[Preparation and Evaluation of Intranasal in situ Gel of Bupleuri Radix Volatile Oil and Baicalin].

OBJECTIVE: To prepare and evaluate a new formulation of thermosensitive and ion-sensitive in situ gel for nasal administration, using the volatile oil of Bupleuri radix and baicalin, the effective component extracted from Scutellariae radix . METHODS: Formulation of in situ nasal gel of Bupleuri radix volatile oil and baicalin was prepared by using poloxamer 407 and deacetylated gellan gum as the gel base, 10% pharmasolve and 2% polysorbate 80 as the solubilizer, and 0.8% triethanolamine as the pH regulator. The physical appearance, phase transition temperature, and baicalin release performance of the prepared gel were examined. The pharmacodynamic evaluation was done with the rat fever model developed with dry yeast and the mouse auricle swelling inflammation model. RESULTS: The phase transition temperature of the gel was optimized to be 36 ℃. The release of baicalin from the gel showed obvious features of sustained release, which accorded well the zero-order kinetics equation. The results of experiments with the rat dry yeast fever model and the mouse xylene auricle swelling inflammation model showed that the gel had significant antipyretic and anti-inflammatory effects that were significantly better than those of the groups treated with the blank gel base and the Bupleuri radix and Scutellariae radix granule. Results from the cilia toxicity test showed that the gel did not have obvious toxic effect on toad palate mucosal cilia. CONCLUSION: The in situ nasal gel of Bupleuri radix volatile oil and baicalin prepared in the study had a rapid onset time, high efficiency, and prolonged release of active ingredients, thus showing promises for further applicational development.

Recombinant Tissue Plasminogen Activator-conjugated Nanoparticles Effectively Targets Thrombolysis in a Rat Model of Middle Cerebral Artery Occlusion.

The efficacy and safety of recombinant tissue plasminogen activator (rtPA) need to be improved due to its low bioavailability and requirement of large dose administration. The purpose of this study was to develop a fibrin-targeted nanoparticle (NP) drug delivery system for thrombosis combination therapy. We conjugated rtPA to poly(ethylene glycol)- poly(e-caprolactone) (PEG-PCL) nanoparticles (rtPA-NP) and investigated its physicochemical characteristics such as particle size, zeta potential, enzyme activity of conjugated rtPA and its storage stability at 4°C. The thrombolytic activity of rtPA-NP was evaluated in vitro and in vivo as well as the half-life of rtPA-NP, the properties to fibrin targeting and its influences on systemic hemostasis in vivo. The results showed that rtPA-NP equivalent to 10% of a typical dose of rtPA could dissolve fibrin clots and were demonstrated to have a neuroprotective effect after focal cerebral ischemia as evidenced by decreased infarct volume and improved neurological deficit (P<0.001). RtPA-NP did not influence the in vivo hemostasis or coagulation system. The half-life of conjugated rtPA was shown to be approximately 18 times longer than that of free rtPA. These experiments suggested that rtPA-conjugated PEG-PCL nanoparticles might be a promising fibrin-targeted delivery system for a combination treatment of thrombosis.

Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis.

Hyperactivated Ras regulates many oncogenic pathways in several malignant human cancers including glioblastoma and it is an attractive target for cancer therapies. Ras activation in cancer cells drives protein internalization via macropinocytosis as a key nutrient-gaining process. By utilizing this unique endocytosis pathway, here we create a biologically inspired nanostructure that can induce cancer cells to 'drink drugs' for targeting activating transcription factor-5 (ATF5), an overexpressed anti-apoptotic transcription factor in glioblastoma. Apolipoprotein E3-reconstituted high-density lipoprotein is used to encapsulate the siRNA-loaded calcium phosphate core and facilitate it to penetrate the blood-brain barrier, thus targeting the glioblastoma cells in a macropinocytosis-dependent manner. The nanostructure carrying ATF5 siRNA exerts remarkable RNA-interfering efficiency, increases glioblastoma cell apoptosis and inhibits tumour cell growth both in vitro and in xenograft tumour models. This strategy of targeting the macropinocytosis caused by Ras activation provides a nanoparticle-based approach for precision therapy in glioblastoma and other Ras-activated cancers.

[The progress of novel drug delivery systems].

The development of pharmaceuticals has been providing many kinds of novel drug delivery systems, which are important for improving therapeutic effect and one of the most important fields in pharmaceutics. According to their application, we can generally divide the novel drug delivery systems into three categories: quickly performed drug delivery system, long-term drug delivery system and high effective drug delivery system. Some diseases, such as asthma, angina pectoris and migraine, require therapeutics urgently, and the drugs have to be absorbed in several minutes. Therefore, quickly performed drug delivery systems are developed, such as oral disintegrating tablets and nasal spray. For normal tablets and capsules, especially the drugs with short blood half life, the drug concentration in blood shows obvious peak-valley phenomenon, which reduces the therapeutic effect and requires multiple administration. To solve this problem, sustained drug release system was developed, which could release the drugs slowly and sustainably even in zero-order kinetics. The pulse drug delivery system was developed that can delayed and pulsed release drug for one or several times. This system is especially useful in the management of asthma and heart disease, which are often found in midnight or early morning when patients are in bed. Transdermal drug delivery system could release drugs sustainably and deliver the drugs through skin to blood circulation, providing long term activity. The water-insoluble drugs are difficult for pharmaceutical development, thus many methods were developed to improve the solubility and bioavailability of drugs. Although biopharmaceuticals are important for disease treatment, the application shadows by the poor stability and low bioavailability. Thus the biopharmaceutical delivery system was developed, which mainly focused on structure modification and encapsulation by carriers. Considering therapeutic effect requires interaction between drugs and their targets, it is important to deliver drugs to their targets. Therefore, targeting delivery systems were developed, which mainly based on the nanoparticles. Furthermore, on-demand release drug delivery systems are also developed with the property of environment-triggered drug release. In conclusion, the novel drug delivery systems were reviewed in this study.

[The development of novel tumor targeting delivery strategy].

Tumor is one of the most serious threats for human being. Although many anti-tumor drugs are approved for clinical use, the treatment outcome is still modest because of the poor tumor targeting efficiency and low accumulation in tumor. Therefore, it is important to deliver anti-tumor drug into tumor efficiently, elevate drug concentration in tumor tissues and reduce the drug distribution in normal tissues. And it has been one of the most attractive directions of pharmaceutical academy and industry. Many kinds of strategies, especially various nanoparticulated drug delivery systems, have been developed to address the critical points of complex tumor microenvironment, which are partially or mostly satisfied for tumor treatment. In this paper, we carefully reviewed the novel targeting delivery strategies developed in recent years. The most powerful method is passive targeting delivery based on the enhanced permeability and retention(EPR) effect, and most commercial nanomedicines are based on the EPR effect. However, the high permeability and retention require different particle sizes, thus several kinds of size-changeable nanoparticles are developed, such as size reducible particles and assemble particles, to satisfy the controversial requirement for particle size and enhance both tumor retention and penetration. Surface charge reversible nanoparticles also shows a high efficiency because the anionic charge in blood circulation and normal organs decrease the unintended internalization. The charge can change into positive in tumor microenvironment, facilitating drug uptake by tumor cells. Additionally, tumor microenvironment responsive drug release is important to decrease drug side effect, and many strategies are developed, such as p H sensitive release and enzyme sensitive release. Except the responsive nanoparticles, shaping tumor microenvironment could attenuate the barriers in drug delivery, for example, decreasing tumor collagen intensity and normalizing tumor microvessels to decrease the internal fluid pressure. All these strategies could enhance the accumulation and penetration of nanoparticles into tumor, leading to a homogenous distribution of drugs in tumor. To enhance the internalization by specific cells, active targeting delivery strategies are developed. There were many surface markers, receptors or carriers overexpressed on specific kinds of cells, thus the corresponding ligands were utilized to mediate active targeting to certain cells, including tumor cells, cancer stem cells, tumor neovasculatures, tumor associated macrophages and other tumor stroma cells. Targeting more than one cell type may provide an improved antitumor effect. Although these passive and active targeting strategies all have promising outcome in the treatment of tumor, some shortages are still unaddressed, such as the specificity of responsive is not good enough, and the active targeting may be diminished by the protein corona. Thus more research is required to promote the drug delivery study.

High-density lipoprotein-biomimetic nanocarriers for glioblastoma-targeting delivery: the effect of shape.

Rational design of the physicochemical properties of nanocarriers can optimize their pharmacokinetics, biodistribution, intratumoral penetration and tumor bioavailability. In particular, particle shape is one of the crucial parameters that can impact the circulation time, tumor accumulation and tumor cell internalization of nanocarrier. Biomimetic reconstituted high-density lipoprotein (rHDL), by mimicking the endogenous shape and structure of high-density lipoprotein, has been indicated as a promising tumor-targeting nanoparticulate drug delivery system whereas the effect of shape on tumor-targeting efficiency has not been fully evaluated. Herein, we constructed apolipoprotein E-based biomimetic rHDL in both discoidal form (d-rHDL) and spherical form (s-rHDL), and compared their efficiency in glioblastoma multiforme (GBM)-targeting delivery. s-rHDL showed higher cellular association in GBM cells especially at a high exposure dosage or after a long incubation time. Moreover, it exhibited deeper penetration in 3D GBM spheroids in vitro and higher accumulation at the GBM site in vivo with the GBM-targeting accumulation of s-rHDL increased by 73% when compared with that of d-rHDL at 24 h post-injection. The findings collectively indicated that s-rHDL might serve as a more efficient nanocarrier for glioblastoma-targeting drug delivery.

Anti-CD69 monoclonal antibody treatment inhibits airway inflammation in a mouse model of asthma.

OBJECTIVE: Airway inflammation and airway hyper-responsiveness (AHR) are principle pathological manifestations of asthma. Cluster of differentiation 69 (CD69) is a well-known co-stimulatory factor associated with the activation, proliferation as well as apoptosis of immune cells. This study aims to examine the effect of anti-CD69 monoclonal antibody (mAb) on the pathophysiology of a mouse model of asthma. METHODS: A murine model of ovalbumin (OVA)-induced allergic airway inflammation was used in this study. Briefly, mice were injected with 20 µg chicken OVA intraperitoneally on Days 0 and 14, followed by aerosol provocation with 1% (0.01 g/ml) OVA on Days 24, 25, and 26. Anti-CD69 mAb or isotype IgG was injected intraperitoneally after OVA challenge; dexamethasone (DXM) was administrated either before or after OVA challenge. AHR, mucus production, and eosinophil infiltration in the peribronchial area were examined. The levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-5 (IL-5) in bronchoalveolar lavage fluid (BALF) were also assayed as indices of airway inflammation on Day 28 following OVA injection. RESULTS: Pretreatment with DXM together with anti-CD69 mAb treatment after OVA provocation completely inhibited AHR, eosinophil infiltration and mucus overproduction, and significantly reduced BALF IL-5. However, treatment with DXM alone after OVA challenge only partially inhibited AHR, eosinophil infiltration and mucus overproduction, and did not diminish BALF IL-5. Treatment with either DXM or anti-CD69 mAb did not alter the concentration of BALF GM-CSF. CONCLUSIONS: Anti-CD69 mAb treatment inhibits established airway inflammation as effectively as DXM pretreatment. This study provides a potential alternative therapeutic opportunity for the clinical management of asthma and its exacerbation.

Determination of sulphasalazine and its main metabolite sulphapyridine and 5-aminosalicylic acid in human plasma by liquid chromatography/tandem mass spectrometry and its application to a pharmacokinetic study.

A simple and sensitive liquid chromatography/positive-ion electrospray ionization mass spectrometry (LC-ESI-MS/MS) method has been developed for the simultaneous determination of sulphasalazine (SASP) and its main metabolite sulphapyridine (SP) and 5-aminosalicylic acid (5-ASA) with 100 µL of human plasma using dimenhydrinate as the internal standard (I.S.). The API-3000 LC-MS/MS was operated under the multiple reaction-monitoring mode (MRM) using the electrospray ionization technique. Protein precipitation process was used to extract SASP, SP, 5-ASA and I.S. from human plasma. The total run time was 9.0 min and the elution of SASP, SP and 5-ASA was at 4.8 min, 2.5 min and 2.0 min, respectively. The separation was achieved with a mobile phase consisting of 0.2% formic acid, 2 mM ammonium acetate in water (mobile phase A) and 0.2% formic acid, 2 mM ammonium acetate in methanol (mobile phase B) by using gradient elution on a XBP Phenyl column (100 mm × 2.1 mm, 5 µm). The developed method was validated in human plasma with a lower limit of quantitation of 10 ng/mL for SASP, SP and 5-ASA, respectively. A linear response function was established for the range of concentrations 10-10,000 ng/mL (r>0.99) for SASP and 10-1000 ng/mL (r>0.99) for SP and 5-ASA. The intra and inter-day precision values for SASP, SP and 5-ASA met the acceptance as per FDA guidelines. SASP, SP and 5-ASA were stable during stability studies, i.e., long term, auto-sampler and freeze/thaw cycles. The method was successfully applied for the evaluation of pharmacokinetics of SASP, SP and 5-ASA after single oral doses of 250 mg SASP to 10 healthy volunteers.

Determination of vinpocetine and its primary metabolite, apovincaminic acid, in rat plasma by liquid chromatography-tandem mass spectrometry.

A precise and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of vinpocetine (VP) and its primary metabolite, apovincaminic acid (AVA), in rat plasma was developed and validated. The analytes and the internal standard-dimenhydrinate were extracted from 50 microL aliquots of rat plasma via solid-liquid extraction. Chromatographic separation was achieved in a run time of 3.5 min on a C(18) column under isocratic conditions. Detection of analytes and IS was done by tandem mass spectrometry, operating in positive ion and multiple reaction monitoring (MRM) acquisition mode. The protonated precursor to product ion transitions monitored for VP, AVA and IS were m/z 351.4-->280.2, 323.2-->280.2 and 256.2-->167.3 respectively. The method was fully validated for its sensitivity, selectivity, accuracy and precision, matrix effect, stability study and dilution integrity. A linear dynamic range of 0.5-500 ng/mL for both VP and AVA was evaluated with mean correlation coefficient (r) of 0.9970 and 0.9984 respectively. The precision of the assay (RSD%) was less than 8.55% at all concentrations levels for both VP and AVA. This method was successfully applied to a pharmacokinetic study of VP in rats after intravenous (1 mg/kg) and oral (1 mg/kg) administration.

Effect of lactoferrin- and transferrin-conjugated polymersomes in brain targeting: in vitro and in vivo evaluations.

AIM: To evaluate the effect of lactoferrin (Lf) and transferrin (Tf) in brain targeting. METHODS: Polymersomes (PSs), employed as vectors, were conjugated with Lf or Tf and were characterized by morphology, particle size, zeta potential, and surface densities of the Lf or Tf molecules. In vitro uptake of Lf-PS and Tf-PS by bEnd.3 cells was investigated using coumarin-6 as a fluorescent probe. In vivo tissue distribution and pharmacokinetics of (125)I-Lf-PS and (125)I-Tf-PS were also examined. RESULTS: The mean particle size of PS, Lf-PS, and Tf-PS was around 150 nm and the zeta potential of the PSs was about -20 mV. Less than 0.12% of the coumarin was released from coumarin-6-loaded PS in 84 h indicating that coumarin-6 was an accurate probe for the PSs' behavior in vitro. It was shown that the uptake of Lf-PS and Tf-PS by bEnd.3 cells was time-, temperature-, and concentration-dependent. Both Lf and Tf could increase the cell uptake of PSs at 37 degrees C, but the uptake of Tf-PS was significantly greater than that of Lf-PS. In vivo tissue distribution and pharmacokinetics in mice revealed higher brain uptake and distribution of Tf-PS than Lf-PS, which was in accordance with in vitro uptake results. The drug targeting index (DTI) of Tf-PS with regard to Lf-PS was 1.51. CONCLUSION: Using a PS as the delivery vector and bEnd.3 cells as the model of the blood-brain barrier (BBB), Tf was more effective than Lf in brain targeting.

[Development of gene therapy in major brain diseases].

In recent years, the development of molecular biology and medicine has prompted the research of gene therapy for brain diseases. In this review, we summarized the current gene therapy approaches of major brain diseases. Against the pathogenesis of major brain diseases, including brain tumors, Parkinson's disease, Alzheimer's disease and cerebrovascular disorders, there are several effective gene therapy strategies. It is no doubt that, gene therapy, as a novel treatment, is of great significance for understanding the causes, as well as comprehensive treatment for brain diseases.

Preparation of nasal temperature-sensitive in situ gel of Radix Bupleuri and evaluation of the febrile response mechanism.

OBJECTIVE: This study developed a nasal temperature-sensitive in situ gel system for Radix Bupleuri. METHOD: Using 20% Poloxamer 407 as the gel base and 6% PEG 4000 adjusting the gelation temperature. RESULTS: The system is liquid at 4 degrees C. It can change its phase to gel above 30 degrees C, which is close to the temperature in nasal cavity. The antipyretic effect produced by Radix Bupleuri in situ gel formulation was investigated in fevered rabbits. The results show that it can prolong the effective time to 24 hours compared with 4-6 hours in Radix Bupleuri intranasal solution. The antipyretic response mechanism was researched by evaluating the relationship between body temperature and concentrations of cyclic adenosine monophosphate in cerebrospinal fluid. The results showed that the two parameters were positively correlated (r = 0.9435, P < 0.05). Six hours later after given in situ gel, the concentrations of cAMP were significantly lower than those in the solution group. It confirmed that temperature-sensitive Radix Bupleuri in situ gel applied in the nasal sprays had a longer residence and release time. CONCLUSION: Radix Bupleuri nasal temperature-sensitive in situ gel has a higher medical effect and a longer effective time. Compared to the traditional nasal spray, it is more applicable for the treatment of fever.

Hydrophilic nasal gel of lidocaine hydrochloride. 2nd communication: Improved bioavailability and brain delivery in rats with low ciliotoxicity.

Intranasal lidocaine hydrochloride (LID, CAS 73-78-9) has been widely and commonly used in the treatment of a series of symptoms such as migraine, cluster headache and trigeminal neuralgia in clinical studies. Nevertheless, rapid nasal mucociliary clearance of intranasal solution presents the predominant obstacle impacting its efficiency. In order to prolong the residence time of LID in the nasal cavity and increase its absorption, a LID nasal gel had been developed previously using hydroxypropyl methyl cellulose (HPMC) as base material. The LID nasal gel formulation has been optimized through central composite design and its in vitro release behavior has been investigated. In the present study, safety studies employing in situ toad palate model and in vivo rat nasal mucosa model showed that compared with LID nasal spray, LID nasal gel was less toxic to mucocilia. The pharmacokinetic parameters, along with olfactory and ventricle delivery of LID from nasal gel were compared with those of LID from nasal spray, intravenous injections and oral solutions in rats using microdialysis, and the drug targeting index (DTI) was used to evaluate their brain delivery. The absolute bioavailability of the optimized LID nasal gel was about 1.5 times of that of LID nasal spray which suggested a better absorption of LID from nasal gel. Moreover, the drug targeting index (DTI) of olfactory/ventricle after nasal gel and spray administration was 2.15/1.51 and 1.66/1.26, respectively. This suggested that a fraction of the LID dose could be transported directly from the nasal cavity into the central nervous system (CNS), and the brain delivery of LID can be enhanced by nasal gel.

Hydrophilic nasal gel of lidocaine hydrochloride. 1st Communication: Preparation, formulation optimization and in vitro release study.

Intranasal lidocaine hydrochloride (LID, CAS 73-78-9) has been shown useful in the control of a series of symptoms such as migraine, cluster headache and trigeminal neuralgia in clinical studies. However, rapid nasal mucociliary clearance of intranasal solution usually affects its efficiency. In this study, a nasal gel formulation was designed using hydroxypropyl methyl cellulose (HPMC) as mucoadhesive polymer to increase the residence time of LID on the nasal mucosa. Based on the results of a preliminary single factor study, the gel formulation was optimized by central composite design to provide better drug release and bioadhesive intensity. The methods for investigating the gel's bioadhesive intensity and for spectrophotometric determination of LID were established. Then the parameters for the LID in vitro release study such as release medium, release apparatus and rotation rate were decided upon a method of f2 fit factor. The in vitro drug release property of the optimized formulation was proved to comply with the Higuchi equation.

In situ gel based on gellan gum as new carrier for nasal administration of mometasone furoate.

The main purpose of this study was to prepare a novel in situ gel system for nasal delivery of MF and study its efficacy on allergic rhinitis model. An ion-activated in situ gel was developed and characterized with gellan gum as a carrier. The system was stable kept at 40+/-2 degrees C for 6 months, and the micrographic results showed that in situ gel was safety without mucosa irritation when given at 20 microg once daily for 1 month to rats with allergic rhinitis. MF in gellan gum produced obviously effect on allergic rhinitis at the doses of 20 microg/body following intranasal administration, and the efficacy was significantly superior to that of the common suspension (P<0.01). The in situ gel system is a promising approach for the intranasal delivery of MF for the therapeutic effects improvement.

[Advances in the study of lipid-based cubic liquid crystalline nanoparticles as drug delivery system].

Various geometric shapes and structures self-assembled of amphiphilic lipids when present in an aqueous environment, as active delivery vehicles, are becoming one of focuses of drug delivery system. Lipid-based cubic liquid crystalline nanoparticles (or Cubosomes) consisting of "honeycombed (cavernous)" structure spontaneously formed when a certain concentration of amphiphilic lipids dispersed in aqueous solution has curved bicontinuous lipid bilayer in three dimensions, separating two congruent networks of water channels. Its unique structure consists of internal double water channels and large interfacial areas, which reveal great flexibility in encapsulation efficiency of various polarities and amount of drugs, and has variegated range of drugs encapsulated. As a drug delivery vehicle, high drug payloads, stabilization of peptides or proteins and simple preparation process are also its advantages. The ability of cubic phase to incorporate and control release of drugs of varying size and polar characteristics, and biodegradability of lipids make it an interesting drug delivery system for various routes of administration, including oral, topical (or mucosal) and intravenous administrations, with extensive application in a multitude of dosage forms. Furthermore, a number of different proteins in cubic phase appear to retain their native conformation and bioactivity, and are protected against chemical and physical inactivation. In this paper, investigations of lipid-based cubic liquid crystalline nanoparticles are reviewed and summarized, with a hope to provide a reference for its in-depth study. At the end, the authors made a development prospect of this novel excellent candidate for active ingredients delivery vehicle.

A novel nasal delivery system of a Chinese traditional medicine, Radix Bupleuri, based on the concept of ion-activated in situ gel.

The purpose of this study was to develop a nasal in situ gel system for Radix Bupleuri employing gellan gum as a polymer. Radix Bupleuri in situ gel containing 0.2 mL essential oil extracted from 450 g Radix Bupleuri, proper solubilizing agents and gellan gum (0.5% w/v) was prepared and characterized. The antipyretic effect produced by in situ gel formulation was investigated in fevered rabbits and compared to an intranasal solution. The resulting in situ gel was a clear and light-yellow liquid, with viscosity of 346 mPa x s and caproic acid content of 1.31 +/- 0.01 mg/mL. Intranasal administration of this preparation to fevered rabbits decreased body temperature markedly (1.1 degree C at the doses of oil from 1.5 g Bupleuri/body) and the effect could last for 20-30 h. The results suggest that Radix Bupleuri in situ gel can be greater effective than the solution in the treatment of fever.

Preparation of ion-activated in situ gel systems of scopolamine hydrobromide and evaluation of its antimotion sickness efficacy.

AIM: To develop a novel, in situ gel system for nasal delivery of scopolamine hydrobromide (SCOP) and study its efficacy on motion sickness. METHODS: SCOP in situ gels at 0.2%, 0.5%, and 1.0% gellan gum concentration (w/v) were prepared, respectively, and characterized in terms of viscosity, in vitro release, and nasal ciliotoxicity. Single photon emission computing tomography technique was used to evaluate the nasal residence time of gel containing (99m)Tc tracer. The antimotion sickness efficacy produced by the in situ gel formulation was investigated in rats and compared with those achieved after subcutaneous and oral administration. RESULTS: The viscosity of the gellan gum formulations either in solution or in gel increased with increasing concentrations of gellan gum. Its release in vitro was moderate in artificial nasal fluid. The micrographic results showed that in situ gels were safe, without nasal ciliotoxicity. In comparison with phosphate buffer saline, a prolonged radioactivity of (99m)Tc in the rabbit nasal cavity was observed after administration of the gellan gum formulation. Intranasal SCOP in situ gel at a dose of 100 microg/kg decreased symptoms of motion sickness significantly in comparison with subcutaneous and oral administration (P<0.01). CONCLUSION: SCOP nasal in situ gel is a safe and promising therapeutic alternative to existing medications for motion sickness.

Evaluation of the bioequivalence and pharmacokinetics of two formulations of secnidazole after single oral administration in healthy volunteers.

The pharmacokinetic parameters of two oral formulations of a 1 g dose of secnidazole (CAS 3366-95-8, secnidazole tablet as reference and another capsule preparation as test) were compared in an open-label, randomized, single oral dose, two-period cross-over design in 18 healthy volunteers under fasting conditions. Plasma concentrations of secnidazole were measured by a validated HPLC chromatographic assay. The parametric 90% confidence intervals of the geometric mean values of the test/reference ratios were 91.9% to 105.9% (point estimate: 99.39%) for AUC(0-infinity), 92.7% to 104.4% (point estimate: 98.61%) for AUC(0-t), 97.6% to 107.1% (point estimate: 102.31%) for C(max), being within the acceptance criteria for bioequivalence (80%-125%). T(max) values were analyzed by the nonparametric Wilcoxon test and the difference was not statistically significant. Therefore, it is concluded that the test and reference secnidazole formulations are bioequivalent for both the extent and the rate of absorption.

Cationic albumin-conjugated pegylated nanoparticles allow gene delivery into brain tumors via intravenous administration.

Patients with malignant gliomas have a poor prognosis because these tumors do not respond well to conventional treatments. Studies of glioma xenografts suggest that they may be amenable to gene therapy with cytotoxic genes, such as the proapoptotic Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL). Gene therapy of gliomas ideally employs i.v. given vectors, thus excluding viral vectors as they cannot cross the brain microvascular endothelium or blood-brain barrier. Recently, we reported the synthesis of cationic albumin-conjugated pegylated nanoparticles (CBSA-NP) and showed their accumulation in mouse brain cells upon i.v. administration. In this study, plasmid pORF-hTRAIL (pDNA) was incorporated into CBSA-NP, and the resulting CBSA-NP-hTRAIL was evaluated as a nonviral vector for gene therapy of gliomas. Thirty minutes after transfection of C6 glioma cells, CBSA-NP-hTRAIL was internalized and mostly located in the cytoplasm, whereas NP-hTRAIL was entrapped in the endolysosomal compartment. At 6 and 48 hours after transfection, respectively, released pDNA was present in the nuclei and induced apoptosis. At 30 minutes after i.v. administration of CBSA-NP-hTRAIL to BALB/c mice bearing i.c. C6 gliomas, CBSA-NP-hTRAIL colocalized with glycoproteins in brain and tumor microvasculature and, via absorptive-mediated transcytosis, accumulated in tumor cells. At 24 and 48 hours after i.v. administration of CBSA-NP-hTRAIL, respectively, hTRAIL mRNA and protein were detected in normal brain and tumors. Furthermore, repeated i.v. injections of CBSA-NP-hTRAIL induced apoptosis in vivo and significantly delayed tumor growth. In summary, this study indicates that CBSA-NP-hTRAIL is a promising candidate for noninvasive gene therapy of malignant glioma.