从《黄帝内经》“有故无殒”谈儿童风湿免疫疾病治疗中的药“毒”及“毒”药的应用

儿童风湿免疫疾病缠绵难愈、易于反复,严重影响患儿身心健康,是临床的治疗难点。目前该类疾病的治疗多依赖激素、免疫抑制剂、生物制剂等,然此类药物在发挥治疗作用的同时也具有较大的副作用。中医将药物的副作用归属于药“毒”范畴,具有药“毒”的药物被称为“毒”药。对于“毒”药。《黄帝内经》中“有故无殒”理论提示,临床应因“故”用药,药虽有“毒”,而病先受之,于人体无碍。基于这一理论,本文提出“毒”药峻猛,非“急”不用;病衰大半,止药缓“毒”;权衡“效”与“毒”,以平为期;耐“毒”不同,应因人制宜;因证施药,配伍减“毒”的“毒”药运用原则,并提出精准用药、采取减毒举措、提高效益与风险比的“毒”药施用策略,对儿科临床安全用药具有指导意义。

中医药干预TLR4/MyD88/NF-κB通路治疗溃疡性结肠炎研究综述

溃疡性结肠炎(UC)的发病机制与炎症通路的激活密切相关,其中Toll样受体4(TLR4)/髓样分化因子88(MyD88)/核因子-κB(NF-κB)信号通路在UC发病中起关键作用。综述了姜黄素、小檗碱、鸦胆子苦醇、黄芩苷、雷公藤多苷等中药活性成分及泄浊解毒方、乌梅丸、芍药汤、葛根芩连汤等中药复方制剂,通过干预TLR4/MyD88/NF-κB信号通路中不同细胞因子的结合及影响其表达水平,抑制NF-κB的活化,从而降低信号通路下游炎症因子的水平,缓解UC病情。参考文献50篇。

“有故无殒,亦无殒”理论内涵及拓展应用

“有故无殒,亦无殒”最初为妇人妊娠用药的原则,后来逐渐演变为临床用药指导原则。其规范了有毒药物的用药法度,体现了中医学治疗用药的基本原则和指导思想,涵盖了“急则治标”“中病即止”“顾护正气”“以毒攻毒”“以平为期”“因人制宜”“辨证论治”等中医治则和理念。该理论实质是对药物的“毒”“效”“证”“量”“时”关系的调控平衡,要求医者掌握药物毒性与效用之间的转化与联系,强调病证关系和用药时机。时下,“有故无殒”的临床应用已不局限于妊娠疾病,其在肿瘤、儿科等疾病中亦具广泛指导意义。但需明确的是,“有故无殒”并非简单打破用药局限,而是强调辨证论治,尽可能降低药物不良反应,提高临床治疗效果。

Effect of interferon in combination with ribavirin on the plus and minus strands of HCV RNA in patients with chronic hepatitis C

AIMS To probe the effect of interferon in combination with rib- avirin on the plus and minus strands of hepatitis C virus RNA (HCV RNA). METHODS Twenty-three cases diagnosed as chronic hepatitis C (CHC) according to positive HCV RNA/anti-HCV,fluctuating levels of aminotransferase activities (>1 year) and absence of other hepatitis virus marker,were studied. Among them,13 pa- tients received combined antiviral therapy (subcutaneous injection of 3MU of interferon-α three times per week for 3 months and intra- venous drip of 1 g of ribavirin per day during the first month of treatment with interferon) and 10 patients received single interfer- on therapy (the same as above-mentioned) as control. The plus and minus strands of HCV RNA in sera and peripheral blood mononuclear cells (PBMCs) of these patients were tested by means of nested reverse transcription-polymerase chain reaction (nested RT-PCR). RESULTS At the end of therapy,the abnormal ALT levels de- creased to normal range in 9 (69.23%) cases in the combined antiviral group. Of them,5 (55.56%)experienced post-therapy relapse and 4 (44.44%) were complete responders. In the inter- feron group,the ALT decreased to normal in 6 (60%) cases,of which,4 (66.67%) had post-therapy relapse and 2 (33.33%) were complete responders. The differences between the two groups were nonsignificant (P>0.05). At the end of therapy,the positive rate of the plus strand in sera decreased from 92.3% to 38.46% (P<0.05) and that of the minus strand in PBMCs,from 76.92% to 38.46% (P<0.05) in the combined antiviral group; and in the interferon group,the former decreased from 100% to 50% (P<0.05) and the latter,from 90% to 40% (P<0.05). Again,no significant differences were found between groups (P >0.05). The relapse occurred in patients whose plus strand HCV RNA in PBMCs remained positive before and after treatment. CONCLUSIONS Ribavirin could not enhance the antiviral effect of interferon. The absence of HCV RNA in serum does not mean complete clearance of HCV,and its value for evaluating the an- tiviral effect and prognosis is limited. Therefore,it is essential to measure the plus and minus strands of HCV RNA in sera and PBM- Cs simultaneously.

Study on the Effective Prevention and Control of Maize Rough Dwarf Disease in Different Areas with Varying Epidemic Intensity in Shandong Province

[ Objective] This study aimed to investigate the effective prevention and control of maize rough dwarf disease in different areas with varying epidemic inten-sity in Shandong Province. [Method] Control effects of single application of virus in-hibitors and composite application of virus inhibitors with seed dressing agents and pesticides on maize rough dwarf disease in different areas with varying epidemic intensity were investigated. [Result] The same treatment possessed entirely different effects in severely affected areas and slightly affected areas. To be specific, single application of virus inhibitors in slightly affected areas exhibited good control effects, with a control efficiency of 76.59% and yield increment rate of 158.21%; in severely affected areas, single application of virus inhibitors led to low control efficiency and yield increment rate. The highest control efficiency of composite application of virus inhibitors with seed dressing agents and pesticides in severely affected areas was 71.38%, and experimental plots changed from total crop failure to have certain eco-nomic output. [Conclusion] ln different areas with varying epidemic intensity of maize rough dwarf disease, different application modes should be adopted according to lo-cal conditions, thereby saving cost and improving control efficiency.

Survey of HIV Infection among Injection Drug Users in Guangdong, China

Objective： To understand the prevalence and behavioral risk factors of HIV infection among injection drug users in the Pearl River Delta Region （PRDR） of Guangdong province, and to provide evidence for establishing effective intervention strategies. Methods： Face to face interviews were conducted and serum samples from injection drug users from detoxification centers and the community were collected for HIV screening. Results： 655 drug users were recruited and interviewed. The HIV seropositive rate was 29.0%. 99.5 % of subjects were injection drug users （IDUs）, of whom,75.4% reported sharing injection equipment. Conclusion： HIV prevalence among injection drug users is high in the PRDR of Guangdong. Injection drug use is the principal behavioral risk factor for HIV transmission. Pragmatic harm reduction programs should be implemented to prevent the spread of HIV infection.

Effects of Biological Pesticides on Prevention and Treatment of Virus Diseases in Greenhouse Tomato in Autumn

To alleviate the damage of tomato virus diseases, reduce chemical pesticide consumption and residue, and prevent environmental pollution, forecasting, randomized block design and statistical analysis were adopted to conduct field efficacy tests for Lentinan ＋ Gibberellin-heteroauxin-brassinolide （GHB） and Ningnanmycin ＋ GHB. The results showed that when the virus diseases in greenhouse tomato were serious, 0.5% Lentinan AS 3 000 ml ＋ GHB WP 600 g and 8% Ningnanmycin AS 900 ml ＋ GHB WP 600 g per hectare were applied 4 times with an interval of 7 days, and the control effects on the 10th, 17th, 26th and 35th day were above 88%, 87%, 78% and 67%, respectively. The difference in control effect of the two biological pesticides was insignificant, while their control effects were all significantly better than that of moroxydine hydrochloride （CK） ＋ GHB. The obtained results indicated that Lentinan ＋ GHB and Ningnanmycin ＋ GHB were the ideal biological pesticides, which could be used not only for controlling tomato virus diseases, but also for realizing modern, pollution-free, green and organic agricultural production.

Development of a New Azithromycin Glutamate for Parenteral Preparation, the Toxicity in Sprague-Dawley Rats and Pharmacokinetics in Human Healthy Volunteers

Aim In order to improve the solubility of azithromycin, the objectives of the present study were to screen an appropriate salt for azithromycin by comparing acute hepatic and renal toxicities in animals, and study the pharmacokinetics of final chosen azithromycin salt. Methods Various salts of azithromycin, such as glutamate, citrate, hydrochloride, sulphate, dihydrogen phosphate, lactobionate, tartrate, and aspartate were given intravenously to Sprague Dawley rats at a dose of 10 mg once daily for 14 consecutive days via tail vein. The acute hepatic and renal indicators were measured before and after administration. A pharmacokinetic study was performed on 12 healthy human volunteers. The subjects were equally divided into two groups by a randomized crossover design. Azithromycin glutamate injection was administered by intravenous infusion or intramuscular injection at a single dose of 500 mg, respectively. Azithromycin concentrations in plasma were determined by microbial inhibition zone assay, and the pharmacokinetic parameters were calculated using a practical pharmacokinetic software 3P87 program. Results Azithromycin glutamate was least toxic to the liver and kidney of the rats, thus being selected as a final salt for parenteral preparation of azithromycin. Pharmacokinetic results showed that the area under the plasma concentration-time curves （AUC0-120h） were 21.47 ± 1.57 h·μg·mL^-1 for intravenous infusion, and 19.36 ± 2.44 h·μg·mL^-1 for intramuscular injection. The absolute bioavailability of intramuscular injection was 92.59%. Conclusion Azithromycin glutamate is suitable for the future clinical application, and its pharmacokinetics is characterized in human volunteers in the present study.

Telbivudine:A new treatment for chronic hepatitis B

Three hundred and fifty million people worldwide are estimated to be chronically infected with hepatitis B virus. 15%-40% of these subjects will develop cirrhosis, liver failure or hepatocellular carcinoma during their life. The treatment of chronic hepatitis B has improved dramatically over the last decade merits to the advent of nucleoside/nucleotide analogues and the use of pegylated interferons. Approved drugs for chronic hepatitis B treatment include： standard interferon- alpha 2b, pegylated interferon-alpha 2a, lamivudine, adefovir dipivoxil, and entecavir. Unfortunately, these agents are not effective in all patients and are associated with distinct side effects. Interferons have numerous side effects and nucleoside or nucleotide analogues, which are well tolerated, need to be used for prolonged periods, even indefinitely. However, prolonged treatment with nucleoside or nucleotide analogues is associated with a high rate of resistance. Telbivudine is a novel, orally administered nucleoside analogue for use in the treatment of chronic hepatitis B. In contrast to other nucleoside analogues, Telbivudine has not been associated with inhibition of mammalian DNA polymerase with mitochondrial toxicity. Telbivudine has demonstrated potent activity against hepatitis B with a significantly higher rate of response and superior viral suppression compared with lamivudine, the standard treatment. Telbivudine has been generally well tolerated, with a low adverse effect profile, and at its effective dose, no dose- limiting toxicity has been observed. Telbivudine is one of the most potent antiviral agents for chronic hepatitis B virus and was approved by the FDA in late 2006.

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.

Efficacy of low dose peginterferon alpha-2b with ribavirin on chronic hepatitis C

AIM: To assess the effi cacy of peginterferon alpha 2b at doses of 50 μg weekly and 80 μg weekly (based on body weight) plus ribavirin in HCV genotype 2 and genotype 3 chronic hepatitis C patients. METHODS: During the study period of Jan 2002 to Dec 2003, all patients diagnosed as chronic hepatitis C or HCV related compensated cirrhosis were treated with peginterferon alpha 2b 50 μg S/C weekly (body weight < 60 kg) or 80 μg S/C weekly (body weight > 60 kg) plus ribavirin 800 mg/d for 24 wk. RESULTS: Overall 28 patients, 14 patients in each group (based on body weight) were treated during the period. Out of 28 patients, 75% were genotype 3, 18% were genotype 2 and 7% were genotype 1. The mean dose of peginterferon alpha 2b was 0.91 μg/kg in group 1 and 1.23 μg/kg in group 2 respectively. The end of treatment and sustained virologic response rates were 82% and 78% respectively. Serious adverse effects were seen in 3.5% patients. CONCLUSION: Low dose peginterferon alpha 2b in combination with ribavirin for 24 wk is effective in HCV genotype 2 and 3 chronic hepatitis C patients.

Ribavirin and IFN-α combination therapy induces CD4+ T-cell proliferation and Th1 cytokine secretion in patients with chronic hepatitis B

AIM: To investigate the anti-viral mechanism of combination therapy of interferon (IFN)-α and ribavirin in patients with chronic hepatitis B. METHODS: Twenty patients were assigned to receive either IFN-α plus ribavirin (group A,n = 14) or no treatment as a control (group B,n = 6). Patients were analyzed for T-cell proliferative responses specific for hepatitis B virus (HBV)-antigen and cytokine production by peripheral blood mononuclear cells (PBMCs). RESULTS: Combination therapy induced HBV-antigen specific CD4+ T-cell proliferative responses in four patients (28.6%). Production of high levels of HBV-specific IFN-γ,tumor necrosis factor (TNF)-α,interleukin (IL)-12 by PBMCs was found in five patients (35.7%),who showed significantly lower HBV DNA levels in serum at 12 mo after treatment ended (P = 0.038) and at 24 mo of follow-up (P = 0.004) than those without high levels of cytokine production. CONCLUSION: HBV-antigen specific CD4+ T cells may directly control HBV replication and secretion of anti-viral T helper 1 (Th1) cytokines by PBMCs during combination therapy of chronic hepatitis B with ribavirin and IFN-α.

T cell immunopathogenesis and immunotherapeutic strategies for chronic hepatitis B virus infection

Hepatitis B is caused by the host immune response and T cells play a major role in the immunopathogenesis. More importantly,T cells not only destroy hepatocytes infected by hepatitis B virus(HBV),but also control HBV replication or eradicate HBV in a noncytolytic manner.Therefore,analysis of T cell immune response during acute and chronic HBV infection is important to develop a strategy for successful viral control,which could lead to immunotherapy for terminating persistent HBV infection.There have been many attempts at immunotherapy for chronic HBV infection,and some have shown promising results.High viral load has been shown to suppress antiviral immune responses and immunoinhibitory signals have been recently elucidated, therefore,viral suppression by nucleos(t)ide analogs, stimulation of antiviral immune response,and suppression of the immunoinhibitory signals must be combined to achieve desirable antiviral effects.

Novel approaches towards conquering hepatitis B virus infection

Currently approved treatments for hepatitis B virus （HBV） infection include the immunomodulatory agent, IFN-α, and nucleos（t）ide analogues. Their efficacy is limited by their side effects, as well as the induction of viral mutations that render them less potent. It is thus necessary to develop drugs that target additional viral antigens. Chemicals and biomaterials by unique methods of preventing HBV replication are currently being developed, including novel nucleosides and newly synthesized compounds such as capsid assembling and mRNA transcription inhibitors. Molecular therapies that target different stages of the HBV life cycle will aid current methods to manage chronic hepatitis B （CriB） infection. The use of immunomodulators and gene therapy are also under consideration. This report summarizes the most recent treatment possibilities for CHB infection. Emerging therapies and their potential mechanisms, efficacy, and pitfalls are discussed.

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).

Isolation and Characterization of a Dichlorvos-Degrading Strain DDV-1 of Ochrobactrum sp.

The objective of this research was to isolate a dichlorvos (2,2-dichlorovinyl dimethyl phosphate)-degrading strain of Ochrobactrum sp., and determine its effectiveness in remediation of a dichlorvos-contaminated soil. A dichlorvos-degrading bacterium (strain DDV-1) was successfully isolated and identified as an Ochrobactrumsp. based on its 16S rDNA sequence analysis. Strain DDV-1 was able to utilize dichlorvos as a sole carbon source, and the optimal pH and temperature for its cell growth and degradation were 7.0 and 30 ℃, respectively. Also, the growth and degradation of strain DDV-1 showed the same response to dissolved oxygen. In addition, the soil degradation test indicated that in soil spiked with 100 mg L-1 or 500 mg L-1 dichlorvos and inoculated with 0.5% or 1.0% (v/v) strain DDV-1, complete degradation of dichlorvos could be achieved in 24 h. The present study showed that strain DDV-1 was a fast dichlorvos-degrading bacterium in soil. However, further research will be needed to clarify the degradation pathway and the properties of the key enzymes involved in its biodegradation.

Current prophylactic strategies against hepatitis B virus recurrence after liver transplantation

Prophylactic strategies against hepatitis B virus(HBV) recurrence after liver transplantation(LT) are essential for patients with HBV-related disease.Before LT, lamivudine(LAM) was proposed to be down-graded from first-to second-line therapy.In contrast, adefovir dipivoxil(ADV) has been approved not only as first-line therapy but also as rescue therapy for patients with LAM resistance.Furthermore, combination of ADV and LAM may result in lower risk of ADV resistance than ADV monotherapy.Other new drugs such as entecavir, telbivudine and tenofovir, are probably candidates for the treatment of hepatitis-B-surface-antigen-positive patients awaiting LT.After LT, low-dose intramuscular hepatitis B immunoglobulin(HBIG), in combination with LAM, has been regarded as the most cost-effective regimen for the prevention of post-transplant HBV recurrence in recipients without pretransplant LAM resistance and rapidly accepted in many transplant centers.With the introduction of new antiviral drugs, new hepatitis B vaccine and its new adjuvants, post-transplant HBIG-free therapeutic regimens with new oral antiviral drug combinations or active HBV vaccination combined with adjuvants will be promising, particularly in those patients with low risk of HBV recurrence.

In vitro screening of traditionally used medicinal plants in China against Enteroviruses

AIM： To search for new antiviral agents from traditional Chinese medicine, specifically anti-enterovirosuses agents. METHODS： The aqueous extracts （AE） of more than 100 traditionally used medicinal plants in China were evaluated for their in vitro anti-Coxsackie virus B3 activities with a MTT-based colorimetric assay. RESULTS： The test for AE of 16 plants exhibited anti- Coxsackie virus B3 activities at different magnitudes of potency. They can inhibit three steps （inactivation, adsorption and replication） during the infection. Among the 16 plants, Sargentodoxa cuneata （Oliv.） Rehd. et Wils., Sophora tonkinensis Gapnep., Paeonia veitchii Lynch, Spatholobus suberectus Dunn. and Cyrtorniurn fortunei J, sm. also have activity against other enterovirus, including Coxsackie virus 135, Polio virus I, Echo virus 9 and Echo virus 29. Cell cytotoxic assay demonstrated that all tested AE had CC50 values higher than their EC50 values. CONCLUSION： The sixteen traditionally used medicinal plants in China possessed antMral activity, and some of them merit further investigations.

Expression and function of renal and hepatic organic anion transporters in extrahepatic cholestasis

Obstructive jaundice occurs in patients suffering from cholelithiasis and from neoplasms affecting the pancreas and the common bile duct.The absorption,distribution and elimination of drugs are impaired during this pathology.Prolonged cholestasis may alter both liver and kidney function.Lactam antibiotics,diuretics,non-steroidal anti-inflammatory drugs,several antiviral drugs as well as endogenous compounds are classified as organic anions.The hepatic and renal organic anion transport pathways play a key role in the pharmacokinetics of these compounds.It has been demonstrated that acute extrahepatic cholestasis is associated with increased renal elimination of organic anions.The present work describes the molecular mechanisms involved in the regulation of the expression and function of the renal and hepatic organic anion transporters in extrahepatic cholestasis,such as multidrug resistanceassociated protein 2,organic anion transporting polypeptide 1,organic anion transporter 3,bilitranslocase,bromosulfophthalein/bilirubin binding protein,organic anion transporter 1 and sodium dependent bile salt transporter.The modulation in the expression of renal organic anion transporters constitutes a compensatory mechanism to overcome the hepatic dysfunction in the elimination of organic anions.

Treatment modalities for hypersplenism in liver transplant recipients with recurrent hepatitis C

Hepatitis C is the most common indication for orthotopic liver transplantation in the United States. Unfortunately, hepatitis C recurs universally in the transplanted liver and is the major cause of decreased graft and patient survival. The combination therapy of interferon and ribavirin has been shown to be the most effective therapy for recurrent hepatitis C. However, pre-and post-transplant hypersplenism often precludes patients from receiving the antiviral therapy. Splenectomy and partial splenic embolization are the two invasive modalities that can correct the cytopenia associated with hypersplenism. In this report we review the two treatment options, their associated outcomes and complications.