Zinc Chloride and Lead Acetate-Induced Passive Avoidance Memory Retention Deficits Reversed by Nicotine and Bucladesine in Mice.

It is very important to investigate the neurotoxic effects of metals on learning and memory processes. In this study, we tried to investigate the effects and time course properties of oral administration of zinc chloride (25, 50, and 75 mg/kg, for 2 weeks), lead acetate (250, 750, 1,500, and 2,500 ppm for 4, 6 and 8 weeks), and their possible mechanisms on a model of memory function. For this matter, we examined the intra-peritoneal injections of nicotine (0.25, 0.5, 1, and 1.5 mg/kg) and bucladesine (50, 100, 300, and 600 nM/mouse) for 4 days alone and in combination with mentioned metals in the step-through passive avoidance task. Control animals received saline, drinking water, saline, and DMSO (dimethyl sulfoxide)/deionized water (1:9), respectively. At the end of each part of studies, animals were trained for 1 day in step-through task. The avoidance memory retention alterations were evaluated 24 and 48 h later in singular and combinational studies. Zinc chloride (75 mg/kg) oral gavage for 2 weeks decreased latency times compared to control animals. Also, lead acetate (750 ppm oral administrations for 8 weeks) caused significant lead blood levels and induced avoidance memory retention impairments. Four-days intra-peritoneal injection of nicotine (1 mg/kg) increased latency time compared to control animals. Finally, findings of this research showed that treatment with intra-peritoneal injections of nicotine (1 mg/kg) and/or bucladesine (600 nM/mouse) reversed zinc chloride- and lead acetate-induced avoidance memory retention impairments. Taken together, these results showed the probable role of cholinergic system and protein kinase A pathways in zinc chloride- and lead acetate-induced avoidance memory alterations.

Prediction of pharmacokinetic parameters using a genetic algorithm combined with an artificial neural network for a series of alkaloid drugs.

An important goal for drug development within the pharmaceutical industry is the application of simple methods to determine human pharmacokinetic parameters. Effective computing tools are able to increase scientists' ability to make precise selections of chemical compounds in accordance with desired pharmacokinetic and safety profiles. This work presents a method for making predictions of the clearance, plasma protein binding, and volume of distribution for alkaloid drugs. The tools used in this method were genetic algorithms (GAs) combined with artificial neural networks (ANNs) and these were applied to select the most relevant molecular descriptors and to develop quantitative structure-pharmacokinetic relationship (QSPkR) models. Results showed that three-dimensional structural descriptors had more influence on QSPkR models. The models developed in this study were able to predict systemic clearance, volume of distribution, and plasma protein binding with normalized root mean square error (NRMSE) values of 0.151, 0.263, and 0.423, respectively. These results demonstrate an acceptable level of efficiency of the developed models for the prediction of pharmacokinetic parameters.

Epirubicin loaded super paramagnetic iron oxide nanoparticle-aptamer bioconjugate for combined colon cancer therapy and imaging in vivo.

Every year a large number of new cases of colorectal cancer are diagnosed in the world. Application of Epirubicin (Epi) in treatment of cancer has been limited due to its cardiotoxicity. Specific delivery of chemotherapy drugs is an important factor in reducing the side effects of drugs used in chemotherapy. Enhanced permeability, retention effect and magnetic resonance (MR) traceability of super paramagnetic iron oxide nanoparticles (SPION) make them a great candidate in cancer therapy and imaging. In this study, Epirubicin-5TR1 aptamer-SPION tertiary complex was evaluated for the imaging and treatment of murine colon carcinoma cells (C26 cells, target). For cytotoxic studies (MTT assay), C26 and CHO-K1 (Chinese hamster ovary cells, nontarget) cells were treated with either Epi or Epi-Apt-SPION tertiary complex. Internalization was evaluated by flow cytometry. Finally, Apt-SPION bioconjugate was used for imaging of cancer in vivo. Flow cytometric analysis showed that the tertiary complex was internalized effectively to C26 cells, but not to CHO-K1 cells. Cytotoxicity of Epi-Apt-SPION tertiary complex also confirmed internalization data. The complex was less cytotoxic in CHO-K1 cells when compared to Epi alone. No significant change in viability between Epi- and complex-treated C26 cells was observed. Magnetic resonance imaging (MRI) indicated a high level of accumulation of the nano-magnets within the tumor site. In conclusion Epi-Apt-SPION tertiary complex is introduced as an effective system for targeted delivery of Epi to C26 cells. Moreover this complex could efficiently detect tumors when analyzed by MRI and inhibit tumor growth in vivo.

Targeted delivery of Epirubicin to cancer cells by PEGylated A10 aptamer.

Clinical administrations of anthracyclines are limited by cardiotoxicity and myelosuppression. Targeted delivery of anticancer agents is especially important in reducing their side effects. In this work, A10 (Apt), an aptamer for prostate-specific membrane anytigen (PSMA), was applied for targeted delivery of Epirubicin (Epi) to LNCaP cells (PSMA(+)). Flow cytometry analysis showed that PEG-Apt-Epi complex was internalized effectively to LNCaP cells (PSMA(+)), but not to PC3 cells (PSMA(-)). This fact was confirmed by less cytotoxicity of PEG-Apt-Epi complex in PC3 cells in comparison with Epi alone. No significant change in viability between Epi- and complex-treated LNCaP cells was observed. In conclusion, PEG-Apt-Epi complex is an efficient and simple system for specific delivery of drug to PSMA-expressing cell lines.

Improvement of electrophoretic enantioseparation of amlodipine by polybrene.

In chiral and non-chiral electrophoretic resolution of basic drugs, adsorption of analytes to negatively charged capillary wall could lead to poor repeatability of migration time and peak area. In addition, chiral resolutions of basic drugs are commonly performed in low pH buffers. Therefore, longer analysis time due to suppression of electroosmotic flow (EOF) is another dilemma. In this work the improvement effect of polybrene (PB), a cationic polymer, on chiral separation of a model basic drug, amlodipine (AML), was investigated. PB both as a semi-permanent coating agent and as an additive in the running buffer was utilized. Better results were obtained with PB as a buffer additive. Compare to untreated bare silica without using PB in running buffer, addition of 0.0005% PB buffer decreased analysis time downed to 3 folds; efficiency improved up to 5 folds; limit of detection (LOD) and limit of quantification (LOQ) downed to 8 folds and within-day migration time and peak area repeatabilities, in terms of relative standard deviations (RSD) downed to 5 and 20 folds, respectively.