Lipid nanoparticles for intranasal administration: application to nose-to-brain delivery

Introduction: The blood brain barrier is a functional barrier allowing the entry into the brain of only essential nutrients, excluding other molecules. Its structure, although essential to keep the harmful entities out, is also a major roadblock for pharmacological treatment of brain diseases. Several alternative invasive drug delivery approaches, such as transcranial drug delivery and disruption of blood brain barrier have been explored, with limited success and several challenges. Intranasal delivery is a non-invasive methodology, which bypasses the systemic circulation, and, through the intra- and extra- neuronal pathways, provides direct brain drug delivery. Colloidal drug delivery systems, particularly lipidic nanoparticles offer several unique advantages for this goal .

Areas covered: This review focuses on key brain diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis, and provide a detailed overview of the current lipid nanoparticle based treatment options explored thus far. The review also delves into basic preparation, challenges and evaluation methods of lipid drug delivery systems.

Expert opinion: Brain diseases present complex pathophysiology, in addition to the practically inaccessible brain tissues, hence according to the authors, a two-pronged approach utilizing new target discovery coupled with new drug delivery systems such as lipid carriers must be adopted.     

Single exposure to a serotonin 1A receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin, produces a prolonged heterologous desensitization of serotonin 2A receptors in neuroendocrine neurons in vivo

We previously demonstrated colocalization of serotonin 1A (5-HT(1A)) and serotonin 2A (5-HT(2A)) receptors in oxytocin and corticotropin-releasing factor neurons in the hypothalamic paraventricular nucleus (PVN). Because a functional imbalance between hypothalamic 5-HT(1A) and 5-HT(2A) receptors has been implicated in several neuropsychiatric disorders, in this study we investigated whether acute in vivo activation of 5-HT(1A) receptors in the PVN results in desensitization of 5-HT(2A) receptor signaling. Functional desensitization of hypothalamic 5-HT(2A) receptors was assessed via a reduction in oxytocin and adrenocorticotropin (ACTH) responses to the 5-HT(2A/2C) receptor agonist (-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl [(-)DOI]. We report here that a single systemic injection of the 5-HT(1A) receptor agonist (+)-8-hydroxy-2-(di-n-propylamino)-tetralin [(+)8-OH-DPAT] (200 microg/kg) significantly reduced the 5-HT(2A) receptor-mediated oxytocin responses for at least 72 h. Direct intraparaventricular injection of (+)8-OH-DPAT (0.2 nmol) 24 h before a submaximal dose of (-)DOI (0.35 mg/kg) significantly inhibited the 5-HT(2A) receptor-mediated increases in both oxytocin and ACTH (-39 and -16%, respectively). In addition, the (+)8-OH-DPAT-induced desensitization of the 5-HT(2A) receptor-mediated oxytocin but not the ACTH response was inhibited in rats pretreated with either a systemic (0.1 mg/kg) or intraparaventricular (10 nmol) injection of the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100635). This is the first in vivo demonstration of a prolonged heterologous intracellular desensitization of 5-HT(2A) receptors after acute activation of 5-HT(1A) receptors. These findings may provide insight into the long-term heterologous interactions between 5-HT(1A) and 5-HT(2A) receptor signaling that could occur in response to antidepressants, antipsychotics, or drugs of abuse that target these receptor subtypes.     

The effect of solvent/detergent-treated plasma on stored platelet concentrates

The treatment of fresh-frozen plasma (FFP) with a solvent/detergent (S/D) solution to inactivate contaminating viruses has been shown to be effective in reducing virus transmission while maintaining the hemostatic properties of the plasma. FFP is treated with tri(n- butyl)phosphate (solvent) and Triton X-100 (detergent) and then purified; the in vivo effect of the residual S/D has been reported to be minimal. In clinical transfusion practice, ABO-incompatible, HLA- matched, single-donor platelets may have to be resuspended in ABO- compatible plasma. The use of S/D-treated plasma for this purpose would remove the added risk of transfusion-transmitted diseases due to the use of another blood component. As there are no data on the use of S/D- treated plasma as a platelet-resuspending medium, the potential toxicity of the residual solvent and detergent on the in vitro function and integrity of platelets stored in S/D-treated plasma for 5 days was studied. A repeated-measures analysis of variance was used for statistical analysis. Results showed that, as compared to controls (non- S/D-treated plasma), platelets resuspended in S/D-treated plasma maintained their functional properties, including morphology score and osmotic recovery, for up to 5 days of storage (p > 0.05, NS). No significant changes were seen among S/D-treated plasma and control groups for platelet count, lactate dehydrogenase discharge, beta- thromboglobulin release, glucose utilization, or generation of lactate. Measurement of pO2 and pCO2 values showed some differences between S/D- treated plasma and control groups that were significant, but not clinically significant. The pH values for all four groups ranged from 7.1 to 7.4 on Day 5.(ABSTRACT TRUNCATED AT 250 WORDS)     

神经干细胞移植治疗帕金森病的研究与应用

目的:总结神经干细胞的来源以及伸经干细胞移植治疗帕金森病的进展。方法:应用计算机检索中文科技期刊数据库1994-01/2007-06期间与神经干细胞移植和帕金森病相关的文献,检索词"神经干细胞移植、帕金森病",限定文章语言种类为中文。对资料进行初审,并查看每篇文献后的引文,文献所述内容应与神经干细胞移植、帕金森病相关,且以近5年发表在较权威杂志优先。排除重复性文章及Meta分析类文章。结果:①神经干细胞有很强的增殖能力和迁移能力,并替代受损伤的脑细胞,神经干细胞通过体外培养使其增殖后,移植到宿主脑内能够迁移并分化为黑质多巴胺能神经元。②神经干细胞联合基因治疗将神经干细胞作为基因治疗的载体,庄体外转基因移人病变的冲经组织,可阻止神经元变性并恢复其功能。③胶质细胞系源性神经营养因子的神经营养作用和酪氨酸羟化酶分泌黑质多巴胺能神经递质的功能,既能提高脑内黑质多巴胺水平,又能使黑质多巴胺能神经元长期存活,阻止黑质多巴胺能神经元变性,重建宿主神经通路。④神经干细胞作为基因载体,进行神经干细胞移植联合多基因治疗,为帕金森病治疗提供了新的思路。结论:随着神经干细胞研究的逐渐成熟及发展,神经干细胞移植已成为帕金森病治疗的主要发展方向。     

Three-Year Experience with a Stylet for Lead Extraction: A Multicenter Study

The extraction of chronically implanted and infected pacemaker and defibrillator leads is an important issue. This article describes the experience gathered between 1990 and 1994 by seven European centers regarding a locking stylet that is uniformly applicable for a wide variety of internal pacing coil diameters. This interventional locking stylet for lead extraction has an outer diameter of 0.4 mm (0.016 inches). The stylet consists of a hollow shaft in which an inner traction wire is embedded. At the tip of the inner traction wire an anchoring mechanism, which can be opened by retraction, is applied. Removal attempts were made for 150 leads, 110 in ventricular and 40 in atrial positions. Results : Complete removal was possible in 122 cases (81 %). Partial removal was possible in 18 cases (12%). Failure to remove the lead with the extraction stylet was experienced in 10 cases (7%). In seven patients, the leads were removed by cardiothoracic surgery; 3 defective leads were left in place. There were no serious complications associated with the procedure. None of the patients died. Conclusion : The experience with this extraction stylet for lead removal has shown good results. Despite a low complication rate thus far, each case for lead removal should be judged on the individual basis of benefit-to-risk ratio.     

Programmable VT Detection Enhancements in Implantable Cardioverter Defibrillator Therapy

This report describes the distribution of automatically measured values of enhanced arrhythmia detection parameters such as “rate stability” and “rate onset” in various forms of spontaneous arrhythmia episodes in patients treated with a new, third-generation, tiered therapy implantable cardioverter defibrillator (ICD). The study population consisted of 27 patients who received the Ventak PRxII cardioverter defibrillator, which provides extensive diagnostic options such as electrogram storage capabilities, and the ability to store measured values of additional arrhythmia detection parameters such as rate stability and rate onset during spontaneous arrhythmia episodes. During a follow-up period of 11.1 ± 5.2 months, this device detected 264 arrhythmia episodes. The analysis of stored electrograms revealed 13 episodes of sinus tachycardia, 52 episodes of atrial tachyarrhythmias, and 201 episodes of monomorphic ventricular tachycardias (VTs). The mean measured values of rate stability and rate onset were: 2.2 ± 0.9 msec, 0% in sinus tachycardias; 41.0 ± 24.1 msec, 8.5%± 9.5% in atrial tachyarrhythmias; and 7.8 ± 6.0 msec, 30.6%± 12.1% in monomorphic VTs. There was a wide zone of overlapping measured values for rate stability and rate onset in ventricular and nonventricular rhythms. No episode of VT showed a measured rate stability criterion > 35 msec. The subanalysis of arrhythmia episodes presenting with a heart rate < 160 beats/mm revealed no episode of VT with a rate stability value > 24 msec. The calculated, rate dependent specificities for these programmed rate stability parameters in detecting VTs were 46.2% and 81.8%, respectively. The analysis of the rate onset algorithm revealed no comparable relationship between sensitivity and specificity in the detection of VTs. Additional arrhythmia detection algorithms such as rate stability and rate onset may contribute to a significant enhancement in the specificity of lCD therapy.     

无机活性元素骨组织工程支架材料修复山羊颌骨缺损

目的:应用无机活性元素骨组织工程支架材料,对山羊的下颌骨角部大型箱状缺损施行骨重建,观察支架材料骨构建效能和生物相容性的情况。方法:实验于2004-02/12在安徽医科大学附属省立医院实验中心及相关实验室完成。①实验材料:无机活性元素骨组织工程支架材料由美国波士顿大学分子生物相容学研究室研制提供;21只雌性健康山羊由安徽医科大学动物实验中心(皖医实动准字01号)提供,实验过程中动物处置符合动物伦理学标准。②实验方法:取山羊15只,按4,8,12周3个时间点分为3组,位下颌角部手术制备30 mm×25 mm×10 mm的大型箱状缺损。采用自身配对设计,左侧置入支架材料为实验组,右侧空白对照为对照侧;剩余6只山羊为对照组,不手术。③观察指标:术后4,8,12周应用X射线片、组织学和放射性核素显像观察缺损区新骨形成情况;并测定骨密度;应用血液学检查及骨髓基质细胞体外复合细胞培养评价材料的生物相容性。结果:①一般观察:实验山羊无手术死亡,创口Ⅰ期愈合。②X射线片:实验侧有渐进性骨密度增高,阻射影逐级增强,对照侧呈透光阴影。③放射性核素显像:实验侧有较明显的核浓聚和再生血管化现象,对照侧无骨重建,故无骨代谢变化。④骨密度测量系数:实验侧呈递增式上升,对照侧维持较低水平,提示无自发性成骨。⑤组织学观察:实验侧呈时间递增性骨重建现象,在12周时新骨已完全形成并钙化基本完成,而对照侧直到12周仍无成骨现象。⑥生物相容性:各组的血常规、细胞形态、生化和相关酶学指标均在正常范围内。结论:无机活性元素骨组织工程支架材料有良好的成骨和再血管化功能,且生物相容性好,提示由该支架材料诱导的组织工程化骨构建有望成为临床骨组织大型缺损的替代材料。     

Sumatriptan inhibits neurogenic vasodilation of dural blood vessels in the anaesthetized rat-intravital microscope studies

This study used intravital microscopy to measure the diameter of dural arteries in anaesthetized rats. Electrical stimulation of the surface of a closed cranial window produced increases in dural vessel diameter which were blocked by the CGRP receptor antagonist human-CGRP_(8–37) but unaffected by the NK1 receptor antagonist RP67580. Sumatriptan (3 and 0 mg kg⁻¹, iv) significantly reduced the response to electrical stimulation. In contrast, sumatriptan (3 mg kg⁻¹) had no effects on the response to exogenously administered CGRP. These results indicate that neurokinins play no role in neurogenic vasodilation in this preparation and that neurogenic vasodilation in rat dural vessels is mediated predominantly by CGRP. Furthermore, the data indicate that sumatriptan attenuates neurogenic vasodilation, probably by inhibiting the release of CGRP from perivascular trigeminal nerve endings innervating the dura. These experimental data parallel the clinical findings that CGRP levels are elevated in migraine and normalized, concomitantly with headache relief, by sumatriptan.     

Chronic fluoxetine differentially affects 5-hydroxytryptamine (2A) receptor signaling in frontal cortex,oxytocin- and corticotropin-releasing factor-containing neurons in rat paraventricular nucleus

Differential adaptive changes in serotonin2A [5-hydroxytryptamine (5-HT)2A] receptor signaling during treatment may be one mechanism involved in the latency of therapeutic improvement with antidepressants, such as fluoxetine. We examined the effects of fluoxetine (2, 3, 7, 21, or 42 days) on hypothalamic 5-HT2A receptor signaling. The hormone responses to an injection of the 5-HT2A receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI) were used as an index of hypothalamic 5-HT2A receptor function. Treatment with fluoxetine for 21 or 42 days produced diminished adrenocorticotropic hormone (ACTH) and oxytocin (but not corticosterone) responses to DOI injections (2.5 mg/kg i.p.; 15 min postinjection). Regulators of G protein signaling 4 and Galphaq protein levels in the hypothalamic paraventricular nucleus were not altered during fluoxetine treatment. Because previous studies indicate that treatment with fluoxetine for 21 days resulted in increased hormone responses to DOI when measured at 30 min after injection, we examined the effect of fluoxetine (21 days) on DOI-induced increase hormone levels at 15, 30, and 60 min after DOI injection. Fluoxetine decreased the oxytocin response at 15 but not at 30 min post-DOI injection, and potentiated the ACTH and corticosterone responses at 30 min post-DOI injection. For comparison, we examined the effect of fluoxetine on 5-HT2A receptor-mediated increase in phospholipase C (PLC) activity in the frontal cortex. 5-HT-stimulated, but not guanosine 5'-O-(3-thio)triphosphate-stimulated PLC activity was increased after 21 days of fluoxetine-treatment. Overall, these results indicate that chronic fluoxetine treatment can potentiate 5-HT2A receptor signaling in frontal cortex but differentially alters 5-HT2A receptor signaling in oxytocin-containing neurons and corticotropin-releasing factor-containing neurons in the paraventricular nucleus.     

Impact of donor–recipient gender on kidney graft and patient survival: short- and long-term outcomes

Purpose

Donor and recipient gender influence on post-transplant kidney and patient survival is still controversial, and the literature data do not present unanimous conclusions. The aim of this study was to evaluate the effect of gender disparities between donor and recipient in 963 kidney transplants performed at our center from January 2000 to December 2010.

Methods

The patients were subdivided into four groups according to recipient and donor gender: male donor-to-male recipient (M_DM_R; n = 305), male donor-to-female recipient (M_DF_R; n = 203), female donor-to-female recipient (F_DF_R; n = 206), and female donor-to-male recipient (F_DM_R; n = 249). Independent sample’s t test and one-way ANOVA were used for statistical analyses. Graft and patient survival were calculated by the Kaplan–Meier method and compared using the log rank test.

Results

There were no statistically significant differences between the groups with regard to age, cold ischemia time, delayed graft function, primary non-function, and episodes of acute and chronic rejection. Moreover, no difference in either graft (p = 0.92) or patient (p = 0.41) survival at 1, 3, and 5 years was observed. However, female recipients had significantly lower serum creatinine values and higher estimated GFR, particularly if they received a male donor kidney, and these findings were stable up to 3-year post-transplantation.

Conclusions

No impact of gender on short- or long-term graft and patient survival was observed in deceased kidney transplantation. However, we report a lower creatinine level in the male donors to female recipients group as compared with other recipient–donor gender combinations, although this difference loses statistical significance after the third-year post-transplantation.