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The objective of this study was to investigate the acute toxicity, pharmacokinetics and pharmacodynamics of paliperidone derivatives (PDs) compared with paliperidone and risperidone. The i.g. LD 50 and i.v. maximum tolerated doses of PD1, PD5 and PD6 were greater than those of paliperidone and risperidone in mice. Pharmacokinetic study showed that PDs were quickly metabolized to paliperidone to take effect in the treatment of schizophrenia in rats after i.g. administration. Only traces of the parent substances were found. Pharmacodynamic study showed that PDs significantly reduced MK-801-induced hyperlocomotion in mice. The electrocardiogram (ECG) was recorded at 0,5,10,15,20, 25, 30, 45 and 60 min. in anaesthetized rats after i.v. injection of 0.21, 0.59, 1.69 lmol ⁄ kg drugs. Heart rate reduction had a linear relation with dose after i.v. injection of PDs, paliperidone and risperidone. No significant change in the ECG parameters was found in all groups after administration of the low dose. Although the reductions in heart rate and the corrected QT interval (QTc) were observed in all drugs at the high dose, PD5 and PD6 were associated with smaller effects on the ECG parameters than other compounds, including paliperidone and risperidone. Therefore, PD5 and PD6 could be potential candidates for the treatment of schizophrenia.Risperidone, 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidin]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido-[1,2-a]py rimidine-4-one, is a serotonin 5-HT 2 and dopamine D 2 receptor antagonist and widely used in the treatment of schizophrenia as an atypical antipsychotic drug. In human beings, risperidone is mainly metabolized to 9-hydroxyrisperidone by cytochrome P450 in the liver [1]. Because of its antipsychotic activity, 9-hydroxyrisperidone has been reported under the name of paliperidone for the treatment of schizophrenia. Johnson and Johnson launched paliperidone under the trade name of Invega in the end of 2006. The poor absolute oral bioavailability (only 28%) and the high daily dose of Invega may lead to an increased risk of side effects [2]. Consequently, it is very important to search for new derivatives of paliperidone for the treatment of schizophrenia with higher oral bioavailability and lower side effects [3]. A series of paliperidone derivatives (PDs) were synthesized ( fig. 1) and their physical and chemical properties are listed in table 1.Among patients with schizophrenia, accelerated heart disease is a major cause of sudden death and the risk of dying from cardiovascular disease is two to three times higher than in the general population [4]. Numerous antipsychotic drugs are well-documented for their effects on the QT interval [5]. Prolongation of the QT interval by risperidone has also been reported in a clinical study [6]. In vitro electrophysiological studies showed that supra-therapeutic doses of risperidone induced the prolongation of ventricular repolarization in a dose-related and reverse use-dependent manner, which prolonged the terminal repolariza...

The preparation and investigation of sustained-release risperidone-encapsulated microspheres using erodible poly(D, L-lactide-co-glycolide) (PLGA) of lower molecular weight were performed and compared to that of commercial Risperdal Consta™ for the treatment of schizophrenia. The research included screening and optimizing of suitable commercial polymers of lower molecular weight PLGA50/50 or the blends of these PLGA polymers to prepare microspheres with zero-order release kinetics properties. Solvent evaporation method was applied here while studies of the risperidone loaded microsphere were carried out on its drug encapsulation capacity, morphology, particle size, as well as in vitro release profiles. Results showed that microspheres prepared using 50504A PLGA or blends of 5050-type PLGAs exerted spherical and smooth morphology, with a higher encapsulation efficiency and nearly zero-order release kinetics. These optimized microspheres showed great potential for a better depot preparation than the marketed Risperdal Consta™, which could further improve the patient compliance.

Biotin was conjugated on poloxamer to prepare biotin-poloxamer (BP) conjugate micelles for chemotherapeutics. Epirubicin (EPI) was encapsulated in BP micelles. The EPI-loaded BP micelles were characterized in terms of size, ζ-potential, morphology, drug loading, drug encapsulation and drug release. Marrow leukemic HL-60 cells were used for evaluating the in vitro cytotoxicity of EPI-loaded BP micelles. Nude mice were axillainoculated subcutaneously HL-60 cells to establish tumour model for investigating the inhibition effects of EPI-loaded BP micelles. From the results, the sizes of these nanoparticles were about 100 nm. Fluorescence microscope observation supported the enhanced cellular uptake of the micelles. The order of the inhibition on tumour volume growth was: EPI-loaded BP micelles >EPI-loaded MATP micelles >EPI-loaded poloxamer micelles >EPI. BP micelles showed significant antitumour activity and low toxicity, compared with the non-targeted micelles. With the advantage of EPR effect and tumour-targeting potential, BP conjugate micelles might be developed as a new system for chemotherapeutics.

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Characterization and antitumor activity of basic fibroblast growth factor-mediated active targeting doxorubicin microbubbles (bFGF-DOX-MB) were investigated. Pluronic F68 with chemical conjugation of doxorubicin (DOX-P) and peptide KRTGQYKLC-conjugated DSPE-PEG2000 were prepared. bFGF-DOX-MB had a normal distribution of particle size, with average particle size of 2.7 μm. Using A549 mouse model, bFGF-DOX-MB combined ultrasound showed the best inhibition effect on tumor volume growth among all the test groups. Similar conclusion was obtained from experimental measurements of tumor weight change and blood cell count. From the results, chemotherapeutic drug inhibition on tumor growth could be enhanced by local ultrasound combined with active targeting bFGF-DOX-MB, which might provide a potential application for ultrasound-mediated chemotherapy.

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