Trypanosoma is a human parasite severely affecting poor tropical areas.However,current frontline drugs for Trypanosoma treatment have severe side-effects with decreased effectiveness.Based on the fact that aminoacyl-tRNA synthetase is a bonafide drug target for several microorganisms,including bacteria and fungi,it is plausible that it may also be effective target of Trypanosoma.The Trypanosoma brucei leucyl-tRNA synthetase(tbLeuRS)was cloned,expressed and purified to develop an in vitro enzymatic assay system.The assay conditions were further optimized for the effective screening of tbLeuRS inhibitors thus establishing an anti-Trypanosoma drug screening system targeting tbLeuRS.The results indicated that this system can be employed for the effective screening of anti-Trypanosoma drugs with satisfactory specificity.In addition,this system can also be used for compound optimization,as well as IC50 testing.Using this system a series of compounds are identified that are effective Trypanosoma inhibitors without toxicity to human cells.Therefore,targeting tbLeuRS may represent a new venue for the development of anti-Trypanosoma drugs.

Human protein tyrosine kinases play an essential role in carcinogenesis and have been recognized as promising drug targets. By the end of 2012, eight small molecule tyrosine kinase inhibitors (TKIs) have been approved by State Food and Drug Administration of China for cancer treatment. In this paper, the pharmacokinetic characteristics (absorption, distribution, metabolism and excretion) and drug-drug interactions of the approved TKIs are reviewed. Overall, these TKIs reach their peak plasma concentrations relatively fast; are extensively distributed and highly protein bound (> 90%); are primarily metabolized by CYP3A4; most are heavily influenced by CYP3A4 inhibitors or inducers except for sorafenib; are mainly excreted with feces and only a minor fraction is eliminated with the urine; and are substrate of the efflux transporters ABCB1 (P-gp) and ABCG2 (BCRP). Additionally, many of the TKIs can inhibit some CYP450 enzymes, UGT enzymes, and transporters. Gefitinib, erlotinib, dasatinib, and sunitinib are metabolized to form reactive metabolites capable of covalently binding to biomolecules.
Antineoplastic Agents ; pharmacokinetics ; pharmacology ; Crown Ethers ; pharmacokinetics ; pharmacology ; Cytochrome P-450 Enzyme System ; metabolism ; Dasatinib ; pharmacokinetics ; pharmacology ; Drug Interactions ; Erlotinib Hydrochloride ; pharmacokinetics ; pharmacology ; Glucuronosyltransferase ; metabolism ; Humans ; Imatinib Mesylate ; pharmacokinetics ; pharmacology ; Indoles ; pharmacokinetics ; pharmacology ; Niacinamide ; analogs & derivatives ; pharmacokinetics ; pharmacology ; Phenylurea Compounds ; pharmacokinetics ; pharmacology ; Protein Kinase Inhibitors ; pharmacokinetics ; pharmacology ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Pyrimidines ; pharmacokinetics ; pharmacology ; Pyrroles ; pharmacokinetics ; pharmacology ; Quinazolines ; pharmacokinetics ; pharmacology

BACKGROUND:Hidden blood loss is an important risk for the intertrochanteric fracture patients, especial y the elderly patients, which can cause anemia in patients after internal fixation and can affect wound healing and patient recovery. OBJECTIVE:To compare the perioperative hidden blood loss and the risk factors of proximal femoral anti-rotation intramedul ary nail internal fixation and dynamic hip screw fixation for the treatment of femoral intertrochanteric fracture. METHODS:We selected 70 cases of femoral intertrochanteric fracture patients who treated with proximal femoral anti-rotation intramedul ary nail and dynamic hip screw fixation, including 21 patients with the age ≥ 80 years and 49 patients with the age<80 years;28 patients with the body mass index>30 kg/m2 and 42 patients with the body mass index ≤ 30 kg/m2;30 patients received anti-rotation intramedul ary nail internal fixation and 40 patients received dynamic hip screw fixation. The perioperative blood loss was calculated with Gross formula according to the changes of height, body mass index and the hematocrit before and after fixation. RESULTS AND CONCLUSION:The mean total blood loss was 936 mL, the mean dominant blood loss was 237 mL and the mean hidden blood loss was 699 mL. The hidden blood loss was accounted for 74.7%in total blood loss. The dominant blood loss in the dynamic hip screw fixation group was higher than that in the anti-rotation intramedul ary nail internal fixation group, and the hidden blood loss was lower than the anti-rotation intramedul ary nail internal fixation group. The total blood loss and the hidden blood loss of the elderly patients were higher than those of the non-elderly patients;there was no significant difference between male and female patients, obesity and normal patients. The results indicate that hidden blood loss is the major reason for total blood loss of femoral intertrochanteric fracture after internal fixation. The hidden blood loss of anti-rotation intramedul ary nail internal fixation is larger than that of dynamic hip screw fixation, and elder is the risk factor for hidden blood loss.

The study aims to develop a rapid, sensitive and specified method of liquid chromatography with heated electrospray ionization tandem mass spectrometry (LC-HESI/MS/MS) for simultaneous determination of amlodipine, benazepril and benazeprilat in human plasma using amlodipine-d4 and ubenimex as internal standards (ISs). Selected reaction monitoring (SRM) with heated electrospray ionization (HESI) was used in the positive mode for mass spectrometric detection. Analytes and ISs were extracted from plasma by simple protein precipitation. The reconstituted samples were chromatographed on a C18 (100 mm x 4.6 mm, 5 microm) column with mixture of methanol-acetonitrile-5 mmol.L- ammonium acetate-formic acid (30 : 30 : 40 : 0.1) as mobile phase at a flow rate of 0.6 mL.min-1. The standard curves were demonstrated to be linear in the range of 0.02 to 6.00 ng.mL-1 for amlodipine, 0.2 to 1,500 ng.mL-1 for benazepril and benazeprilat with r2>0.99 for each analyte. The lower limit of quantitation was identifiable and reproducible at 0.02, 0.2 and 0.2 ng mL-1 for amlodipine, benazepril and benazeprilat, respectively. The intra-day and inter-day precision and accuracy results were within the acceptable limit across all concentrations. The plasma samples were stable after four freeze-thaw cycles and being stored for 93 days at -20 degrees C. The method was applied to a pharmacokinetic study of a fixed-dose combination of amlodipine and benazepril on Chinese healthy volunteers.
Administration, Oral ; Amlodipine ; administration & dosage ; blood ; Benzazepines ; administration & dosage ; blood ; Chromatography, Liquid ; Humans ; Sensitivity and Specificity ; Spectrometry, Mass, Electrospray Ionization ; Tandem Mass Spectrometry

OBJECTIVETo evaluate the academic level and the popularity of the Chinese Journal of Hepatology in China in 2005.

METHODSWe used bibliometrics to analyze statistically the original articles of the Chinese Journal of Hepatology cited by Chinese periodicals included in the Wanfang Data in 2005.

RESULTS(1) 699 published papers in the journal in 2005 were cited 1673 times and 44 of them were cited 720 times in total. (2) The papers published in the Chinese Journal of Hepatology were cited by journals in China starting from 1993 through 2005. Of all the cited articles, 1.49% of them were cited in the same year as they were published. (3) Non-specific rate of the Chinese Journal of Hepatology was 96.17%, and self-cite rate was 3.83%. (4) Papers published in the Chinese Journal of Hepatology were cited by 400 Chinese periodicals, 99 of them are journals included in the Chinese Science Citation Database, and 110 of them are Chinese core periodicals.

CONCLUSIONThe Chinese Journal of Hepatology is one of the high level academic Chinese periodicals. This journal reflects the progress in research on liver diseases in China.

Bibliometrics ; China ; Gastroenterology ; Humans ; Liver Diseases ; Periodicals as Topic

A simple, sensitive, selective, and reproducible liquid chromatography-tandem mass spectrometric method was developed for the simultaneous determination of repaglinide and metformin in human plasma using d5-repaglinide and d6-metformin as internal standards (ISs). After a simple protein precipitation using acetonitrile as the precipitation solvent, both analytes and ISs were separated on a Venusil ASB C 18 (150 mm x 4.6 mm, 5 microm) via gradient elution using acetonitrile--10 mmol x L(-1) ammonium acetate as the mobile phase. A chromatographic total run time of 7.5 min was achieved. Mass spectrometric detection was conducted with atmospheric pressure chemical ionization under positive-ion and multiple-reaction monitoring modes. The method was linear over the 0.2 to 60.0 ng x mL(-1) concentration range for repaglinide and over the 4 to 1 000 ng x mL(-1) range for metformin. For both analytes, the intra- and inter-accuracies and precisions were within the +/- 15% acceptable limit across all concentrations. The validated method was successfully applied to a clinical bioequivalence study.
Administration, Oral ; Adolescent ; Adult ; Area Under Curve ; Carbamates ; administration & dosage ; blood ; pharmacokinetics ; Chromatography, Liquid ; Drug Stability ; Female ; Humans ; Hypoglycemic Agents ; administration & dosage ; blood ; pharmacokinetics ; Male ; Metformin ; administration & dosage ; blood ; pharmacokinetics ; Middle Aged ; Piperidines ; administration & dosage ; blood ; pharmacokinetics ; Tandem Mass Spectrometry ; Therapeutic Equivalency ; Young Adult

Objective To determine whether atorvastatin will induce depressive symptoms in patients with cerebral infarction. Methods The clinical data of 404 patients with large artery atherosclerotic cerebral infarction, admitted to our hospital from June 2009 to December 2010, were clinically analyzed; these patients were divided into common treatment group (atorvastatin ([7.72±3.01])mg/d,n=151) and intensive lipid lowering group (atorvastatin [18.58±9.93] mg/d,n=201) and control group (n=52); 189 males and 163 females accepted lipid-lowering treatment.Hamilton Depression Rating Scale (HAMD) was employed before treatment and 3 months after the treatment and statistical analysis was performed on their scores. Results No significant deviation in scores of HAMD before and after treatment was noted in these patients (P＞0.05).No significant deviation in scores of HAMD was noted neither between intensive lipid lowering group and control group,nor between common treatment group and control group (P＞0.05). No significant deviation in HAMD was observed between the treatment groups with mild/no depression symptoms and control group (P＞0.05).The scores of HAMD in female patients were significantly higher than that in male patients 3 months after treatment (P＜0.05),but no significant deviations in the level of cholesterol, the lowering degree of cholesterol and the dosage of atorvastatin were observed between female and male patients (P＞0.05). Conclusion The lipid-lowering treatment with atorvastatin will not induce depressive symptoms in patients with cerebral infarction.The depressive symptoms of female is not related with the level of cholesterol,the lowering degree of cholesterol and the dosage ofatorvastatin.

The contents of 2011 Tokyo Declaration on Japanese Acupuncture and Moxibustion (Declaration for short) and its effect on development situation, current status, features, opportunities and challenges of Japanese acupuncture and moxibustion are introduced, some proposals brought up in the Declaration are analyzed as well. The Declaration summarizes six characteristics of Japanese acupuncture and moxibustion, including paying great attention to palpation techniques such as pulse and abdominal diagnosis, always selecting response point in the meridian during acupuncture treatment, etc. Also six proposals have been brought up to promote the development of Japanese acupuncture and moxibustion, such as being devoted to spread the latest knowledge of acupuncture and moxibustion to medical professionals and the public in order to get correct understanding and proper evaluation, etc. What's more, the Declaration makes a prospection of improving international academic exchange and promoting the globalization of acupuncture and moxibustion and so on. The Declaration is served as a link between past and future in the history and developing process of Japanese acupuncture and moxibustion, which has a great meaning to the development of Japanese acupuncture and moxibustion. We should have a clear understanding of weakness and strength in the development of acupuncture and moxibustion, seize the opportunity and develop science of acupuncture and moxibustion with our own characteristics, which makes more contribution to development of international acupuncture and moxibustion.
Acupuncture Therapy ; trends ; Humans ; Japan ; Moxibustion ; trends ; Tokyo

OBJECTIVETo explore possible mechanism of electroacupuncture (EA) for regulating immune function in anxiety disorder (AD) rats by observing the effect of acupuncture on the histology of thymus and expressions of atrial natriuretic peptide (ANP) and natriuretic peptide receptor type A (NPR- A) in thymus.

METHODSTotally 34 SD healthy rats were randomly divided into the blank control group (n = 10), the model group (n = 12), the EA group (n = 12). Anxiety model was established in rats of the model group and the EA group by using chronic unpredictable stress (CUS) stimulation. EA (15/25 Hz) at Neiguan (PC6) and Shenmen (HT7) was performed in the EA group, with 15-min needle retaining, once every other day, 15 days in total. Needle was fixed at same acupoints for 15 min without electric stimulus in the other two groups. Anxiety-like behavior was measured by elevated plus-maze (EPM) test. Pathological changes of thymus tissue were observed by optical microscope. Expressions of ANP and NPR-A in thymus were measured by immunohistochemical assay.

RESULTSThe thymus tissue in the model group was severely atrophied, with unclear structure of thymic lobules, unclear margin of thymic medulla, loosely arranged lymphocytes ,and obviously enlarged volume of thymic corpuscle. The thymus tissue in the EA group was mildly atrophied, with existent structure of thymic lobules, clear margin of thymic medulla, densely arranged lymphocytes in cortical region, and widened medullary area. Com- pared with the blank control group, the percentage of open-arms entries (OE%) in the total QE times ob- viously decreased in the model group (P < 0.05), ANP expression obviously increased (P < 0.05), and NPR-A expression obviously decreased (P < 0.01). Compared with the model group, OE% was obviously elevated (P < 0.05), ANP expression obviously decreased (P < 0.05), and NPR-A expression obviously increased (P < 0.01) in the EA group.

CONCLUSIONEA not only could reduce anxiety of rats, but also could improve chronic stress induced thymus injury through intervening synthesis and secretion of ANP, as well as the expression of NPR-A (a specific receptor of ANP).

Acupuncture Points ; Animals ; Anxiety Disorders ; therapy ; Atrial Natriuretic Factor ; metabolism ; Electroacupuncture ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, Atrial Natriuretic Factor ; metabolism ; Thymus Gland ; pathology

OBJECTIVETo study the clinicopathological and molecular genetic characteristics of hereditary nonpolyposis colorectal cancer (HNPCC), to enable the early diagnosis and to evaluate the treatment.

METHODSWe analyzed 12 families of HNPCC from Wenzhou, Zhejiang province, China. Mismatch repair genes hMSH2 and hMLH1 expression and microsatellite instability of tumor tissue were studied using microdissection, microsatellite analysis, immunohistochemical staining and Gene Scan analysis. Direct DNA sequencing of hMSH2 and hMLH1 were performed subsequently.

RESULTSAltogether 32 patients with colorectal cancer were recognized in 12 HNPCC families, with the median age of 45.2 years (75.0% before the age of 50 years). The proximal tumors accounted for 51.1%, while multiple colorectal cancers accounted for 34.4%. Poor differentiation cancers occupied half of the patients (53.1%). And 68.8% of the patients had the tumor of Dukes A and B. Among 12 HNPCC families, 7 cases in 6 HNPCC families developed extracolonic cancer. 13 cases died during follow up of 1 - 23 years. The median survival time was 6.4 years. 19 alive cases followed up from 1 to 28 years. All tumors (9/9) displayed microsatellite instability, with the half losing hMSH2 or hMLH1 expression. In the 5 genetic analyzed kindreds 3 possessed germline mutation. Two of three mutations have not been reported in the worldwide database previously.

CONCLUSIONHNPCC showed distinct clinicopathological characteristics. Microsatellite instability analysis and immunohistochemical staining might be the effective screening methods before direct DNA sequencing for the detection of mutation in mismatch repair genes. It is important to analyze the members of affected families.

Adaptor Proteins, Signal Transducing ; Adult ; Aged ; Carrier Proteins ; China ; Colorectal Neoplasms, Hereditary Nonpolyposis ; genetics ; metabolism ; pathology ; DNA Mutational Analysis ; DNA, Neoplasm ; chemistry ; genetics ; DNA-Binding Proteins ; analysis ; genetics ; Family Health ; Female ; Humans ; Immunohistochemistry ; Male ; Microsatellite Repeats ; genetics ; Middle Aged ; MutL Protein Homolog 1 ; MutS Homolog 2 Protein ; Mutation ; Neoplasm Proteins ; analysis ; genetics ; Nuclear Proteins ; Proto-Oncogene Proteins ; analysis ; genetics