Delivery of 125I-NGF to the Brain via the Olfactory Route

The blood-brain barrier presents a major problem in the administration and testing of neurotropins as it prevents a sufficient concentration of these potential therapeutic agents from reaching the target areas of the human brain. The olfactory neuroepithelium is the only area of the body in which an extension of the central nervous system comes into direct contact with the environment. Following intranasal administration of ¹²⁵I-labeled nerve growth factor (¹²⁵I-NGF), radiolabel appeared rapidly in the olfactory bulb and other brain regions. Radiolabel accumulation in the olfactory bulb of the brain was a linear function of the intranasal dose and of the radiolabel concentration in the olfactory epithelium. Concentration of radiolabel in the olfactory bulb and brain with intranasal administration, but not with intravenous administration, suggests direct transport of label into the brain along the olfactory route following intranasal administration. The rapid appearance of label in the olfactory bulbs, cerebrum, and brain stem is more consistent with entry of label through intercellular clefts in the olfactory epithelium and extracellular transport along the olfactory neural pathway to reach the cerebrospinal fluid and brain than with uptake by olfactory neurons and subsequent intracellular axonal transport. At least 80% of the radiolabel found in the brain following intranasal delivery of ¹²⁵I-NGF precipitates in cold 5% trichloroacetic acid, suggesting that a significant amount of intact NGF reaches the brain. Preliminary studies using a sandwich enzyme-linked immunosorbent assay have confirmed the uptake of NGF into the brain following intranasal but not intravenous administration to rats. This is the first evidence for noninvasive delivery of unconjugated NGF to the brain.     

In Vivo Absorption Studies of Insulin from an Oral Delivery System

The objectives of our study were two fold: to examine enantioselective release of controlled delivery granules based on molecularly imprinted polymers (MIPs) for various racemic drugs, including ibuprofen and ketoprofen (NSAIDs) and propranolol (β-blockers); to evaluate the use of controlled delivery granules containing a combination of different MIPs for the multiple simultaneous enantioselective-controlled delivery of mixed racemic drugs. In this work, the MIP beads selective to S-Ibuprofen, S-ketoprofen, and R-propranolol were prepared using multistep swelling and thermal polymerization method. Afterward, the MIP beads were formulated with racemate of the chiral drugs and a binder and followed by granulation. Then, the enantioselective release of racemic drugs from the prepared MIP granules was investigated by an in vitro dissolution test using a chiral HPLC for assays of enantiomers. The influence of drug/polymer ratio and medium pH on the selective enantiomeric release of MIP granules was explored. Further, the release of the enantiomers of racemic ibuprofen and racemic ketoprofen from the granule containing two MIPs - S-ibuprofen MIP and S-ketoprofen MIP - was examined. The release profiles of both S-ibuprofen MIP granule and R-propranolol MIP granule exhibited differential release of enantiomers. Also, the findings indicated the stereoselective retardation of those controlled delivery granules as well as the influence of MIP formulation on enantioselective release mechanism. The enantioselective release of S-ibuprofen MIP granule and R-propranolol MIP granule appeared to depend on polymer loading and medium pH. In this case, the drug/polymer ratio of 1:25 showed the best enantioselective release with initial enantiomeric excess of 100%. On the other hand, the enantioselectivity of both granules was the greatest in buffer pH 7.4. Furthermore, the efficiency in enantioselective release of the combined MIP granule was higher than its relative single MIP granules, as a result of the cross-reactivities of the MIPs. In our study, controlled delivery granules based on MIPs demonstrated significant enantioselective release for several chiral drugs, and thus it may be developed as a tool to administer chiral pharmaceutical as a single enantiomer.     

Visualization of In Vivo Olfactory Uptake and Transfer Using Fluorescein Dextran

Nasal administration of a 3 kDa fluorescein dextran (FD3) solution to rats resulted in transcellular absorption across the olfactory epithelium and transfer to the olfactory bulb within 15 min. After entering the lamina propria, FD3 was transferred in the connective tissue surrounding the olfactory nerve bundles to the olfactory bulb of the brain. More FD3 was absorbed across the olfactory epithelium than across the respiratory epithelium and to the nasal associated lymphoid tissue. Further, the amount of FD3 crossing the olfactory epithelium was region-dependent, with higher amounts absorbed in the turbinates than in the nasal septum. Plastic embedding and sectioning followed by fluorescence microscopy, enabled simultaneous visualization of FD3 in the mucosa and olfactory bulb, as well as the opportunity to store the tissue blocks for a prolonged period of time.     

Absorption Enhancing Effect of Labrasol on the Intestinal Absorption of Insulin in Rats

The oral absorption enhancing effect of Labrasol? has been studied in rats using insulin as a model peptide/protein drug. Insulin solution was prepared by dissolving insulin in pH 7.4 buffer followed by the addition of Labrasol. The insulin concentration was 50.0 IU/ml. The test insulin/Labrasol solution was administered to the jejunum, ileum and ascending colon of rats at 10.0 IU/kg. After administration, blood samples were collected for 5 h and serum glucose levels and insulin levels were measured. In another group of rats, insulin solution was injected intravenously at 1.0 IU/kg, and both serum glucose and insulin levels were measured. The pharmacological availability of insulin from Labrasol solution was found to be 3.9, 8.9 and 9.1% following jejunal, ileal and colonic administrations, respectively, by comparing the serum glucose level vs. time profiles obtained after intestinal and i.v. administrations. By comparing the serum insulin levels vs. time profiles, the bioavailability of insulin was found to be 0.25 and 0.20% for intra-ileum and colonic administrations, respectively. The hypoglycemic effect of insulin after intra-ileum administration showed a dose-dependency in the insulin dose range from 10.0 to 1.0 IU/kg. These results suggest the absorption enhancing effect of Labrasol on the intestinal absorption of insulin in rats.     

胰岛素肺部给药：各种吸收促进剂对胰岛素经肺吸收的促进作用

通过肺部导入胰岛素溶液的方法研究各种吸收剂对胰岛素肺部吸收的影响,以血糖的下降程度为吸收评价指标（ＰＡ％）。研究发现,２０ ｍｍｏｌ·Ｌ~(－１)胆酸钠（ＰＡ％＝６９．１％）, １％辛酸钠ＰＡ％＝４０．４％）, １％苄泽３５ （ＰＡ％＝４６．６％）,１％苄泽７８（ＰＡ％＝５３．６％）以及稀土化合物氯化钆［ＰＡ％＝３２．２％,（０．０４ｍｇ·ｋｇ~(－１)）和ＰＡ％＝３６.３％, ０．２ ｍｇ·ｋｇ~(－１)）］等能显著增强胰岛素对大鼠血糖的下降作用,而 １％ ＥＤＴＡ（ＰＡ％＝１９．１％）, ５％油酸（ＰＡ％＝２０．８％）和稀土化合物氯化镥（ＰＡ％＝２５.１％, ０.２ ｍｇ·ｋｇ~(－１)）无明显的吸收促进作用。结果表明,选用合适的吸收促进剂有利于胰岛素的肺部吸收。     

GM1 Delivery to the CSF Via the Olfactory Pathway

The objective of this study was to determine if monosialogan- glioside (GM1) can be delivered to the brain via the olfactory neural pathway (o.p.). GM1 solution was administered via the o.p. and i.v. route to rats, after which cerebrospinal fluid (CSF) was collected. Two other formulations of GM1, GM1-lipid nanospheres (GM1-LNS) and GM1-DOTAP (a positively charged lipid) complex, were also tested. The results showed that GM1 can be delivered to the brain via the o.p. However, GM1-LNS administered i.v. delivered the highest concentrations of GM1 to the CSF; this formulation may potentially be useful in treatment of spinal cord injury.     

Modulation of the Cellular Junction Protein E-Cadherin in Bovine Brain Microvessel Endothelial Cells by Cadherin Peptides

Cadherins are calcium-dependent glycoproteins involved in homophilic cell-cell adhesion of tight intercellular junctions. The ability of cadherin peptides to inhibit cadherin-mediated cell-cell adhesion of bovine brain microvessel endothelial cells (BBMECs) was investigated. This was accomplished by using two cadherin function assays, the inhibition of calcium-dependent reaggrega-tion and the dissociation of BBMECs. Peptides that exhibit inhibitory and dissociating properties are presumably bound to cadherins on the surface of BBMECs, inhibiting cadherin-cadherin interactions. We have found six peptides from the EC-1 domain of E-and N-cadherins that inhibit cell-cell adhesion of BBMECs. A very significant inhibitory activity was displayed by a 24-mer peptide (3) derived from the human-E-cadherin sequence. One hexapeptide (7) derived from the E-cadherin sequence can effectively inhibit aggregation of BBMECs. These results will improve our ability to design peptides that can modulate cell-cell adhesion in the intercellular tight junctions.     

Drug Targeting to the Brain: Transfer of Picolinic Acid Along the Olfactory Pathways

Picolinic acid (PA) protects against quinolinic acid- and kainic acid-induced neurotoxicity in the brain. To study the uptake of PA to the brain, we administered [3 H]PA via a unilateral nasal instillation or iv injection to mice. Autoradiography demonstrated a rapid uptake of radioactivity in the olfactory nerve layer and in the ipsilateral olfactory bulb (OB) following nasal instillation of [3 H]PA. After 4 h, there was a high level of radioactivity in the central parts of the ipsilateral OB and olfactory peduncle. Moreover, iv injection of [3 H]PA demonstrated a selective uptake and retention of radioactivity in the OB. Gas chromatography-mass spectrometry (GC-MS) demonstrated the presence of PA and PA-glycine conjugate in the OB. In mice with reduced peripheral olfactory innervations there was a decreased uptake of [3 H]PA in the OB as compared to controls suggesting that an intact olfactory neuroepithelium is a prerequisite for an uptake of PA to the OB. There is an increased interest in brain targeting of drugs with limited ability to pass the blood-brain barrier. The present results demonstrate that PA fulfils structural requirements for a transfer along the olfactory pathways to the brain.     

Intranasal Bioavailability of Insulin from Carbopol-Based Gel Spray in Rabbits

The purpose of this study was to investigate the nasal absorption of insulin from a carbopol-based nasal gel spray in rabbits. An insulin nasal gel was prepared by dispersing carbopol in distilled water, followed by the addition of insulin solution, then neutralization and viscosity adjustment. The nasal absorption of insulin from the gel, in conscious rabbits, was evaluated in comparison with absorption from an insulin solution. The absolute bioavailability of insulin from the nasal gel was studied using blood glucose level in comparison to intravenous injection. The insulin gel formulation produced a significant hypoglycemic response in rabbits, whereas no response was seen following administration of the insulin solution formulation. The bioavailability of insulin from the nasal gel formulation was 20.6% compared with the intravenous injection. The results of the present study suggest that the carbopol gel promotes the nasal absorption of insulin in rabbit model and due to its sprayability with commercially available spray pumps, could be considered as a preferred platform in nasal drug administration.     

Drug Transport into the Mammalian Brain: The Nasal Pathway and its Specific Metabolic Barrier

It is generally accepted that the rate of entry into and distribution of drugs and other xenobiotics within the central nervous system (CNS) depends on the particular anatomy of the brain microvessels forming the blood-brain barrier (BBB), and of the choroid plexus forming the blood-cerebrospinal fluid barrier (CSF), which possess tight junctions preventing the passage of most polar substances. Drug entry to the CNS also depends on the physicochemical properties of the substances, which can be metabolised during this transport to pharmacologically inactive, non-penetrating polar products. Finally, the entry of drugs may be prevented by multiple complex specialized carriers, which are able to catalyse the active transport of numerous drugs and xenobiotics out of the CNS. Nasal delivery is currently considered as an efficient tool for systemic administration of drugs that are poorly absorbed via the oral route, and increasing evidence suggests that numerous drugs and potentially toxic xenobiotics can reach the CNS by this route. This short review summarizes recent knowledge on factors controlling the nasal pathway, focusing on drug metabolising enzymes in olfactory mucosa, olfactory bulb and brain, which should constitute a CNS metabolic barrier.     

Niosomes with Sorbitan Monoester as a Carrier for Vaginal Delivery of Insulin: Studies in Rats

To prepare and investigate the potential of the niosomes vaginal delivery system for systemic treatment of insulin is the goal of this study. Two kinds of vesicles with Span 40 and Span 60 were prepared by lipid phase evaporation methods with sonication. The niosomal entrapment efficiency was determined by column chromatography. The particle size and morphology of the vesicles also were evaluated. The results showed optimized niosomes prepared in this study had niosomal entrapment efficiency 26.68 ± 1.41% for Span 40 and 28.82 ± 1.35% for Span 60, respectively. The particle sizes of Span 40 niosomes and Span 60 niosomes were 242.5 ± 20.5 nm and 259.7 ± 33.8 nm, respectively. There were no significant differences in appearance between the two types of vesicles. The hypoglycemic effects, and insulin concentrations after vaginal administration of insulin vesicles to rats were investigated. Compared with subcutaneous administration of insulin solution, the relative pharmacological bioavailability and the relative bioavailability of vaginal administration of insulin vesicles were determined. Compared with subcutaneous administration of insulin solution, the relative pharmacological bioavailability and the relative bioavailability of insulin-Span 60 vesicles group were 8.43% and 9.61%, and insulin-Span 40 niosomes were 9.11% and 10.03% (p > 0.05). Span 60 and Span 40 niosomes were both higher than blank Span 40, Span 60 vesicles, and free insulin physical mixture groups (p < 0.05). The results indicates insulin-Span 60, Span 40 niosomes had an enhancing effect on vaginal delivery of insulin. Although the factors controlling the process for penetration of a portion of vaginally administrated niosomes into bloodstream from vaginal tract is still not fully understood, our results demonstrated that after encapsulation in niosomes of definite type, insulin became an active and efficiently therapeutic agent when administrated vaginally and might be a good carrier for vaginal delivery of protein drugs.     

In vivo absorption studies of insulin from an oral delivery system

Alginate microspheres prepared by an emulsion-based process were loaded with insulin by a remote loading process. We observed that the time of exposure, pH of the remote loading medium, and beta-cyclodextrin complexation of insulin influenced drug loading. In vivo absorption studies of insulin from optimized microspheres were carried out in diabetic albino rats. Serum sugar levels on administration of multiple oral doses of the microspheres and a radioimmunoassay for serum insulin indicated absorption of insulin from the gastrointestinal region. This process could be utilized for the development of an oral insulin delivery system.     

吸收环节的药物相瓦作用案例分析（二）

目的：说明药物在吸收阶段发生的相互作用。方法：分析文献和案例。结果：4例临床案例使用的药物因为在吸收阶段发生相互作用而增加或减少另一种药物的吸收,从而使血药浓度增高或降低。结论：两种药物在吸收阶段可以通过改变肠道菌群,胃肠动力及络合作用等机制而影响药物的吸收。     

胰岛素强化治疗重型颅脑损伤60例的疗效观察

目的探讨强化胰岛素治疗重型颅脑损伤的临床疗效。方法60例重型颅脑损伤病例分为强化治疗组（强化组）和胰岛素常规治疗组（常规组）,观测治疗前后两组血糖、临床恢复效果及死亡率。结果强化组的血糖比常规治疗组的低（P〈0．05）,强化组的疗效优于治疗组（P〈0．05）。结论胰岛素强化治疗能有效改善重型颅脑损伤患者的预后。     

胰岛素经眼给药制剂的研究

实验研制了胰岛素滴眼剂。通过对缓冲液、增粘剂和吸收促进剂的筛选，确定了最佳处方组成：2％胰岛素、1％Brij－78、0．5％EDTA、1％玻璃酸钠的含0.03％对羟基苯甲酸乙酯的硼酸缓冲液。对兔眼试验证明该制剂无刺激性。药效学实验表明用其滴眼后吸收迅速，可显著降低糖尿病兔的血糖。血糖下降持续时间和最大降血糖均与给药剂量呈正相关。     

EDTA-Na2对胰岛素经眼吸收的作用

为了探讨金属螯合剂 EDTA 对多肽药物胰岛素经眼吸收给药的作用,用36只纯种新西兰大耳白家兔以经眼给药的方式对 EDTA 与国产胰岛素进行了研究,结果表明:①加 EDTA 与不加 EDTA 的胰岛素溶液经眼给药后其血中药物峰值浓度前者要比后者高3—4倍,并使生物利用度提高4—6倍,药物浓度一时间下曲线面积(AUC)和血药浓度均大于不加 EDTA 组。②降血糖的效果加 EDTA 的比不加 EDTA 的胰岛素溶液提高3—4倍。故而初步认为金属螯合剂 EDTA 对胰岛素经眼吸收有促进作用。     

基于案例的药物相互作用住吸收环节的影响（一）

目的：了解药物在吸收阶段发生的相互作用的机制。方法：通过文献检索和案例分析,对吸收阶段药物相互作用对药物疗效的影响进行探讨。结果：4例患者使用的药物因在吸收阶段发生的相互作用．一种药物可增加或减少另一种药物的吸收,致使后一种药物血药浓度增高或降低,影响治疗效果。结论：两种药物在吸收阶段可因改变肠道菌群．胃肠动力及络合作用等机制而影响药物的吸收。     

Nasal delivery of insulin using bioadhesive chitosan gels

Recently nasal delivery of insulin has gained considerable attention. Some limitations of this route include rapid mucociliary clearance of the drug from the site of deposition resulting in short time span available for absorption and low permeability of the nasal membrane for peptides. The objective of the present study was development of a chitosan bioadhesive gel for nasal delivery of insulin. A nasal perfusion test was used to study the toxicity of 4 absorption enhancers: saponin, sodium deoxycholate, ethylendiamine tetra-Acetic Acid (EDTA) and lecithin. The gels contained 4000 Iu/dl insulin, 2 or 4% of low and medium molecular weight of chitosan, and lecithin or EDTA. Drug release was studied by a membraneless diffusion method and bioadhesion by a modified tensiometry test. The optimized gel was administered nasally in diabetic rats. The serum insulin levels were analyzed by an insulin enzyme immunoassay kit and serum glucose by glucose oxidase method kits. Formulations containing 2% of low molecular weight of chitosan with EDTA had higher release percentage and dissolution efficiency (DE)_2.5%, lower T_50% (Time required to release 50% of the drug), mean dissolution time, and bioadhesion than gels containing 4% of medium molecular weight of chitosan with lecithin. Insulin was released by a zero-order kinetic from the gels. The gel of 2% medium molecular weight of chitosan with EDTA caused increase in insulin absorption and reduction the glucose level by as much as 46% of the intravenous route. Considering our in vitro and in vivo studies, the proposed gel formulation could be a useful preparation for controlled delivery of insulin through the nasal route.     

浅谈中药给药方式对药物吸收的影响

目的研究临床不同给药方式对药物吸收的影响,提高临床用药的准确性。方法随机抽取2012年10月至2013年10月,在我院接受中药用药治疗的80例患者资料,对其临床用药方式及用药成效回顾性分析,判断几种常见用药方法对药物吸收的影响情况。本次80例选择的重要给药方式:直肠给药、舌下给药、注射给药、吸入给药、经皮给药等,根据患者实际病况要求应用针对性的给药方法。患者用药后48 h检测中药吸收水平,对每一种给药方式的吸收状态进行统计。结果本次80例中药给药过程中,所有患者均起到了良好的用药治疗效果,但不同患者对药物吸收的水平不一样。分析影响药物吸收水平的影响,主要与药物性质、剂型、制剂和给药方式等因素有关。结论中药给药方式需符合患者的实际需求,以保证最终用药效果。