F]2-fluoroethyl triazole linked [Tyr³]octreotate analogues FET-G-TOCA (3b) and FET-βAG-TOCA (5b) under mild conditions and with short synthesis times (5 min at 20 °C). As well as ease of synthesis, in vitro binding to the pancreatic tumour AR42J cells showed that both FET-G-TOCA and FET-βAG-TOCA have high affinity for the somatostatin receptor with IC₅₀ of 4.0 ± 1.4, and 1.6 ± 0.2 nM, respectively.     

应用奥曲肽预防胰十二指肠切除术后胰漏作用的研究

目的：预防性使用奥曲肽是否能减少胰十二指肠切除术后胰漏发生率存在着争议。本研究旨在研究奥曲肽在不同胰腺情况下预防胰十二指肠切除术后胰漏发生的作用。方法：本研究将＂软胰腺＂、＂细胰管＂作为术后胰漏发生的高危险因素,将184例胰十二指肠切除术病例分为4组：低危险/非奥曲肽组、低危险/奥曲肽组、高危险/非奥曲肽组、高危险/奥曲肽组。观察术后胰漏等术后并发症情况。结果：共发生术后胰漏35例（19%）,其中高危险组胰漏发生率是低危险组2倍以上（27%versus 10%,P〈0.01）。在胰漏发生低危险胰腺情况下,奥曲肽组与非奥曲肽组术后胰漏发生无显著差别;在胰漏发生高危险胰腺情况下,奥曲肽能显著降低术后胰漏发生率。结论：在胰十二指肠切除术围手术期应根据胰腺的具体情况选择性使用奥曲肽既能有效预防术后胰漏的发生,又能避免不必要的浪费。     

内镜套扎术联合奥美拉唑、奥曲肽治疗食管静脉曲张出血的疗效及安全性

目的:探究内镜套扎术联合奥美拉唑、奥曲肽治疗食管静脉曲张出血的疗效及安全性。方法:选取2014年5月至2016年5月于我院诊治的肝硬化合并食管静脉曲张出血患者127例,分为研究组和对照组。对照组在常规治疗的基础上予以奥美拉唑和奥曲肽治疗,研究组则在对照组基础上予以内镜下食管静脉曲张套扎术(EVL)治疗。分析比较两组患者的临床疗效、住院情况、不良反应的发生情况及治疗后再出血率。结果:研究组所有患者的均成功完成手术,未出现大出血情况,对照组有10例患者表现为呕血和黑便,其中1例患者转为手术治疗。治疗后,研究组的临床总有效率显著高于对照组(P0.05)。治疗期间,研究组的止血时间、输血量、住院天数和住院费用均显著少于对照组(P0.05),研究组和对照组分别有10例和7例患者出现了恶心呕吐、食管异物感、头昏、心悸、腹痛腹胀、大便次数增多和发热等不良反应,其中对照组的大便次数增多的发生率显著高于研究组(P0.05),而其余不良反应发生率和不良反应总发生率比较差异无统计学意义。治疗后1年随访时间内,无死亡患者,研究组在第0.5、1、3、6、12个月的再出血率均显著低于对照组(P0.05)。结论:内镜套扎术联合奥美拉唑、奥曲肽治疗食管静脉曲张出血的临床疗效明显,能够有效、快速止血,缩短住院天数,降低住院费用和再出血率,且安全性高。     

Chromogranin A as a determinant of midgut carcinoid tumour volume

Neuroendocrine (NE) tumours are characterized by their capacity to synthesize, store and release hormonal products. These substances are stored in neurosecretory vesicles together with chromogranin A (CgA). The concentration of plasma CgA in patients with NE tumours is thought to reflect the degree of NE differentiation, total tumour burden and effect of medical treatment. The aim of this study was to analyse the correlation between tumour weight and plasma CgA levels as well as the influence of treatment with a long-acting somatostatin analogue (octreotide) using nude mice with xenografted human ileal carcinoid tumours. There was a correlation between tumour weight and plasma CgA levels in all animals (p<0.00001). In octreotide-treated mice, plasma CgA levels were significantly reduced versus untreated animals (p=0.037).

In conclusion, this study demonstrates that plasma CgA levels are closely correlated to tumour burden, and that plasma CgA is well suited for monitoring the clinical course and outcome of treatment in patients with NE tumours.     

Radioiodine and 211At-labeled guanidinomethyl halobenzoyl octreotate conjugates: potential peptide radiotherapeutics for somatostatin receptor-positive cancers

Derivatives of the somatostatin analogues octreotide and octreotate labeled with radioiosotopes are used in the diagnosis and therapy of somatostatin receptor (SSTR)-positive tumors. A method has been devised to synthesize {N-(4-guanidinomethyl-3-iodobenzoyl)-Phe1-octreotate (GMIBO). Receptor binding assay and scatchard analysis yielded a Kd of 4.83 +/- 0.19 nM for this peptide. Derivatives of this peptide labeled with radioiodine ([*I]GMIBO) and the alpha-particle-emitting radiohalogen 211At N-(3-[211At]astato-4-guanidinomethylbenzoyl)-Phe1-octreotate; [211At]AGMBO} were prepared in a single step from a tin precursor in radiochemical yields of 30-35% and 15-20%, respectively. Paired-label internalization assays performed with the SSTR-positive D341 Med human medulloblastoma cell line demonstrated that [125I]GMIBO and [211At]AGMBO were specifically internalized 20-40% more than Nalpha-(1-deoxy-D-fructosyl)-[131I]I-Tyr3-octreotate ([131I]I-Glu-TOCA), the radioiodinated octreotide derivative previously shown to exhibit maximum internalization in this cell line. Uptake of [131I]GMIBO in D341 Med subcutaneous xenografts in a murine model (8.34 +/- 1.82 versus 8.10 +/- 2.23% ID/g at 1h) and SSTR-expressing normal tissues was comparable to that of [125I]I-Glu-TOCA and was shown to be specific. However, the uptake of [131I]GMIBO also was substantially higher in liver (16.9 +/- 3.15 versus 1.39 +/- 0.45% ID/g at 1 h) and in kidneys (44.33 +/- 6.47 versus 3.44 +/- 0.68% ID/g at 1h) compared to that of [125I]I-Glu-TOCA. These data suggest that these novel peptide conjugates retain their specificity for SSTR both in vitro and in vivo; however, because of their higher accumulation in normal tissues they would be best applied in settings amenable to loco-regional administration such as medulloblastoma neoplastic meningitis.     

Evaluation of astatine-211-labeled octreotide as a potential radiotherapeutic agent for NSCLC treatment

Octreotide is a somatostatin (SST) analogue currently used in the treatment of neuroendocrine tumors (NETs) with high binding affinity for the somatostatin receptor-2 (SSTR2) that is also overexpressed in non-small cell lung cancer cell (NSCLC). Alpha-particle-emitting astatine-211 (²¹¹At) is a promising radionuclide with appropriate physical and chemical properties for use in targeted anticancer therapies. To obtain an additional pharmacological agent for the treatment of NSCLC, we present the first investigation of the possible use of ²¹¹At-labeled octreotide as a potential alpha-radionuclide therapeutic agent for NSCLC treatment. ²¹¹At-SPC-octreotide exhibited observable higher uptake in lung, spleen, stomach and intestines than in other tissues. Through histological examination, ²¹¹At-SPC-octreotide demonstrated much more lethal effect than control groups (PBS, octreotide and free ²¹¹At). These promising preclinical results suggested that ²¹¹At labeled octreotide deserved to be further developed as a new anticancer agent for NSCLC.