性病治疗药物的现状与进展

本文对淋病、非淋球菌性尿道炎和尖锐湿疣等3种最常见性病的治疗药物进行了综述介绍。

Insulin resistance and hepatitis C

Insulin resistance is the major feature of the metabolic syndrome and depends on insulin secretion and insulin sensitivity. In chronic hepatitis C, insulin resistance and type 2 diabetes mellitus are more often seen than in healthy controls or chronic hepatitis B patients. Hepatitis C virus （HCV） infection promotes insulin resistance, mainly by increased TNF production together with enhancement of suppressor of cytokine （SOC-3）; both events block PI3K and Akt phosphorylation. Two types of insulin resistance could be found in chronic hepatitis C patients＇. ＂viral＂ and ＂metabolic＂ insulin resistance. Insulin resistance in chronic hepatitis C is relevant because it promotes steatosis and fibrosis. The mechanisms by which insulin resistance promotes fibrosis progression include： （1） steatosis, （2） hyperleptinemia, （3） increased TNF production, （4） impaired expression of PPARy receptors. Lastly, insulin resistance has been found as a common denominator in patients difficult-to-treat like cirrhotics, overweight, HIV coinfected and Afro-American. Insulin resistance together with fibrosis and genotype has been found to be independently associated with impaired response rate to peginterferon plus ribavirin. Indeed, in genotype 1, the sustained response rate was twice （60%） in patients with HOMA ≤ 2 than patients with HOMA 〉 2. In experiments carried out on Huh-7 cells transfected by full length HCVRNA, interferon alpha blocks HCV replication. However, when insulin （at doses of 128 μU/mL, similar that seen in the hyperinsulinemic state） was added to interferon, the ability to block HCV replication disappeared, and the PKR synthesis was abolished. In summary, hepatitis C promotes insulin resistance and insulin resistance induces interferon resistance, steatosis and fibrosis progression.

Efflux pump gene hefA of Helicobacter pylori plays an important role in multidrug resistance

AIM: To determine whether efflux systems contribute to multidrug resistance of H pylori. METHODS: A chloramphenicol-induced multidrug resistance model of six susceptible H pylori strains (5 isolates and H pylori NCTC11637) was developed. Multidrug-resistant (MDR) strains were selected and the minimal inhibitory concentration (MIC) of eryth-romycin, metronidazole, penicillin G, tetracycline, and ciprofloxacin in multidrug resistant strains and their parent strains was determined by agar dilution tests. The level of mRNA expression of hefA was assessed by fluorescence real-time quantitative PCR. A H pylori LZ1026 knockout mutant (ΔH pylori LZ1026) for (puta-tive) efflux protein was constructed by inserting the kanamycin resistance cassette from pEGFP-N2 into hefA, and its susceptibility profiles to 10 antibiotics were evaluated. RESULTS: The MIC of six multidrug-resistant strains (including 5 clinical isolates and H pylori NCTC11637) increased signifi cantly (≥ 4-fold) compared with their parent strains. The expression level of hefA gene was significantly higher in the MDR strains than in their parent strains (P = 0.033). A H pylori LZ1026 mutant was successfully constructed and the ΔH pylori LZ1026 was more susceptible to four of the 10 antibiotics. All the 20 strains displayed transcripts for hefA that con-fi rmed the in vitro expression of these genes.CONCLUSION: The efflux pump gene hefA plays an important role in multidrug resistance of H pylori.

Efficacies of β-L-D4A against Hepatitis B virus in 2.2.15 cells

AIM： To investigate the antiviral effect of beta-L- enantiomer of 2;3＇-didehydro-2＇,3″-dideoxyadenosine （13-L-D4A） on 2.2.15 cells transfected with the hepatitis B virus （HBV） genome.METHODS： Lamivudine （3TC） as a positive control. Then, HBV DNA in treated 2.2.15 cells and the Hepatitis B surface antigen （HBsAg） in the culture supernatants were detected to determine the inhibitory effect of β-L- D4A. At the same time, 3-（4,5-dimethylthiazol-2-yl）-2,5- diphenyltetrazolium bromide （MTT） was used to detect the survival ratio of 2.2.15 cells.RESULTS： β-L-D4A has a dose-dependent inhibitory effect on HBV DNA replication; this effect was apparent when the concentration was above 1 mol/L. When β-L- D4A was at the highest concentration, 100 mol/L, the HBsAg inhibition ratio was above 50%. The Therapeutic index （TI） of β-L-D4A was above 2.1.CONCLUSION： β-L-D4A has a dose-dependent inhibitory effect on the replication of HBV DNA and the secretion of HBsAg at low toxicity,

Antiviral Activity of the Effective Monomers from Folium Isatidis Against Influenza Virus in Vivo

In order to evaluate the anti-influenza virus activity of the effective monomer from Folium Isatidis (FI) in vivo,we established mice model with viral pneumonia and divided them into 3 different dose groups,then observed their lung indexes,pulmonary pathological changes,pulmonary virus hemagglitination titers,living time and death rates.The results showed that the monomer could reduce the pulmonary index from 2.64 to 1.93,1.63 and 1.40 (P<0.01) and decrease the hemagglitination titer from 1.15 to 0.84,0.70 and 0.59 (P<0.01).In addition,different groups of FI could significantly lessen the mortality rate from 100% to 30%,25% and 15%,and prolong the living time from 5.1d to 6.5d,8.4d and 8.9d respectively(P<0.01).The high dose (75 mg/kg/d) has the similar effect with 100 mg/kg/d dose of virazole(P>0.05),and more effective than 200 mg/kg/d dose of antiviral liquor (P<0.05).

Solid lipid nanoparticles loading adefovir dipivoxil for antiviral therapy

Herein,solid lipid nanoparticles(SLN)were proposed as a new drug delivery system for adefovir dipivoxil(ADV). The octadecylamine-fluorescein isothiocynate(ODA-FITC)was synthesized and used as a fluorescence maker to be incorporated into SLN to investigate the time-dependent cellular uptake of SLN by HepG2.2.15.The SLN of monostearin with ODA-FITC or ADV were prepared by solvent diffusion method in an aqueous system.About 15 wt%drug entrapment efficiency(EE)and 3 wt% drug loading(DL)could be reached in SLN loading ADV.Comparing with free ADV,the inhibitory effects of ADV loaded in SLN on hepatitis B surface antigen(HBsAg),hepatitis B e antigen(HBeAg)and hepatitis B virus(HBV)DNA levels in vitro were significantly enhanced.

Diagnostic and therapeutic progress of multi-drug resistance with anti-HBV nucleos(t)ide analogues

Nucleos(t)ide analogues(NA) are a breakthrough in the treatment and management of chronic hepatitis B.NA could suppress the replication of hepatitis B virus(HBV) and control the progression of the disease.However,drug resistance caused by their long-term use becomes a practical problem,which influences the long-term outcomes in patients.Liver transplantation is the only choice for patients with HBV-related end-stage liver disease.But,the recurrence of HBV after transplantation often caused by the development of drug resistance leads to unfavorable outcomes for the recipients.Recently,the multi-drug resistance(MDR) has become a common issue raised due to the development and clinical application of a variety of NA.This may complicate the antiviral therapy and bring poorly prognostic outcomes.Although clinical evidence has suggested that combination therapy with different NA could effectively reduce the viral load in patients with MDR,the advent of new antiviral agents with high potency and high genetic barrier to resistance brings hope to antiviral therapy.The future of HBV researches relies on how toprevent the MDR occurrence and develop reasonable and effective treatment strategies.This review focuses on the diagnostic and therapeutic progress in MDR caused by the anti-HBV NA and describes some new research progress in this field.

Sarcoidosis and chronic hepatitis C:A case report

Several case reports deal with the relationship between hepatitis C virus （HCV） infection and pulmonary or he- patic sarcoidosis. Most publications describe interferon m-induced sarcoidosis. However, HCV infection per se is also suggested to cause sarcoqdosis. The present case report describes a case of biopsy-verified lung and liver sarcoidosis and HCV infection, and the out- come of antiviral therapy. In March 2009, a 25-year-old man presented with moderately elevated liver enzymes without any clinical symptoms. The patient was posi- tive for HCV antibodies and HCV RNA of genotype lb. Four months later the patient became dyspnoic and pulmonary sarcoidosis was diagnosed by lung biopsy and radiography. A short course of corticosteroid treat- ment relieved symptoms. Three months later, liver biopsy showed noncaseating granulomas consisting of epithelioid histiocytes and giant cells with a small amount of peripheral lymphocyte infiltration, without any signs of fibrosis. Chronic HCV infection with co- existence of pulmonary and hepatic sarcoidosis was diagnosed. Antiviral therapy with peginterferon ~ and ribavirin at standard doses was started, which lasted 48 wk, and sustained viral response was achieved. A second liver biopsy showed disappearance of granulo- mas and chest radiography revealed normalization of mediastinal and perihilar glands. The hypothesis that HCV infection perse may have triggered systemic sar- coidosis was proposed. Successful treatment of HCV infection led to continuous remission of pulmonary and hepatic sarcoidosis. Further studies are required to un- derstand the relationship between systemic sarcoidosis and HCV infection.

Antitumor drug-induced acute pancreatitis:report of a special case

Drug-induced acute pancreatitis （DAP） is defined as pancreatitis with corresponding clinical manifestations resulted from drug-induced pancreatic secretion dysfunction and pancreatic tissue damage. One case of DAP resulted from chemotherapeutics （Nimustine） was diagnosed and treated our in hospital in 2009. This patient belonged to pancreatitis induced by anticancer drugs, and the toxicity of anticancer drugs acted directly on pancreatic cells, leading to the occurrence of pancreatitis. After treatment, the pancreatitis was effectively treated in this patient, but the final the patient and his family eventually gave up the treatment due to aggravated primary diseases

关注女性骨骼健康

女性绝经后,经常无缘无故地感到＂周身骨痛＂,可能是关节、肌肉劳损所致,也可能是骨质疏松的症状。骨质疏松疼痛常不典型骨质疏松症是一种慢性病,可以从绝经早期持续到老年期的全过程,骨量下降的程度随着年龄的增长日渐加重。骨质疏松的患者80%是女性,多数在绝经初期骨量快速下降,这是雌激素急剧下降的结果。近年来,女性骨质疏松还有年轻化的趋势,有的女性在40多岁骨量就已经明显低下。专家认为,

An epidemiological study of resistant tuberculosis in Chongqing,China

Background The epidemiological characteristics of drug-resistant tuberculosis （DR-TB） is fundamental to improving the prevention and control of DR-TB. Mutations in katG315 is thought to be the most predictive molecule markers for Isoniazid （INH） resistance in Mycobacterium tuberculosis （MTB）. However, mutations to these genes have not been thoroughly studied in China, and epidemiological evidence of their expression levels are especially lacking in the southwest of China, which has a high TB burden within the population. Methods MTB isolates were obtained from patients with active pulmonary tuberculosis at the TB dispensary and Chest hospital in Chongqing city between June 2003 and June 2006. Proportion methods were used to test the sensitivity to INH, RFP, SM and EMB of cultured MTB. A total of 100 MTB isolates were also randomly selected for analysis of the molecular mutation spectrum of katG by DNA sequencing. Results Totally 1 089 MTB isolates that completed positive sputum cultures and evaluated for their sensitivity to the four first-line drugs among 2 777 patients with TB. The prevalence of DR-TB and multi-drug resistant tuberculosis （MDR-TB） were 27.7% （302/1 089） and 7.3% （79/1 089）, respectively. The resistance to anti-TB drugs was found to be highest for SM （16.3%） and INH （14.0%）. There was also a significant increase in the prevalence of resistance to RFP and EMB （P〈0.01）, and an increase in MDR-TB between June 2003 and June 2004 and between July 2005 and June 2006. The total mutation rate of katG315 was 75＂5% （37/49） in INH-resistant MTB, and mutation sites included $315T, $315N and $315I with mutation rates of 81.1% （30/37）, 13.5% （5/37） and 5.4% （2/37）, respectively No katG315 mutants were found in any of the 48 INH-sensitive MTB. Our preliminary diagnostic results suggest that mutations in katG315 may potentially serve as molecular markers that can be used to diagnose the resistance to anti-TB drug of INH. Conclusion In the Chongqing, DR-TB and MDR-TB are increasing, and are becoming key problems for tuberculosis control. The use of katG315 mutations as potential molecule markers for drug resistance to INH may help improve patient treatment and decrease the spread of the disease

Synthesis and antiviral bioactivities of novel chiral bis-thiourea-type derivatives containing α-aminophosphonate moiety

Starting from 1-((1R,2R)-2-aminocyclohexyl)-3-substituted thioureas (3a–c) and substituted isothiocyanates (9a–d),chiral bis-thiourea derivatives containing α-aminophosphonate moiety 10a–l were prepared and completely characterized by elemental analysis,physical and spectral (IR,1H NMR,13C NMR,31P NMR) data.The results of bioassay revealed that compounds 10a and 10e possessed appreciable curative bioactivities on cucumber mosaic virus (CMV) at 0.5 mg/mL in vivo (inhibitory rate = 60.3%,64.8% respectively) and tobacco mosaic virus (TMV) at 0.5 mg/mL in vivo (inhibitory rate = 50.3%,50.8% respectively),which were comparable to the values shown by standard reference (58.7%) and commercial product Ningnanmycin (56.3%),respectively.Chiral compound 10e displayed more potent antiviral activity (EC50 = 0.149 mg/mL) than Ningnanmycin (EC50 = 0.201mg/mL) against CMV.

Spike protein homology between the SARS-associated virus and murine hepatitis virus implies existence of a putative receptor-binding region

Coronavirus has been determined to be the cause of the recent outbreak of severe acute respiratory syndrome (SARS). Human coronavirus 229E had been studied well and its receptor-binding domain was restricted to aa417—547 of S protein. However, this region has no homology with the newly separated SARS-associated virus (Hong Kong isolate CUHK-W1). Then we analyzed the phylogenesis of S1 subunit of the coronavirus spike protein (SARS-associated virus, Hong Kong isolate CUHK-W1). Interestingly, the highest homology between murine hepatitis virus (MHV) and SARS-associated coronavirus was found. And the important sites (aa62—65 and aa214—216) on the spike protein of MHV with receptor-binding capacity were highly conservative in comparison with the newly separated SARS-asso- ciated virus (the corresponding sites are aa51—54 and aa195—197). These results from bioinformatics analysis might help us to study the receptor-binding sites of SARS-associ- ated virus and the mechanism of the virus entry into the target cell, and design antiviral drugs and potent vaccines.

Identification of an allosteric hotspot for additive activation of PPARγ in antidiabetic effects

Thiazolidinediones(TZDs),such as rosiglitazone(RSG),which activates peroxisome proliferator activated receptor-y(PPARy),are a potent class of oral antidiabetic agents with good durability.However,the clinical use of TZDs is challenging because of their side effects,including weight gain and hepatotoxicity.Here,we found that bavachinin(BVC),a lead natural product,additively activates PPARγ with lowdose RSG to preserve the maximum antidiabetic effects while reducing weight gain and hepatotoxicity in db/db mice caused by RSG monotherapy.Structural and biochemical assays demonstrated that an unexplored hotspot around Met329 and Ser332 in helix 5 is triggered by BVC cobinding to RSG-bound PPARy,thereby allosterically stabilizing the active state of the activation-function 2 motif responsible for additive activation with RSG.Based on this hotspot,we discovered a series of new classes of allosteric agonists inducing the activity of TZDs in the same manner as BVC.Together,our data illustrate that the hotspot of PPARγ is druggable for the discovery of new allosteric synergists,and the combination thera py of allosteric synergists and TZD drugs may provide a potential alternative approach to the treatment of type 2 diabetes mellitus.

An update on the management of chronic hepatitis D

Hepatitis D virus(HDV)infection is associated with severe liver-related morbidity and mortality.The prevalence of HDV is rising especially among people who abuse drugs and immigrants from endemic areas.Reliable diagnostic assays with enhanced sensitivity and specificity are essential for screening at-risk populations.Until recently,interferon has been the only treatment for hepatitis D.Its efficacy is,however,limited and it is associated with significant side effects.A number of novel antiviral agents that target various stages of the HDV life cycle show promising results.They are currently in different phases of clinical development.This review focuses on the changing epidemiology,novel therapeutic agents,and updated management of chronic hepatitis delta.