转铁蛋白受体介导的药物转运在急性脑梗死治疗中的应用

在急性脑缺血的超早期，完整的血脑屏障(BBB)使许多治疗药物无法在有效治疗时间窗内进入脑组织发挥作用。转铁蛋白受体(TfR)单克隆抗体能有效通过受体介导的细胞内吞作用使结合的药物通过BBB，从而大大增加了治疗药物的定向选择性，使之更好地发挥治疗作用。     

中药及有效成分通过血脑屏障机制的研究进展

中枢神经系统(CNS)疾病,如阿尔兹海默病,帕金森病,艾滋痴呆,脑膜炎已经成为威胁人类健康的严重疾病,这些疾病致使患者的生活质量下降,且给社会和家庭增添了巨大的负担.而用于治疗这类疾病的药物,由于人体中血脑屏障(BBB)的存在,无法到达患病部位或到达后有效浓度不足导致治疗效果不佳.据报告,美国食品与药物管理局2006～ 2009年间批准上市的74种新药中,仅有小部分新药是针对老年痴呆症、帕金森氏病、亨廷顿舞蹈病等CNS疾病的,且取得的疗效并不理想.药物无法有效通过BBB是CNS疾病新药开发的主要制约因素,如何使药物透过BBB或增大透过率成为人们治疗CNS疾病所面临的一道难题.     

药物与血脑屏障

药物对中枢神经系统(CNS)直接作用的先决条件是药物必先由血液透过血脑屏障(BBB),进入 CNS 的细胞外液,才能发挥药效。不能透过 BBB 的药物难在 CNS 内发生作用。神经药物与 BBB 的关系固然密切,某些抗菌素、抗肿瘤药物和抗胆碱酯酶药物要求在 CNS起作用时也与 BBB 有关。故药物与 BBB 的关系,不但为神经药理学家所重视,而且也为临     

沙甲喘宁与舒喘宁治疗轻至中度哮喘的比较

沙甲喘宁(S)是一种新的β_2-肾上腺素能受体促效剂,是支气管扩张剂舒喘宁的一种化学类似物。两种药物的结构相似,不同的是沙甲喘宁有一条细长的侧链,通过此侧链使药物分子牢固地结合到β_2-肾上腺素能受体蛋白区,保持固定在该部位并与受体反复接触,从而使药物作用时间延长。本文作者对沙甲喘宁与舒喘宁治疗轻至中度哮喘的作用进行了比较。病人和方法选择234例无吸烟的哮喘病     

闭合蛋白在脑缺血中的作用

血脑屏障(blood-brain barrier, BBB)损伤是缺血性卒中的重要病理学改变.闭合蛋白是构成BBB紧密连接的主要组成部分,在维持BBB完整性中发挥着重要作用.脑缺血通过诱导炎性介质、活性氧和基质金属蛋白酶的激活,启动闭合蛋白降解,并使紧密连接-细胞骨架蛋白相互作用发生改变,导致BBB完整性破坏,通透性增高.文章主要阐述了闭合蛋白与BBB、脑水肿和出血性转化之间的关系以及闭合蛋白作为缺血性卒中干预靶点的可能性.     

科素亚治疗心衰进展

肾素 -血管紧张素 -醛固酮 (RASS)在心衰的病理过程中发挥重要作用。现已证明 ,药物阻断 RASS,如转换酶抑制剂 (ACEI)对心衰疗效已肯定 ,但心肌局部组织通过心脏促胰酶而生成的血管紧张素 (Ang )在心衰中发挥重要作用 ,使 Ang 受体拮抗剂 -科素亚在心衰治疗中有独特的生物药理效应和临床地位。1　 Ang 受体及作用Ang 通过与不同组织浆膜上的特殊受体结合而发挥各种生理作用。Ang 受体分 AT1与 AT2两个亚型。最近报道又已发现 AT3、AT4。 AT1、AT2按不同比例分布于不同器官 ,但目前发现 Ang 调节的绝大部分心血管效应 (包括血管…     

心血管疾病中β-肾上腺素受体阻滞剂的作用

近年来,我国心血管疾病发病率逐渐上升,β-肾上腺素受体阻滞剂(β-受体阻滞剂)广泛受到关注。正确认识β-受体阻滞剂的作用,才能规范其应用。β-受体阻滞剂在慢性心力衰竭(CHF)、稳定型冠心病、急性心肌梗死(AMI)及二级预防、急诊经皮冠状动脉介入治疗和溶栓、高血压、快速心律失常、妊娠、甲状腺功能亢进症、心肌病等疾病中均可发挥重要作用。严格掌握适应证及禁忌证,注意药物种类选择及用法用量,可以使β-受体阻滞剂发挥更大的治疗作用,造福于心血管疾病患者。     

顽固性高血压的降压药物治疗

顽固性高血压临床上并不少见,降压药物使用不当是主要原因之一。在排除假性顽固性高血压、纠正干扰降压药物效果的因素和治疗继发性高血压之后,大多数患者需要个体化地修正降压药物治疗方案,包括正确使用利尿剂、调整降压药物组合、在五大类降压药物(利尿剂、β受体阻滞剂、血管紧张素转换酶抑制剂、血管紧张素受体拮抗剂和钙拮抗剂)的基础上加用其他降压药物、逐一上调药物的剂量。最佳化地使用降压药物能使大多数顽固性高血压患者的血压得到有效控制。     

雌激素受体与骨质疏松症

雌激素受体 (ER)是核受体超家族的成员 ,具有转录因子的作用 ,包括ERα和ERβ两种亚型 ,两种受体亚型在雌激素信号转导中发挥的作用及其相互关系尚不十分清楚。雌激素通过其受体介导的机制具有直接刺激成骨细胞和破骨细胞的作用 ,雌激素缺乏会导致骨质疏松症。同时 ,雌激素受体基因及其多态性与骨质疏松的发生关系密切 ;雌激素受体调控剂已成为治疗骨质疏松的药物     

晚期结直肠癌抗血管生成靶向治疗的若干热点

氟尿嘧啶类药物、伊立替康与奥沙利铂在晚期结直肠癌化学治疗(以下简称化疗)中呈三足鼎立之势,单药(除奥沙利铂)、两药乃至三药组合在临床均有尝试,核心在于高效低毒.随着表皮生长因子受体(epidermal growthfactor receptor,EGFR)单克隆抗体和血管内皮生长因子(vascularendothelial growth factor,VEGF)单克隆抗体等分子靶向治疗药物的出现,合理有效地布局总体治疗策略和选择合适的分子靶向药物,在目前可选药物不多的前提下使所用药物的效应最大化,分子靶向药物与化疗药物发挥协同增效作用以及在分子标志物指导下的个体化治疗等问题,已逐渐成为该领域的研究热点.现以抗血管生成靶向治疗为例,剖析晚期结直肠癌抗血管生成靶向治疗的若干进展.     

Morphine metabolism, transport and brain disposition

The chemical structures of morphine and its metabolites are closely related to the clinical effects of drugs (analgesia and side-effects) and to their capability to cross the Blood Brain Barrier (BBB). Morphine-6-glucuronide (M6G) and Morphine-3-glucuronide (M3G) are both highly hydrophilic, but only M6G can penetrate the BBB; accordingly, M6G is considered a more attractive analgesic than the parent drug and the M3G. Several hypotheses have been made to explain these differences. In this review we will discuss recent advances in the field, considering brain disposition of M6G, UDP-glucoronosyltransferases (UGT) involved in morphine metabolism, UGT interindividual variability and transport proteins.     

Interactions between the blood-brain barrier and endogenous peptides: emerging clinical implications

The effects of peptides on brain function suggest therapeutic and pathologic roles for these substances. Many peptides cross the blood-brain barrier (BBB) by transmembrane diffusion as a function of their lipid solubilities. Other peptides, such as the enkephalins, Tyr-MIF-1, vasopressin-related peptides, and peptide T-like peptides, are transported by carrier-mediated systems. Passage is influenced by aging, stress, lighting, drugs, amino acids, and neurotoxins. Disruption of the BBB results in complex changes in the blood and CSF levels of peptides. Peptides influence the passage of glucose, amino acids, and inorganic acids and may affect the integrity of the BBB. Peptide-BBB interactions have been suggested to play direct roles in dialysis dementia and maple syrup urine disease; they may be expected to be involved in other disorders of the CNS.     

Evaluation of the sites of opioid influence on anterior pituitary hormone secretion using a quaternary opiate antagonist.

Studies were conducted to determine the effects of a potent narcotic antagonist, nalmefene methyliodide, which does not cross the blood-brain barrier (BBB), on the secretion of anterior pituitary hormones and on the anterior pituitary hormonal response to morphine sulfate. Since the localization of opiate receptor responses to inside or outside the BBB depended upon the relative ability of nalmefene HCl and nalmefene methyliodide to penetrate the BBB, initial studies were conducted to document that nalmefene methyliodide does not block opiate receptors inside the central nervous system. While nalmefene HCl blocked morphine-induced antinociceptive responses at doses as low as 10 micrograms/kg, nalmefene methyliodide was ineffective in this regard at doses as high as 500 micrograms/kg. The luteinizing hormone (LH) suppression and prolactin (PRL) secretion induced by morphine was blocked by both nalmefene HCl and its methyliodide analogue, indicating that the opioid receptor type which mediates both responses is located outside the BBB. We observed that basal PRL levels were reduced by nalmefene HCl but not by nalmefene methyliodide indicating that basal PRL secretion is influenced by opioid neurons inside the BBB. While nalmefene HCl blocked morphine-induced suppression of thyroid-stimulating hormone (TSH) release, nalmefene methyliodide was less effective, suggesting that opiate-induced TSH suppression may be mediated by receptors located both within and outside the BBB. Nalmefene HCl caused a growth hormone (GH)-secretory response by itself, but nalmefene HCl and nalmefene methyliodide were ineffective in blocking morphine-induced GH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of peripheral serotonin in the regulation of central sleep apneas in rats.

STUDY OBJECTIVES: The aim of our study was to determine the effects of serotonin (5-HT), which does not penetrate the blood-brain barrier (BBB), and GR38032F, a 5-HT3 receptor antagonist that may cross the BBB, on spontaneous apneas in adult Sprague-Dawley rats. MEASUREMENTS AND RESULTS: Rats were implanted with electrodes for EEG and electromyographic recording to monitor sleep, with a radiotelemetry transmitter for monitoring aortic BP and heart period (HP) and were placed inside a single chamber plethysmograph for monitoring respiration. Sleep, BP, HP, and respiration were monitored for 6 h following administration of drugs. Intraperitoneal injection of 5-HT (0.79 mg/kg) to rats increased spontaneous central apneas during rapid eye movement (REM) sleep by > 250% in comparison to control recording (p = 0.01). GR38032F (0.1 mg/kg), which produced no effect on apnea expression, completely blocked the 5-HT-induced increase in REM apneas. Administration of 5-HT did not affect apnea expression in non-REM sleep and had no effect on sleep or BP. CONCLUSIONS: From these observations, we conclude that binding at 5-HT3 receptors in the peripheral nervous system promotes REM-related apnea genesis in rats. These findings further suggest that endogenous 5-HT, acting at least at peripheral 5-HT3 receptors, may play a baseline physiologic role in the expression of spontaneous central apneas in rats.     

Blood–brain barrier structure and function and the challenges for CNS drug delivery

The neurons of the central nervous system (CNS) require precise control of their bathing microenvironment for optimal function, and an important element in this control is the blood–brain barrier (BBB). The BBB is formed by the endothelial cells lining the brain microvessels, under the inductive influence of neighbouring cell types within the ‘neurovascular unit’ (NVU) including astrocytes and pericytes. The endothelium forms the major interface between the blood and the CNS, and by a combination of low passive permeability and presence of specific transport systems, enzymes and receptors regulates molecular and cellular traffic across the barrier layer. A number of methods and models are available for examining BBB permeation in vivo and in vitro, and can give valuable information on the mechanisms by which therapeutic agents and constructs permeate, ways to optimize permeation, and implications for drug discovery, delivery and toxicity. For treating lysosomal storage diseases (LSDs), models can be included that mimic aspects of the disease, including genetically-modified animals, and in vitro models can be used to examine the effects of cells of the NVU on the BBB under pathological conditions. For testing CNS drug delivery, several in vitro models now provide reliable prediction of penetration of drugs including large molecules and artificial constructs with promising potential in treating LSDs. For many of these diseases it is still not clear how best to deliver appropriate drugs to the CNS, and a concerted approach using a variety of models and methods can give critical insights and indicate practical solutions.     

Penetration and activation of brain endothelium by Salmonella enterica serovar Typhimurium

Salmonella meningitis is a serious disease of the central nervous system, common particularly in Africa. Here, we show that Salmonella enterica serovar Typhimurium is able to adhere, invade, and penetrate human brain microvascular endothelial cells (hBMECs), the single-cell layer constituting the blood-brain barrier (BBB). Cellular invasion was dependent on host actin cytoskeleton rearrangements, while expression of a functional type III secretion system was not essential. In addition, Salmonella infection activated a proinflammatory immune response targeting neutrophil signaling and recruitment. Salmonella invasion and immune activation may represent a crucial step in the penetration of the BBB and development of Salmonella meningitis.     

Epinephrine enhances lysosomal enzyme delivery across the blood brain barrier by up-regulation of the mannose 6-phosphate receptor

Delivering therapeutic levels of lysosomal enzymes across the blood-brain barrier (BBB) has been a pivotal issue in treating CNS storage diseases, including the mucopolysaccharidoses. An inherited deficiency of beta-glucuronidase (GUS) causes mucopolysaccharidosis type VII that is characterized by increased systemic and CNS storage of glycosaminoglycans. We previously showed that the neonate uses the mannose 6-phosphate (M6P) receptor to transport phosphorylated GUS (P-GUS) across the BBB and that this transporter is lost with maturation. Induction of expression of this BBB transporter would make enzyme replacement therapy in the adult possible. Here, we tested pharmacological manipulation with epinephrine to restore functional transport of P-GUS across the adult BBB. Epinephrine (40 nmol) coinjected i.v. with (131)I-P-GUS induced the transport across the BBB in 8-week-old mice. The brain influx rate of (131)I-P-GUS (0.29 mul/g per min) returned to the level seen in neonates. Capillary depletion showed that 49% of the (131)I-P-GUS in brain was in brain parenchyma. No increases of influx rate or the vascular space for (125)I-albumin, a vascular marker, was observed with epinephrine (40 nmol), showing that enhanced passage was not caused by disruption of the BBB. Brain uptake of (131)I-P-GUS was significantly inhibited by M6P in a dose-dependent manner, whereas epinephrine failed to increase brain uptake of nonphosphorylated GUS. Thus, the effect of epinephrine on the transport of (131)I-P-GUS was ligand specific. These results indicate that epinephrine restores the M6P receptor-mediated functional transport of (131)I-P-GUS across the BBB in adults to levels seen in the neonate.     

Crossing the blood-brain barrier with AAV vectors

Metabolic Brain Disease - Central nervous system (CNS) diseases are some of the most difficult to treat because the blood-brain barrier (BBB) almost entirely limits the passage of many therapeutic...     

A comprehensive outlook on intracerebral therapy of malignant gliomas

Glioblastoma multiforme (GBM) is the most frequent and aggressive malignant glioma (MG), with a median survival time of 12–15 months, despite current best treatment based on surgery, radiotherapy and systemic chemotherapy. Many potentially active therapeutic agents are not effective by systemic administration, because they are unable to cross the blood–brain barrier (BBB). As intracerebral administration bypasses the BBB, it increases the number of drugs that can be successfully delivered to the brain, with the possibility of minor systemic toxicity and better effectiveness. This review summarizes the results of the extensive clinical research conducted on intracerebral therapy. Biodegradable drug carriers, implantable subcutaneous reservoirs and convection-enhanced delivery (CED) represent the main techniques for intracerebral delivery, while conventional chemotherapy agents, radiolabeled antibodies and receptor-targeted toxins are the main classes of drugs for intracerebral therapy. At the present time, biodegradable carmustine wafers, commercialized as Gliadel^®, are the only FDA-approved treatment for intracerebral chemotherapy of MG, but intracavitary delivery of mitoxantrone and radiolabeled antitenascin antibodies via implantable reservoirs has yielded promising results in uncontrolled trials. The pressure-driven flow generated by CED can potentially distribute convected drugs over large volumes of the brain, independently on their intrinsic diffusivity. Nevertheless, prominent technical problems, like backflow, are yet to be properly addressed and contributed to the disappointing results of two phase III trials that investigated CED of cintredekin besudotox and TransMid™ in patients with recurrent GBM.     

A method to determine the ability of drugs to diffuse through the blood-brain barrier.

A method has been devised for predicting the ability of drugs to cross the blood-brain barrier. The criteria depend on the amphiphilic properties of a drug as reflected in its surface activity. The assessment was made with various drugs that either penetrate or do not penetrate the blood-brain barrier. The surface activity of these drugs was quantified by their Gibbs adsorption isotherms in terms of three parameters: (i) the onset of surface activity, (ii) the critical micelle concentration, and (iii) the surface area requirement of the drug at the air/water interface. A calibration diagram is proposed in which the critical micelle concentration is plotted against the concentration required for the onset of surface activity. Three different regions are easily distinguished in this diagram: a region of very hydrophobic drugs which fail to enter the central nervous system because they remain adsorbed to the membrane, a central area of less hydrophobic drugs which can cross the blood-brain barrier, and a region of relatively hydrophilic drugs which do not cross the blood-brain barrier unless applied at high concentrations. This diagram can be used to predict reliably the central nervous system permeability of an unknown compound from a simple measurement of its Gibbs adsorption isotherm.