加替沙星一聚癸二酸酐局部缓释系统的生物相容性

背景：聚酸酐材料具有表面溶蚀性、生物可降解性和释药速率可调性,已被美国食品和药物管理局批准用于人体药物缓释材料。目的：研究加替沙星-聚癸二酸酐局部缓释系统的制备及生物相容性。方法：采用熔融缩聚的方法制备聚癸二酸酐,将加替沙星与聚癸二酸酐充分混合,制成载药量20％的加替沙星一聚癸二酸酐局部缓释药棒。切开6只新西兰大耳白兔背部皮肤,随机分组：实验组在脊柱两旁椎旁肌肌袋内植入聚癸二酸酐棒,对照组未植入任何材料。术后第5周取材,观察皮下组织和肌肉组织变化,以及心、肝、肾及肺的变化。结果与结论：聚癸二酸酐生物相容性良好,植入期间兔未出现任何食欲和行为改变,植入部位未见明显红肿、出血及糜烂,植入材料表面呈多孔状,表明材料在皮下已发生降解吸收,但未发生脆裂和崩解,与周围组织形成轻微粘连;兔肝、肾、肺、心组织结构未发生改变。表明加替沙星-聚癸二酸酐局部缓释制剂无毒、无致畸作用,组织相容性好。     

局部植入抗生素系统在家兔体内的释药特性

局部植入抗生素系统的制备:将加替沙星与自制聚[1,3-双(对羧基苯氧基)丙烷-癸二酸](P(CPP-SA)),按2∶8于玛瑙研钵内充分混合,加入自制模具内,制成(140±1)mg大小药棒。将药棒植入家兔骨髓腔内,分别于术后1,3,5,8,10,20,30,40,60,80d取血和骨组织,用高效液相色谱法测定家兔骨与血液内加替沙星药物质量浓度。结果表明,骨组织内加替沙星质量浓度明显高于血药浓度,在术后80d时仍明显高于加替沙星对金葡菌的最小抑菌浓度0.1mg/L。可见聚[1,3-双(对羧基苯氧基)丙烷-癸二酸]-加替沙星缓释药棒缓释效果好,并且持续时间长。     

加替沙星-聚癸二酸酐局部缓释系统预防兔骨髓炎

背景：聚酸酐材料具有表面溶蚀性、生物可降解性和释药速率可调性,为人体药物缓释材料,但关于聚癸二酸酐缓释系统的应用至今少有报道。 目的：观察加替沙星-聚癸二酸酐局部缓释系统对兔股骨骨髓炎感染模型的预防作用。 方法：按 Norden法将30只兔制作股骨金黄色葡萄球菌骨髓炎兔模型,分别用加替沙星-聚癸二酸酐缓释制剂和加替沙星进行干预,并与模型组作对照,共分3组,每组10只,观察建模后兔一般情况、解剖学观察、X射线片表现、骨培养及细菌计数、组织学检查。 结果与结论：建模后8周,模型组兔建模后,食欲差,皮毛不光滑,体质量减轻,3只兔于3周内死亡,其他7只X射线片上骨膜反应较重,可见小块死骨形成,解剖学检查均可见脓肿形成,骨培养及组织学检查均可见骨髓炎表现;加替沙星组建模后体质量减轻,2只兔于建模后3周内死亡,解剖学检查可见有4只动物有脓肿形成,X射线片上可见8只动物骨膜反应较轻,未见死骨形成,骨培养及组织学检查6只兔有骨髓炎表现;加替沙星-聚癸二酸酐缓释制剂治疗组兔一般情况好,解剖学检查未见异常,X射线片检查、骨培养和细菌计数、组织学检查均未见骨髓炎表现。结果证实,加替沙星-聚癸二酸酐局部缓释制剂预防股骨骨髓炎感染效果较好。     

骨组织工程诱导性支架材料修复骨缺损

背景:前期实验中发现载淫羊藿苷壳聚糖/胶原/聚己内酯/羟基磷灰石复合支架具有良好的物理和化学性质。目的:研究载淫羊藿苷壳聚糖/胶原/聚己内酯/羟基磷灰石复合支架修复兔胫骨平台骨缺损的效果。方法:利用静电纺丝技术制备胶原/聚己内酯/羟基磷灰石复合支架壳层,真空干燥法制备载淫羊藿苷壳聚糖微球/胶原支架芯层,将芯层嵌入壳层后利用京尼平交联构建载药复合支架。将载淫羊藿苷壳聚糖微球置入PBS中,观察药物缓释效果。将载药复合支架与大鼠骨髓间充质干细胞共培养7 d,观察细胞黏附效果。取青紫蓝兔15只,复制兔左侧胫骨缺损模型,随机分为3组,实验组于骨缺损处植入载药复合支架,对照组植入胶原/聚己内酯/羟基磷灰石复合支架,空白对照组不植入任何材料。术后4,12,24周行X射线观察、样本大体和组织学观察。结果与结论:载药复合支架具有疏松多孔结构,利于骨髓间充质干细胞的黏附、增殖;壳聚糖微球体外缓释在72 h内保持19%释放量的良好缓释效果。术后24周,实验组材料完全被新生骨组织覆盖,硬度与正常骨相近,苏木精-伊红染色观察发现有骨小梁、骨细胞和成骨细胞,但缺损区骨密度低于正常骨组织;对照组材料被纤维组织包裹,苏木精-伊红染色显示有骨小梁、骨髓细胞和纤维组织;空白对照组呈凹陷愈合,但硬度低于正常骨组织,苏木精-伊红染色可见大量骨髓细胞和骨小梁。结果表明载药壳聚糖/胶原/聚己内酯/羟基磷灰石复合支架能有效修复兔骨缺损。     

缓释双药物载体制备与性能

背景：骨结核患者常规用药,病灶处结核药物的有效浓度低,治疗效果差。目的：制备一种可直接植入骨结核病灶内的,且具有在骨结核周围组织能够长期保持一定的抗结核药物浓度,起到提高骨结核的治愈率有效治疗的新型生物材料。方法：采用乳剂-溶剂挥发法制备利福平-聚乳酸-羟基乙酸共聚物微球和异烟肼-聚乳酸-羟基乙酸共聚物微球,利用生物黏合剂α-氰基丙烯酸烷基酯将2种微球加工成长效缓释双组分药物载体,观察缓释双药物载体体外释药特性;然后将缓释双药物载体置入兔股骨转子间骨缺损部位,观察载药缓释载体植入后不同时间点药物释放浓度、组织相容性及骨缺损的愈合情况。结果与结论：利福平-聚乳酸-羟基乙酸微球平均粒径（240±13）μm,载药率为（26±1.5）%。异烟肼-聚乳酸-羟基乙酸微球平均粒径（250±10）μm,载药率为（28±1.8）%。利福平、异烟肼,90 d体外累积释放率可达到80%和90%。90 d体内释放利福平和异烟肼的浓度可达（0.5±0.4）和（0.6±0.3）μg/g。缓释双药物载体置入兔股骨转子间骨缺损部位可见筋膜、肌纤维之间出现少量中性粒细胞浸润,59 d 后肌肉组织中性粒细胞明显减少,X射线平片显示骨缺损明显缩小。提示该载体能够长时间保持骨结核周围组织中一定的药物浓度,弥补血中药物浓度不足,有望在骨结核手术治疗中提供一种新型的双药物缓释载体。     

缓释双药物载体制备与性能*

背景：骨结核患者常规用药,病灶处结核药物的有效浓度低,治疗效果差。目的：制备一种可直接植入骨结核病灶内的,且具有在骨结核周围组织能够长期保持一定的抗结核药物浓度,起到提高骨结核的治愈率有效治疗的新型生物材料。方法：采用乳剂-溶剂挥发法制备利福平-聚乳酸-羟基乙酸共聚物微球和异烟肼-聚乳酸-羟基乙酸共聚物微球,利用生物黏合剂α-氰基丙烯酸烷基酯将2种微球加工成长效缓释双组分药物载体,观察缓释双药物载体体外释药特性;然后将缓释双药物载体置入兔股骨转子间骨缺损部位,观察载药缓释载体植入后不同时间点药物释放浓度、组织相容性及骨缺损的愈合情况。结果与结论：利福平-聚乳酸-羟基乙酸微球平均粒径(240±13)μm,载药率为(26±1.5)%。异烟肼-聚乳酸-羟基乙酸微球平均粒径(250±10)μm,载药率为(28±1.8)%。利福平、异烟肼,90 d体外累积释放率可达到80%和90%。90 d体内释放利福平和异烟肼的浓度可达(0.5±0.4)和(0.6±0.3)μg/g。缓释双药物载体置入兔股骨转子间骨缺损部位可见筋膜、肌纤维之间出现少量中性粒细胞浸润,59 d 后肌肉组织中性粒细胞明显减少,X射线平片显示骨缺损明显缩小。提示该载体能够长时间保持骨结核周围组织中一定的药物浓度,弥补血中药物浓度不足,有望在骨结核手术治疗中提供一种新型的双药物缓释载体。     

血管内皮生长因子缓释系统复合成骨诱导的骨髓间质干细胞修复骨缺损

背景：从目前文献报道来看,生长因子缓释系统在骨科方面的应用研究主要集中在软骨修复方面,关于复合组织工程骨修复骨缺损的研究报道较少。目的：构建复合组织工程骨,观察其修复骨缺损的效果。方法：①通过血管内皮生长因子、肝素和纤维蛋白胶的不同组合构建复合支架缓释系统,经检测选取最优组种植成骨诱导的骨髓间质干细胞构建复合组织工程骨。②36只SD大鼠制备股骨干骨缺损模型后随机分为3组,分别植入上述复合组织工程骨和复合支架缓释系统,空白对照组不植入任何材料,3组均予内固定。③ELISA方法检测样本释放的血管内皮生长因子浓度以评价复合支架缓释系统的缓释性能;于植入后1,4,12,24周行X射线检查及骨组织碱性磷酸酶染色评价各组动物骨缺损修复水平。结果与结论：经血管内皮生长因子/肝素/纤维蛋白修饰的纳米晶胶原基骨复合支架缓释系统在体外环境缓释30d后依然高浓度释放血管内皮生长因子,且缓释曲线平直;动物实验中植入的复合组织工程骨在24周内完全降解,骨缺损修复完成,骨缺损部位碱性磷酸酶活性明显高于复合支架缓释系统组、空白对照组。结果显示该复合支架缓释系统具有优异的缓释性能,在该缓释系统上种植成骨诱导的骨髓间充质干细胞后,能够提高骨缺损修复的速度和质量。     

全反式维甲酸-聚酸酐长效缓释剂研制及其可行性

背景：如何提高全反式维甲酸疗效、稳定性和降低毒副作用是临床治疗所面临的最大问题。近年来用可生物降解的聚合物为材料,通过乳化包囊等分散技术将药物制备成微粒分散体系,用作缓释、控释注射剂的研究日益增多。目的：研制全反式维甲酸-聚酸酐长效缓释微球肿瘤治疗剂,观察其体内外全反式维甲酸经时缓释变化规律。方法：采用乳剂-扩散溶剂挥发法制备全反式维甲酸-聚酸酐长效缓释微球肿瘤治疗剂,扫描电镜检测微球外观及微球粒径,高效液相色谱法检测微球载药量、包封率及体内外释药量。结果与结论：所制微球治疗剂光滑圆整,大小均一,平均粒径（154.42±26.76）nm,载药率（16.5±1.45）%,包封率（87.84±4.79）%;体外释放实验证明该微球治疗剂可持续释放全反式维甲酸约50d,将其肌肉注射到大耳白兔体内,可稳定缓释全反式维甲酸近45d。结果表明该微球治疗剂载药量及包封率均较高,体内外释药平稳并且具有明显的长效缓释作用。     

聚酸酐-吡柔比星长效植入剂在动物模型体内的抑瘤活性

背景:实验证明聚酸酐-吡柔比星植入剂可长时间保持体内血药浓度相对恒定。目的:观察聚酸酐-吡柔比星植入剂在膀胱肿瘤大鼠体内的抑瘤作用。方法:通过N-正丁基-N-(4-羟基-丁基)亚硝胺喂饲构建SD大鼠膀胱癌模型,随机分为实验组与对照组,分别将聚酸酐-吡柔比星植入剂和相同剂量吡柔比星植入模型动物体内膀胱黏膜下,用高效液相色谱仪检测动物体内吡柔比星血药浓度及肿瘤大小变化。结果与结论:实验组吡柔比星在释放过程中无突释效应,基本满足长效局部植入剂应用于膀胱癌治疗的基本要求,可持续释放80d以上;对照组吡柔比星浓度开始明显升高,5d后迅速降低,不能维持有效治疗浓度1.0-3.0mg/L。植入后30d,实验组肿瘤体积较植入前明显缩小,抑瘤率高于对照组(P<0.05),且实验组动物平均存活期长于对照组(P<0.05)。     

血管内皮生长因子缓释系统复合成骨诱导的骨髓间质干细胞修复骨缺损

背景:从目前文献报道来看,生长因子缓释系统在骨科方面的应用研究主要集中在软骨修复方面,关于复合组织工程骨修复骨缺损的研究报道较少。目的:构建复合组织工程骨,观察其修复骨缺损的效果。方法:①通过血管内皮生长因子、肝素和纤维蛋白胶的不同组合构建复合支架缓释系统,经检测选取最优组种植成骨诱导的骨髓间质干细胞构建复合组织工程骨。②36只SD大鼠制备股骨干骨缺损模型后随机分为3组,分别植入上述复合组织工程骨和复合支架缓释系统,空白对照组不植入任何材料,3组均予内固定。③ELISA方法检测样本释放的血管内皮生长因子浓度以评价复合支架缓释系统的缓释性能;于植入后1,4,12,24周行X射线检查及骨组织碱性磷酸酶染色评价各组动物骨缺损修复水平。结果与结论:经血管内皮生长因子/肝素/纤维蛋白修饰的纳米晶胶原基骨复合支架缓释系统在体外环境缓释30d后依然高浓度释放血管内皮生长因子,且缓释曲线平直;动物实验中植入的复合组织工程骨在24周内完全降解,骨缺损修复完成,骨缺损部位碱性磷酸酶活性明显高于复合支架缓释系统组、空白对照组。结果显示该复合支架缓释系统具有优异的缓释性能,在该缓释系统上种植成骨诱导的骨髓间充质干细胞后,能够提高骨缺损修复的速度和质量。     

A collagen cardiac patch incorporating alginate microparticles permits the controlled release of hepatocyte growth factor and insulin‐like growth factor‐1 to enhance cardiac stem cell migration and proliferation

Cardiac stem cells (CSCs) represent a logical cell type to exploit as a regenerative treatment option for tissue damage accrued as a result of a myocardial infarction. However, the isolation and expansion of CSCs prior to cell transplantation is time consuming, costly and invasive, and the reliability of cell expansion may also prove to be a major obstacle in the clinical application of CSC‐based transplantation therapy after a myocardial infarction. In order to overcome this, we propose the incorporation of growth factor‐eluting alginate microparticles into collagen‐based scaffolds as an implantable biomaterial to promote the recruitment and expansion of CSCs in the myocardium. In order to obtain scaffolds able to enhance the motogenic and proliferative potential of CSCs, the aim of this work was to achieve a sustained delivery of both hepatocyte growth factor and insulin‐like growth factor‐1. Both proteins were initially encapsulated in alginate microparticles by spray drying and subsequently incorporated into a collagen scaffold. Microparticles were seen to homogeneously distribute through the interconnected scaffold pore structure. The resulting scaffolds were capable of extending the release of both proteins up to 15 days, a three‐fold increase over non‐encapsulated proteins embedded in the scaffolds. In vitro assays with isolated CSCs demonstrated that the sustained release of both bioactive proteins resulted in an increased motogenic and proliferative effect. As presently practiced, the isolation and expansion of CSCs for autologous cell transplantation is slow, expensive and difficult to attain. Thus, there is a need for strategies to specifically activate in situ the intrinsic cardiac regenerative potential represented by the CSCs using combinations of growth factors obviating the need for cell transplantation. By favouring the natural regenerative capability of CSCs, it is hypothesized that the cardiac patch presented here will result in positive therapeutic outcomes in MI and heart failure patients in the future. Copyright © 2016 John Wiley & Sons, Ltd.     

Bone morphogenetic protein‐2 release profile modulates bone formation in phosphorylated hydrogel

The optimal release profile of locally delivered bone morphogenetic protein‐2 (BMP‐2) for safe and effective clinical application is unknown. In this work, the effect of differential BMP‐2 release on bone formation was investigated using a novel biomaterial oligo[(polyethylene glycol) fumarate] bis[2‐(methacryloyloxy) ethyl] phosphate hydrogel (OPF‐BP) containing poly(lactic‐co‐glycolic acid) microspheres. Three composite implants with the same biomaterial chemistry and structure but different BMP‐loading methods were created: BMP‐2 encapsulated in microspheres (OPF‐BP‐Msp), BMP‐2 encapsulated in microspheres and adsorbed on the phosphorylated hydrogel (OPF‐BP‐Cmb), and BMP‐2 adsorbed on the phosphorylated hydrogel (OPF‐BP‐Ads). These composites were compared with the clinically used BMP‐2 carrier, Infuse® absorbable collagen sponge (ACS). Differential release profiles of bioactive BMP‐2 were achieved by these composites. In a rat subcutaneous implantation model, OPF‐BP‐Ads and ACS generated a large BMP‐2 burst release (>75%), whereas a more sustained release was seen for OPF‐BP‐Msp and OPF‐BP‐Cmb (~25% and 50% burst, respectively). OPF‐BP‐Ads generated significantly more bone than did all other composites, and the bone formation was 12‐fold higher than that of the clinically used ACS. Overall, this study clearly shows that BMP‐2 burst release generates more subcutaneous bone than do sustained release in OPF‐BP‐microsphere composites. Furthermore, composites should not only function as a delivery vehicle but also provide a proper framework to achieve appropriate bone formation.     

Histamine release from leucocytes during migraine attack

Spontaneous histamine release (SHR) from leucocytes (basophils) of 27 migraine patients was investigated during various phases of attack. Mean SHR during the first 3 h of attack (33.7%) was increased compared with the mean SHR from leucocytes of healthy persons (15.9%), but differed insignificantly from the mean SHR in symptom-free periods. Histamine release (HR) from leucocytes of healthy persons suspended in migraine sera from different time-periods of attack was also increased compared with HR in control sera, i.e. high HR could be induced by passive transfer of serum. But the mean HRs in sera from different time-periods of attack were insignificantly different from the mean HR in sera from symptom-free periods. The increased SHR may contribute to vascular hyperreactivity in migraine.     

美斯地浓聚乳酸载药纳米粒的制备及体外释放

背景：美斯地浓临床常用于治疗重症肌无力,但其水溶性较强,半衰期短,生物利用度低,给药频率高,患者依从性差,因此提高其缓释作用对临床应用有蕈要意义。目的：制备美斯地浓聚乳酸纳米粒,并考察其体外释放性能。方法：以聚乳酸为载药材料,采用复乳液中干燥法制备美斯地浓聚乳酸纳米粒,运用单因素实验设计优化处方,动态透析法进行体外药物释放实验。结果与结论：确定以二氯甲烷作为油相制备纳米粒,内水相与油相的比例1：10,聚乳酸浓度6％,外水相聚乙烯醇浓度3％,美斯地浓投药量40mg为最佳制备工艺,此条件制备的药物纳米粒包封率和载药率分别为（67．59±1．46）％和（4．31±0．17）％。美斯地浓聚乳酸纳米粒的平均粒径为937nm,圆球形,表面光滑,未观察到粘连现象。与美斯地浓游离药物相比,美斯地浓聚乳酸纳米粒存在突释现象,之后呈现缓慢释放特性,72h释放量为57．03％,提示成功制备美斯地浓聚乳酸纳米粒,具有缓释效应。     

Histamine release from leucocytes in migraine

The spontaneous histamine release (SHR) from leucocytes in migraine patients during symptom-free periods has been investigated, and also the influence of migraine sufferer serum on histamine release (HR) from blood donor leucocytes. The leucocytes were isolated according to the Day method and histamine assay was made by the Shore spectrofluorometric method modified by Bergendorff and Uvnäs (1). SHR in the 17 female migraine patients was significantly higher (39.7% ± 13.1%) than in 8 controls (25.4% ± 4.2%). Migraine serum increased HR from blood donor leucocytes by 14.6% ± 20.2% compared with the SHR of these cells.     

几种常见牙周致病菌对羧甲基壳聚糖的降解效应

背景：近年来,羧甲基壳聚糖的体内降解已成为牙周组织工程和材料学领域中的研究热点,但在涉及羧甲基壳聚糖酶解的文献中,尚未找到关于牙周致病菌能够产酶降解羧甲基壳聚糖的报道。
　　目的：研究几种常见牙周致病菌对羧甲基壳聚糖的降解作用。
　　方法：制备质量分数1%和2%的羧甲基壳聚糖厌氧微生物培养基。采用透明圈法,分别挑取牙龈卟啉单胞菌、伴放线放线杆菌和黏性放线菌菌落划线接种于羧甲基壳聚糖厌氧微生物培养基中,置于厌氧培养袋中37℃恒温培养,观察结果,如果菌落周围出现明显的透明圈,即为阳性,说明细菌能够分解羧甲基壳聚糖,反之则为阴性,并测量菌落直径。
　　结果与结论：牙龈卟啉单胞菌在1%羧甲基壳聚糖厌氧微生物培养基上生长良好,培养18 d后菌落周围出现明显的透明圈;在2%羧甲基壳聚糖培养基上,牙龈卟啉单胞菌的生长受到抑制,未形成形态规则的菌落;伴放线放线杆菌和黏性放线菌在两种质量分数羧甲基壳聚糖厌氧微生物培养基中,菌落周围均未出现透明圈,培养2周后菌落干枯失去活性。提示牙龈卟啉单胞菌可降解较低质量分数的羧甲基壳聚糖,伴放线放线杆菌和黏性放线菌均不能降解羧甲基壳聚糖。     

Diffusion-controlled drug delivery systems: calculation of the required composition to achieve desired release profiles

The aim of this study was to investigate the effect of the composition of diffusion-controlled release devices (type and amount of plasticizer, type of polymer) on the drug diffusivity and the resulting release kinetics in a quantitative way. Diltiazem hydrochloride and theophylline were investigated in ethyl cellulose (EC) and Eudragit^® RS 100, plasticized with various amounts of acetyltributyl citrate (ATBC), acetyltriethyl citrate (ATEC), dibutyl phthalate (DBP), dibutyl sebacate (DBS), diethyl phthalate (DEP), and tributyl citrate (TBC). Thin drug-containing films (monolithic solutions) were used to determine the diffusion coefficients experimentally. The effect of the type and amount of plasticizer on the drug diffusivity was found to be significant, whereas the chain length of the polymer only played a minor rule in the investigated systems. Interestingly, a quantitative relationship between the diffusion coefficient of the drug and the plasticizer level could be established. Based on these results, the release kinetics of diffusion-controlled drug delivery systems could be predicted. In this study, the release patterns from microparticles were calculated and the significant effect of the composition of the device on the resulting release rate was simulated. The latter could be effectively modified by varying the type and amount of plasticizer. Independent experiments verified the theoretical predictions. The practical benefit of the presented method is to calculate the required composition of diffusion-controlled drug delivery systems (monolithic solutions) to achieve desired release profiles.     

Platelet noradrenaline release in patients with familial hypercholesterolaemia

We have examined resting and thrombin (0.3 units ml-1) induced release of noradrenaline by washed platelets from 15 normal subjects and eight patients with heterozygous familial hypercholesterolaemia. Platelets from both normal and hypercholesterolaemic subjects showed irreversible aggregation with 0.3 units ml-1 thrombin. Extents of aggregation were 76.3% and 90.8% respectively, platelets from hypercholesterolaemic patients being significantly more sensitive (P less than 0.002). Under resting conditions platelet noradrenaline release was 136% greater (P less than 0.02) in hypercholesterolaemic patients than in normal subjects. Thrombin-stimulated release of noradrenaline was also higher (73%, P less than 0.05) in hypercholesterolaemics than in normals. The differences between resting and thrombin-stimulated release were greater for hypercholesterolaemic patients than normal subjects (P less than 0.05). Under resting conditions total platelet noradrenaline levels (sum of supernatant and platelet pellet concentrations) were similar in preparations from the two groups. However, following thrombin stimulation total noradrenaline concentrations were substantially greater (86%) in platelets from hypercholesterolaemics than normals (P less than 0.02). In hypercholesterolaemic patients thrombin stimulation was associated with an 101% increase (over resting levels) in total platelet noradrenaline (P less than 0.01), no increases being observed with normal subjects. We suggest that platelet membranes may be more permeable in patients with familial hypercholesterolaemia leading to increased non-specific release of catecholamines. Platelets from patients with familial hypercholesterolaemia may also be more responsive to stimulation with respect to catecholamine release. The results obtained on calculation of total platelet noradrenaline levels may indicate that abnormalities of platelet dense granules occur in familial hypercholesterolaemia. In this context the relative proportions of free and conjugated catecholamine may be of relevance.