PEG-modified magnetic Fe3O4 (Fe3O4-PEG) nanoparticles were sythesized using a solvothermal reaction and characterized with transmission electron microscopy (TEM) and thermo gravimetric analysis (TGA). The photothermal effect and photothermal destruction of cancer cells were evaluated. Then the doxorubicin loaded Fe3O4-PEG (DOX-Fe3O4-PEG) nanoparticles were prepared. The cytotoxicity and combined chemotherapy/photothermal therapy (PTT) effect were investigated. Uniform PEG coated Fe3O4 nanoparticles with particle size of 155 nm were obtained in the experiment. The loading and release of doxorubicin on Fe3O4-PEG were pH-dependent. The drug loading capacity in water was 21%. The results of MTT indicated a good biocompatiblity of Fe3O4-PEG nanoparticles and high cytotoxicity of DOX-Fe3O4-PEG. In combined therapy experiment, photothermal therapy demonstrated unambiguously enhanced chemotherapy efficacy. In conclusion, the obtained Fe3O4-PEG nanoparticles which exhibit good photothermal effect and drug loading capacity can be used for chemotherapy and photothermal therapy. The synergetic anti-tumor activity indicates the potential for the combined application of chemotherapy and photothermal therapy in cancer treatment.
Antibiotics, Antineoplastic ; administration & dosage ; pharmacology ; Cell Survival ; drug effects ; Doxorubicin ; administration & dosage ; pharmacology ; Drug Carriers ; Ferrosoferric Oxide ; chemistry ; Humans ; Hyperthermia, Induced ; MCF-7 Cells ; Magnetite Nanoparticles ; chemistry ; Particle Size ; Polyethylene Glycols ; chemistry

Dual dopamine D2/5-HT2A receptor antagonists have potent activity and are referred to atypical antipsychotics due to their lower propensity to elicit EPS and their moderate efficacy toward negative symptoms. However, an on-going challenge in developing atypical antipsychotics drugs is to maintain the favorable profiles and avoid of cardiovascular risk. In this paper, comparative pharmacophore analysis of dual dopamine D2/5-HT2A receptor antagonists, hERG K+ channel blockers, and alA adrenoceptor antagonists is carried out, and the results could give some insight into multi-target drug design.
Adrenergic alpha-1 Receptor Antagonists ; Dopamine D2 Receptor Antagonists ; Drug Delivery Systems ; Drug Design ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; antagonists & inhibitors ; chemistry ; Molecular Conformation ; Molecular Structure ; Receptor, Serotonin, 5-HT2A ; chemistry ; Receptors, Adrenergic, alpha-1 ; chemistry ; Receptors, Dopamine D2 ; chemistry ; Serotonin 5-HT2 Receptor Antagonists ; Structure-Activity Relationship

Drugs designed to act on individual molecular targets usually can not combat multigenic diseases such as cancer, or diseases that affect multiple tissues or cell types such as diabetes. Increasingly, it is being recognised that a balanced modulation of several targets can provide a superior therapeutic effect and side effect profile compared to the action of a selective ligand. The multi-target drugs which impact multiple targets simultaneously are better at controlling complex disease systems and are less prone to drug resistance. Here, we compare the disadvantage of the selective ligands and the predominance of multi-targets drugs in detail and introduce the approaches of designing multiple ligands and the procedure of optimization particularly. A key challenge in the design of multiple ligands is attaining a balanced activity at each target of interest while simultaneously achieving a wider selectivity and a suitable pharmacokinetic profile. On this point, the multi-target approach represents a new challenge for medicinal chemists, pharmacologists, toxicologists, and biochemists.
Chemistry, Pharmaceutical ; methods ; Drug Combinations ; Drug Delivery Systems ; methods ; Drug Design ; Humans ; Ligands ; Pharmacokinetics

OBJECTIVETo build 3D-pharmacophore model of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors using distance comparisons method and design novel EGFR inhibitors.

METHODSThirteen typical EGFR inhibitors were selected, and their biologically active conformations were obtained by using DOCK5.0 program, then 3D-pharmacophore model of EGFR inhibitors was built using distance comparisons method.

RESULTSValidation of the 3D-pharmacophore model was carried out and novel structures with potential inhibitory activity were selected by means of 3D-searching and docking method.

CONCLUSIONThis method can improve hit rate of lead compounds discovery and can be used to design novel EGFR inhibitors.

Drug Design ; Enzyme Inhibitors ; Epidermal Growth Factor ; metabolism ; Models, Chemical ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; chemistry ; pharmacology ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; chemistry ; Structure-Activity Relationship

Objective To investigate the efficacy of interferon α(IFNα)and adefovir dipivoxil (ADV)combination therapy in HBeAg positive chronic hepatitis B(CHB)patients and to explore the optimized strategy for individualized treatment.Methods A total of 156 HBeAg positive CHB patients were enrolled in the study from January 2005 to June 2009 in the Third Affiliated Hospital of Hebei Medical University.Fifty-six CHB patients with hepatitis B virus(HBV)DNA≥1 X 107copy/mLand/or liver fibrosis stage≥S3,or previous monotherapy failure(relapse)were treated with initial IFNα and ADV combination therapy.Fifty-two patients who didn't meet any of the above baseline characteristics received initial IFNα monotherapy.The remaining 48 patients treated with IFNα monotherapy for full treatment duration were considered as control.At week 24 of treatment,the treatment regimens were adjusted according to quantitative changes of HBV DNA,HBeAg and HBsAg:16 patients who achieved early response in group of initial IFNα and ADV combination therapy subsequently received IFNα monotherapy,the other patients in group of initial combination therapy together with patients who did not achieved early response in group of initial IFNα monotherapy subsequently received IFNα and ADV combination treatment.The HBV DNA levels,HBeAg and HBsAg titers were detected at the end of 48 weeks of treatment to determine the treatment duration.The treatment efficacy,safety,drug resistance and relapse rates were finally evaluated at week 72.All data were analyzed using chi square test.Results At week 24,the early response rate in group of initial combination therapy was 28.6%,and the HBV DNA negative rate and alanine aminotransferase(ALT)normalization rate were significantly higher than those in groups of initial IFNα monotherapy and control(53.6%vs 32.7%vs 27.1%and 62.5%vs 40.4%vs 37.5%,respectively,P<0.05);in addition,HBeAg loss rate was higher than control group(39.3%vs 18.8%,x2=7.48;P<0.05).At week 48,five of 16 patients who achieved early response developed HBeAg reversion and three cases accompanied with virological breakthrough in group of initial combination therapy after switching to IFNα monotherapy,while the rates of HBV DNA negative,HBeAg seroconversion and HBsAg clearance were 73.2%,41.1%and 12.5%,respectively.The HBV DNA negative rate,HBeAg seroconversion rate and HBsAg clearance rate in 96 patients Who had received different combination treatment regimens were 65.6%,33.3%and 8.3%,respectively.At week 72,the relapse rate in individualized treatment group was comparable to those in control group,while HBsAg clearance rate increased 2.7%in individualized treatment group.Conclusions IFNα and ADV combination treatment could improve early biochemical and virological responses.Individualized treatment strategy based on baseline characteristics and treatment responses may be helpful for optimizing antiviral treatment in CHB patients.

Glomerular hypertrophy is the main pathological characteristic in the early stage of diabetic nephropathy (DN), and its regulatory mechanism is closely related to mammalian target of rapamycin (mTOR) signaling pathway activity. mTOR includes mTOR complex 1 (mTORC1) and mTOR complex 2(mTORC2), in which, the upstream pathway of mTORC1 is phosphatidylinositol-3-kinase (PI3K)/serine-threonine kinase(Akt)/adenosine monophosphate activated protein kinase(AMPK), and the representative signaling molecules in the downstream pathway of mTORC1 are 4E-binding proteins(4EBP) and phosphoprotein 70 S6Kinase(p70S6K). Some Chinese herbal extracts could improve cell proliferation via intervening the expressions of the key molecules in the upstream or downstream of PIK/Akt/mTOR signaling pathway in vivo. As for glomerular mesangial cells(MC) and podocyte, mTOR plays an important role in regulating glomerular inherent cells, including adjusting cell cycle, energy metabolism and matrix protein synthesis. Rapamycin, the inhibitor of mTOR, could suppress glomerular inherent cell hypertrophy, cell proliferation, glomerular basement membrane (GBM) thickening and mesangial matrix deposition in model rats with DN. Some Chinese herbal extracts could alleviate glomerular lesions by intervening mTOR signaling pathway activity in renal tissue of DN animal models or in renal inherent cells in vivo and in vitro.
Animals ; Diabetic Nephropathies ; drug therapy ; enzymology ; genetics ; pathology ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Hypertrophy ; drug therapy ; enzymology ; genetics ; pathology ; Kidney Glomerulus ; drug effects ; metabolism ; pathology ; Signal Transduction ; drug effects ; TOR Serine-Threonine Kinases ; genetics ; metabolism

The study is to prepare taste masking and enteric-coated clarithromycin granules by melting and fluid bed coating technology. Clarithromycin and matrix materials were melted at a certain temperature, and then made into particles by fluidized bed coating. X-ray powder diffraction and scanning electron microscopy were used to identify the crystal and morphology of drug loading granules. In vitro dissolution method was used for the observation of the drug release behavior. The results showed that the drug particles size range was 0.2 - 0.6 mm; the crystal form of clarithromycin in the granule did not change; enteric-coated granules accumulated release in 0.1 mol L(-1) hydrochloric acid in 2 h was less than 10%, while in pH 6.8 phosphate buffer in 1 h was more than 80%. The taste masking and enteric-coated clarithromycin granules not only have good taste masking effect, but also have a good release behavior. It is expected to have better clinical application.
Clarithromycin ; administration & dosage ; chemistry ; Crystallization ; Drug Carriers ; Drug Compounding ; methods ; Excipients ; chemistry ; Microscopy, Electron, Scanning ; Particle Size ; Tablets, Enteric-Coated ; Taste ; Technology, Pharmaceutical ; methods ; X-Ray Diffraction

Objective To evaluate the method of vulvar reconstruction after extended vulvectomy. Methods Retrospectively, fourteen cases of vulva carcinoma were treated by radical wide local excision, and the defects were repaired with anterolateral thigh flap and inferior pedicle rectus abdominal myocutaneous flap. After the flap was harvested, it was put on the defect through the tunnel between the donor and the recipient site and the vulvae was reconstructed. Results All the flaps were survived except 1 anterolateral thigh flap with partial necrosis. One patient was infected at the groin incision but the flap and the grafted skin were survived. The patients were treated with change of the dressing and recovered after skin grafting. All other incisions were healed with first intention. The partial necrosis area was about 4 cm?6 cm, it healed at 36 postoperative days after free skin grafting. The reconstructed vulvae were plump and elastic. It appeared like the normal vulvae and there was no contraction of the vagina. Conclusions Vulvar reconstruction with the anterolateral thigh flap and rectus abdominal flaps after the radical vulvectomy could make the patients recover easily. It produces almost normal appearance and function of the vulvae, reduces the time of would healing. The patient could have the next therapy more quickly and the quality of life improves. It has wide application value in clinics.

Objective:To evaluate the effect of oxygen supply via the transnasal self-made pharyngeal oxygen catheter on the safe apnea time in pediatric patients undergoing tonsil surgery. Methods:Sixty American Society of Anesthesiologists physical status Ⅰ or Ⅱ patients of either sex, aged 2-6 yr, weighing 10-20 kg, scheduled for elective tonsillectomy under general anesthesia, were divided into 2 groups ( n=30 each) using a random number table method: transnasal self-made pharyngeal oxygen catheter for oxygen supply group (group NO) and control group (group C). Anesthesia was induced with intravenous midazolam, propofol, fentanyl and cis-atracurium, and then ventilation was performed with a mask, and the mask was removed when the exhaled oxygen concentration (C ETO 2) reached more than 90%.In group NO, the self-made oxygen catheter was implanted into the oropharynx through the nose, and the 100% oxygen at 10 L/min was aspirated through the humidification bottle until the intubation was successful.In group C, the transnasal self-made oxygen catheter was not implanted, and the rest of the protocol was similar to those previously described in group NO.The visual laryngoscope was implanted to simulate difficult airways.When SpO 2 ≤ 95% or the safe apnoea time reached 600 s, the observation of apnea was stopped, and mechanical ventilation was started after successful rapid endotracheal intubation.The safe apnea time (from removing the mask until SpO 2 decreased to 95%), value of C ETO 2 at the end of mask ventilation, and the minimum value of SpO 2 after stopping mask ventilation were recorded.Heat rate and mean arterial pressure were observed and recorded on admission to the operating room, immediately after onset of apnea and immediately after successful endotracheal intubation.The SpO 2, P ETCO 2 and cross-sectional area of gastric antrum were also recorded immediately after onset of apnea and immediately after successful endotracheal intubation, and the rate of increase in P ETCO 2 was calculated.The nasal bleeding, nasal dryness, postoperative pharyngeal discomfort and other adverse reactions were recorded when the self-made pharyngeal oxygen catheter was placed. Results:Compared with group C, the safe apnea time was significantly prolonged, the rate of increase in P ETCO 2 was decreased, the minimum value of SpO 2 after stopping mask ventilation was increased, and the heat rate, mean arterial pressure, SpO 2 and P ETCO 2 were increased immediately after successful intubation ( P<0.05), no significant change was found in C ETO 2 after stopping mask ventilation and cross-sectional area of gastric antrum at each time point in group NO ( P>0.05). No adverse reactions such as nasal bleeding, nasal dryness and postoperative pharyngeal discomfort were found when the self-made pharyngeal oxygen catheter was inserted in group NO. Conclusions:The oxygen supply with the transnasal self-made pharyngeal oxygen catheter technique can prolong the safe apnea time in the pediatric patients undergoing tonsil surgery.

BACKGROUNDChildhood absence epilepsy (CAE) is one of the most frequently recognized syndromes among the idiopathic generalized epilepsies (IGEs). CAE is considered to be a genetic disease, with a possible polygenic inheritance pattern. The genes responsible for CAE have not been identified yet. The object of this study was to investigate whether or not CAE is associated with the gene encoding the gamma-aminobutyric acid (GABA) type-A receptor subunits alpha5 (GABRA5) and beta3 (GABRB3) in a Chinese population.

METHODSFive microsatellite DNA repeats, 69CA, 85CA, 155CA1, 155CA2, and A55CA1, adjoining chromosome 15q11-q13, were used as genetic markers. Both case-control study and transmission/disequilibrium tests (TDTs), as well as fluorescence-based semi-automated genotyping techniques, were used in 90 CAE patient-mother-father trios and 100 normal controls of Han ethnicity to conduct association analysis.

RESULTSThe frequencies of allele 5 of 69CA, alleles 2 and 8 of 85CA, alleles 6 and 7 of 155CA1, allele 2 of 155CA2, and alleles 1 and 11 of A55CA1 were significantly higher in CAE patients than in normal controls. To prevent spurious associations arising from population admixture, we further conducted TDT tests in the 90 CAE trios. The results of TDT analysis further suggested that microsatellite DNA repeats 85CA, 155CA1, and 155CA2 were associated with CAE.

CONCLUSIONSGABA type-A receptor subunit genes GABRA5 and GABRB3 may be either directly involved in the etiology of CAE in the Chinese population or in linkage disequilibrium with disease-predisposing sites.

Adolescent ; Case-Control Studies ; Child ; Child, Preschool ; Epilepsy, Absence ; genetics ; Female ; Genetic Predisposition to Disease ; Humans ; Linkage Disequilibrium ; Male ; Microsatellite Repeats ; Protein Subunits ; Receptors, GABA-A ; genetics