食蟹猴疟原虫——斯氏按蚊系统猴疟模型的一些生物学特性和对常用抗疟药物的生物效应

本文证明在一定条件下,斯氏按蚊对食蟹猴疟原虫的感染率为77±0.15%;恒河猴易感性强,对照组的感染率非常稳定,用10⁵个以上子孢子静脉接种恒河猴可100%获得感染。在食蟹猴疟原虫—斯氏按蚊系统猴疟模型上,常用抗疟药如乙胺嘧啶、伯喹显示有病因性预防作用。伯喹剂量达到2.5mg(基质)/kg×5天,合并氯喹20mg(基质)/kg×3天显示有权治作用,氯喹20mg(基质)kg×3天则仅能显示抑制性治疗作用。     

头孢他啶/阿维巴坦治疗碳青霉烯类耐药肠杆菌感染疗效和安全性的Meta分析

目的 系统评价头孢他啶/阿维巴坦(ceftazidime/avibactam,CAZ/AVI)治疗耐碳青霉烯类肠杆菌/肺炎克雷伯菌(CRE/CRKP)感染的疗效和安全性,以期为临床治疗提供循证依据.方法 计算机检索PubMed、Embase、The Cochrane Library、CBM、CNKI、VIP电子数据库,...     

Herbal hepatotoxicity by Greater Celandine (Chelidonium majus): causality assessment of 22 spontaneous reports

Toxic liver injury due to the herb Greater Celandine (GC) (Chelidonium majus L.) has been assumed in patients originating from various European countries and created concern. Based on regulatory and liver unspecific ad hoc causality assessments in 22 spontaneous cases of Germany, causality levels for GC were considered probable in 16 and possible in 6 cases. We now analyzed the data of these 22 cases regarding their causality levels employing the liver specific, standardized, structured and quantitative assessment method of the updated scale of CIOMS (Council for International Organizations of Medical Sciences). Causality for GC was found highly probable (n = 2), probable (n = 6), possible (n = 10), unlikely (n = 1), and excluded (n = 3). Thus, causality could be upgraded in 2 cases to a highly probable causality level, but had to be down graded to excluded, unlikely, or possible causality levels in 3, 1, or 9 cases, respectively. GC hepatotoxicity shows a hepatocellular pattern of liver injury with female gender predominance. On average, age of the patients was 56.4 years, treatment 36.4 days, and latency period until first symptoms and jaundice 29.8 and 35.6 days, respectively. This analysis therefore provides further evidence for the existence of GC hepatotoxicity as a distinct form of herb induced liver injury, but due to poor data quality the causal association between GC use and liver injury is less strong than hitherto assumed. We propose replacement of the regulatory organ unspecific by a liver specific causality assessment method in cases of herb induced liver injury as well as stricter pharmacovigilance strategies towards improvements of data quality. Toxicological studies are now warranted to elucidate the mechanism(s) of human GC hepatotoxicity that represents a European issue.     

Natural antibiotic susceptibility of strains of the Enterobacter cloacae complex

The natural susceptibility to 70 antibiotics of 104 strains of the Enterobacter cloacae complex was examined using a microdilution procedure in Isosensitest broth. One hundred and one clinical strains designated as ‘E. cloacae’ were identified as E. hormaechei (n=65), E. asburiae (n=20) and E. cloacae genospecies 1 or 2 (n=16). Apart from fosfomycin susceptibility, there were only minor differences in natural antibiotic susceptibility patterns. All species were naturally sensitive or naturally sensitive and intermediate to numerous β-lactams (e.g. carbapenems, aztreonam, acylaminopenicillins, ticarcillin, and some ‘modern’ cephalosporins), quinolones, aminoglycosides, tetracyclines, antifolates, chloramphenicol, and nitrofurantoin. Uniform natural resistance was found in benzylpenicillin, oxacillin, amoxycillin, amoxycillin/clavulanate, cefoxitin, rifampicin, lincosamides, glycopeptides, streptogramins and fusidic acid. Enterobacter hormaechei was the species most susceptible to fosfomycin. β-Lactam susceptibility patterns pointed to the presence of chromosomally-encoded AmpC enzymes in all taxa of the E. cloacae complex.     

Bacteraemia caused by Mycobacterium abscessus subsp. abscessus and M. abscessus subsp. bolletii: Clinical features and susceptibilities of the isolates

Mycobacterium abscessus complex (M. abscessus subsp. abscessus and M. abscessus subsp. bolletii) is an emerging pathogen causing various human infections. However, few studies have focused on M. abscessus complex bacteraemia with detailed species differentiation. The clinical characteristics of patients with bacteraemia due to M. abscessus complex treated at National Taiwan University Hospital from 2005–2012 were evaluated. Species identification was performed by molecular methods, and minimum inhibitory concentrations (MICs) were determined using a Sensititre RAPMYCO Panel Test for preserved M. abscessus complex isolates. During the study period, 15 patients with M. abscessus complex bacteraemia were found but only 14 isolates from 13 patients were preserved for analysis. One patient had two episodes of bacteraemia (one caused by M. abscessus subsp. bolletii and one by M .abscessus subsp. abscessus with a 9-month interval). Of the remaining 12 patients, 9 patients had M. abscessus subsp. bolletii bacteraemia and 3 had M .abscessus subsp. abscessus bacteraemia. Patients were mainly middle-aged adults with various co-morbidities. Steroid usage and malignancy (5/15) were the most common immunocompromised statuses, followed by diabetes mellitus (4/15). Surgical wound infection was the most common infection foci in all patients (5/15), particularly in M. abscessus subsp. bolletii bacteraemia patients. Clarithromycin and tigecycline exhibited good in vitro activities. Overall, the 14-day mortality was 20% (3/15). M. abscessus complex bacteraemia should be considered an emerging opportunistic infection in immunocompromised hosts. Clarithromycin and tigecycline have potent in vitro activities and are promising agents for treating infections due to M. abscessus complex.     

β-lactam antibiotics vs. vancomycin for the early treatment of enterococcal bacteraemia: A retrospective cohort study

BackgroundThe efficacy of vancomycin compared with ampicillin for enterococcal infections is unknown. This study aimed to compare their efficacy among patients with enterococcal bacteraemia.MethodsRetrospective cohort study including adults aged >16 years with enterococcal bacteraemia, treated with β-lactam antibiotics active against Enterococcus spp. or vancomycin. Treatment classification was based on the first antibiotic used for >4 days in the 7 days after blood culture collection. Subgroup analyses for patients with penicillin-susceptible enterococcal bacteraemia and patients with monomicrobial penicillin-susceptible enterococcal bacteraemia were performed. The dependent variable was 30-day all-cause mortality. The propensity score (PS) for vancomycin treatment was calculated. Univariate and multi-variate analyses adjusted for PS were performed.ResultsIn total, 516 patients with enterococcal bacteraemia were included. Mortality was similar for patients treated with β-lactams (123/315, 39%) and vancomycin (82/201, 40.8%). Independent factors significantly associated with mortality included healthcare-associated or hospital-acquired infection, age, female sex, Charlson Comorbidity Index, dialysis, SOFA score and low albumin. After adjustment for these factors and PS, the odds ratio (OR) for death in patients treated with vancomycin was 0.95 [95% confidence interval (CI) 0.56–1.59]. Results were similar among patients with penicillin-susceptible enterococcal bacteraemia and patients with monomicrobial penicillin-susceptible enterococcal bacteraemia (n=237, adjusted OR 0.59, 95% CI 0.25–1.43).ConclusionNo difference in mortality was observed following treatment with a β-lactam or vancomycin among patients with enterococcal bacteraemia. Vancomycin is not recommended for the treatment of penicillin-susceptible enterococcal infections; however, when needed, it is not inferior to β-lactams and the addition of a β-lactam is not necessary.     

Réévaluation de la colistine

Colistin (polymyxin E) designates two different drugs, colistin sulfate, an oral digestive decontaminant, and colismethate sodium (CMS) intended for intravenous, intrathecal/intraventricular, or inhaled therapy. Colistin interferes with bacterial membranes creating cytoplasmic leaks lethal to bacteria through interactions with membrane proteins and phospholipids (including LPS). This mechanism of action confers bactericidal activity to colistin on frequently multiresistant pathogens such as Acinetobacter spp., P. aeruginosa, and Klebsiella spp. It also leads to specific resistance mechanisms, which arise from modifications in bacterial membrane proteins. New methods applied to pharmacokinetic studies of colistin take into account the in-solution and plasmatic hydrolysis of CMS, the inactive prodrug, into active compounds among which colistin. These studies show that current therapeutic regimens may be optimized. Colistin being a concentration dependent bactericidal antibiotic, the area under the curve (AUC)/MIC was proven the best PK/PD parameter associated with in vivo efficacy, opening new perspectives in alternate dosing regimens. Nephrotoxicity occurs at a rate comparable to aminoglycosides and neurotoxicity is more often benign; both being reversible upon discontinuation of therapy. In multiresistant Gram negative, mostly A. baumanii or P. aeruginosa, nosocomial infections as well as in chronic P. aeruginosa infections and exacerbations in cystic fibrosis patients, the efficacy of colistin has been demonstrated within the limitations inherent to studies of an antibiotic which can only be used after determination of susceptibility in severe infections nonetheless requiring urgent adequate therapy. Further clarifications are required concerning the added benefit of combination with antibiotics considered as synergistic such as rifampicin and carbapenems.     

Multicentre study of risk factors for mortality in patients with Acinetobacter bacteraemia receiving colistin treatment

Colistin remains a last-line antibiotic for the treatment of infections by multidrug-resistant Acinetobacter species. However, mortality rates are high in patients with Acinetobacter infection receiving colistin treatment. This multicentre study evaluated whether colistin susceptibility, additional antimicrobial agents or other prognostic factors influenced the clinical outcomes of patients receiving colistin treatment for Acinetobacter bacteraemia. This retrospective study enrolled 122 adults receiving colistin for monomicrobial Acinetobacter bacteraemia at six medical centres in the ACTION Study Group over an 8-year period. Clinical information, antimicrobial susceptibility and colistin resistance determinants were analysed. The primary outcome measure was 14-day mortality. Among 122 patients, 18 and 104 were infected with colistin-resistant (ColR) isolates [minimum inhibitory concentration (MIC) ≥4 mg/L] and colistin-susceptible (ColS) isolates (MIC ≤2 mg/L), respectively. Patients infected with ColR and ColS isolates did not differ significantly with regard to Charlson comorbidity index, invasive procedures, sources of bacteraemia, disease severity and 14-day mortality rate (44.4% vs. 34.6%; P = 0.592). No specific additional antimicrobial agent was independently associated with higher or lower mortality. Coronary artery disease, higher Acute Physiology and Chronic Health Evaluation (APACHE) II score and bacteraemia caused Acinetobacter baumannii were independent risk factors associated with 14-day mortality. Mechanisms of colistin resistance were associated with amino acid variants in the pmrCAB operon. Finally, previously unreported Acinetobacter nosocomialis amino acid variants related to colistin resistance were identified. In conclusion, colistin susceptibility and colistin combination antimicrobial treatment were not associated with decreased 14-day mortality in patients with Acinetobacter bacteraemia receiving colistin treatment.     

中药败酱草的形态组织学研究——Ⅲ.菊科苦苣菜属、莴苣属和苦荬菜属植物

本文报道我国北方使用的来源于菊科植物的中药败酱草的生药形态组织学的研究结果,它们是:苣荬菜Sonchus arvensis L.S.、苦苣菜oleraceus L.圆耳苦苣菜S.asper (L.)Hill.紫花山莴苣Lactuca tatarica(L.)C.A.Mey.、中华苦荬菜Ixeris ccinensis(Thunb.)Nakai、抱茎苦荬菜I.sonchifolia Hance和苦荬菜I.denticulata(Houtt.)Stebb..文中附有生药组织图7幅以及上述生药的性状检索表和显微特征检索表.     

Retrospective case-control analysis of patients with staphylococcal infections receiving daptomycin or glycopeptide therapy

Glycopeptides have been considered the antimicrobials of choice for serious meticillin-resistant Staphylococcus aureus (MRSA) and meticillin-resistant coagulase-negative staphylococci (MR-CoNS) infections for several years. Daptomycin is a new option for the treatment of these infections, including those exhibiting reduced susceptibility to glycopeptides. The aim of this study was to compare glycopeptides and daptomycin for the treatment of infections caused by MRSA or MR-CoNS. Data for 106 patients with bloodstream infections (bacteraemia or infective endocarditis) or skin and soft-tissue infections (SSTIs) were retrospectively reviewed, of which 43 were treated with daptomycin (DAP group) and 63 were treated with vancomycin or teicoplanin (GLYCO group). Patients included in the two comparison groups were homogeneous in terms of age, risk factors and clinical severity. Aetiology was mainly represented by MRSA in both groups, followed by various species of MR-CoNS. Daptomycin was used more frequently in patients with central venous catheter-associated bacteraemia or pacemaker-associated infection. Patients with SSTIs included in the GLYCO group had a longer mean duration of antibiotic therapy (18.2 days vs. 14.6 days; P = 0.009) and a longer mean length of hospital stay (28.2 days vs. 19.6 days; P = 0.01) compared with those included in the DAP group. A longer mean duration of antibiotic therapy was also observed in patients with bloodstream infections receiving glycopeptide therapy (25.6 days vs. 18 days; P = 0.004). In conclusion, the good clinical efficacy of daptomycin is associated with a more rapid resolution of the clinical syndrome and a reduced length of hospitalisation. This latter aspect may have important pharmacoeconomic implications, promoting the use of daptomycin in the clinical setting.     

Bacteremia due to Enterobacter spp. in cancer patients—analysis of 51 episodes

Fifty one episodes of bacteremia due to Enterobacter spp. appearing within 7 years among 12 301 admissions in a single cancer institution were studied for risk factors, clinical presentation and outcome. Fifteen episodes were due to Enterobacter aerogenes, 23 due to E. cloacae and 13 due to E. agglomerans. The proportion of bacteremia due to Enterobacter spp. among Gram-negative bacteremias was 10.1% and infection associated mortality was 13.8%. The incidence in 1989–1995 varied from 3.7 to 8.7% and was relatively stable. Most common risk factors were: solid tumors as underlying disease, central venous catheter insertion, prior surgery and prior chemotherapy within 48 h. Neutropenia and urinary catheters were not at high risk in either one of the patients subgroups. Comparing two subgroups of 51 bacteremias, monomicrobial and polymicrobial (when Enterobacter spp. was isolated from blood culture with other microorganism), previous chemotherapy, vascular catheter insertion and prior endoscopy were more frequently associated with polymicrobial Enterobacter spp. bacteremia. There was also differences in infection associated mortality: bacteremias due to Enterobacter spp. only had significantly lower mortality in comparison to polymicrobial Enterobacter spp. bacteremias (3.3 vs. 29.3%; P<0.02). Susceptibility of Enterobacter spp. strains isolated from 51 episodes was stable and showed only two episodes due to quinolone-resistant strains, both in 1992 despite of the use of ofloxacin in prophylaxis of neutropenic patients since 1990 in our institute. Ninety-two to 94% of all strains were susceptible to aminoglycosides, 96–98% to ofloxacin and ciprofloxacin, respectively and 94.9% to meropenem but only 75.5% to ceftazidime.     

免疫调节剂抗鲍曼不动杆菌感染的研究进展

鲍曼不动杆菌感染因广泛的抗菌药耐药性和高死亡率而备受关注,常规抗菌药治疗策略的疗效欠佳。鲍曼不动杆菌和机体免疫反应的相互作用影响感染的严重程度以及临床转归,通过免疫调节改善机体免疫反应是有效的治疗方案。免疫调节剂具有单独治疗或作为免疫佐剂联合抗菌药治疗鲍曼不动杆菌感染的潜力,成为有希望改善感染结局的策略,由此开发的新疗法引起了广泛关注。对不同来源的(生物制剂、免疫系统产物、化学合成制剂、中药或植物药成分)免疫调节剂抗鲍曼不动杆菌感染的研究进展进行阐述,以期对免疫治疗提供帮助。     

The effect of 3435C>T MDR1 gene polymorphism on rheumatoid arthritis treatment with disease-modifying antirheumatic drugs

Objective Rheumatoid arthritis (RA) is a multifactorial disease, with immunological, genetical as well as environmental factors being implicated in its pathogenesis. Treatment of RA is based mainly on drugs modulating the course of the disease, e.g. methotrexate (MTX) or sulfasalazine (SL). The MDR1 gene product, P-glycoprotein (P-gp), is probably one of the most important and best defined transporters for drug delivery in humans. P-gp transports a wide range of substrates with diverse chemical structures, among them anticancer agents, cardiac drugs, and immunosuppressants. The aim of this study was to examine the effect of the 3435C>T MDR1 gene polymorphism on the efficacy of RA treatment with disease-modifying antirheumatic drugs, i.e. MTX plus methylprednisolone (MP), and SL.Methods The study was carried out on 255 patients with RA treated according to two regimes: (1) MTX (7.5–15.0 mg weekly) plus low doses of MP (n=174), (2) SL (1.5–3 g daily, n=81).Results The probability of remission of RA symptoms after MTX plus MP therapy was 4.65-fold higher in carriers of the TT genotype compared to patients with CC genotype (P=0.003, OR 4.65, 95%CI 1.66–13.05), whereas the probability of remission of RA symptoms in patients treated with SL was 2-fold higher in carriers of TT genotype compared to patients with CC genotype, but did not reach statistical significance (P=0.358, OR=2.00 95% CI=0.58–6.87).Conclusion The results from the present study suggest that the 3435C>T MDR1 gene polymorphism may influence the efficacy of RA therapy with disease-modifying antirheumatic drugs.     

Epidemiology and molecular characterisation of metallo-β-lactamase-producing Enterobacteriaceae in a university hospital Intensive Care Unit in Greece

The molecular epidemiology of VIM-producing Enterobacteriaceae isolated at the beginning of an epidemic in the Intensive Care Unit (ICU) of a university hospital in Athens, Greece, was studied. All Gram-negative organisms isolated from March 2004 to November 2005 positive for metallo-β-lactamase (MBL) production were submitted to polymerase chain reaction (PCR) and sequencing, to repetitive sequence-based PCR (Rep-PCR) for molecular typing, and to S1 nuclease digestion for plasmid DNA characterisation. Conjugation experiments and isoelectric focusing were performed to identify co-existing β-lactamases. Amongst 23 patients, 12 suffered one or more clinical infections. Eighty-two isolates representing one isolate per clone, source and ICU patient were studied, including Klebsiella pneumoniae (77), Enterobacter cloacae (2), Citrobacter freundii (1) and Pseudomonas aeruginosa (2). High clonal diversity was detected amongst the K. pneumoniae, with 10 distinct clones identified. Conjugation was successful in 54.5% of K. pneumoniae, and five different-sized plasmids were detected. All K. pneumoniae and both E. cloacae isolates shared the same bla_VIM-1-containing class 1 integron structure also carrying aacA7, dhfrI and aadA1 gene cassettes. The C. freundii isolate carried a different integron that included bla_VIM-1 and aac(6′)-IIc. Both P. aeruginosa isolates were positive for bla_VIM-2. It was not possible to identify specific clones with the potential to cause clinical infections. In conclusion, a multiclonal cluster of MBL-producers was responsible for the first cases of colonisation and/or infection in the ICU. A single integron structure, common in Greek hospitals, efficiently disseminated between clones and species, suggesting that the epidemic was mainly the result of successful horizontal transfer of mobile genetic material rather than the result of horizontal transfer of one or a few clones.     

In vitro activity of pentamidine against Tropheryma whipplei

Pentamidine is a group I intron splice inhibitor used as a chemotherapeutic agent to treat parasitic infections. It was recently found to be efficient intracellularly against Coxiella burnetii, the bacterial agent of Q fever. This in vitro activity was linked to the presence of self-splicing group I introns that disrupt the 23S rRNA of C. burnetii. However, there are several indications that pentamidine may have a wider range of antibacterial activity. The aim of this study was to determine the in vitro activity of pentamidine against Tropheryma whipplei, the agent of Whipple's disease, a chronic disease for which antibiotic treatment remains challenging. In vitro susceptibility testing of pentamidine and doxycycline was assessed both in axenic medium and in cell culture against three clinical isolates of T. whipplei using a quantitative real-time polymerase chain reaction (PCR) assay as previously described. Both doxycycline and pentamidine were found to be active against T. whipplei strains both in axenic medium and in cell culture, with minimum inhibitory concentration ranges of 0.5–1 mg/L and 0.125–0.25 mg/L for doxycycline and pentamidine, respectively. Pentamidine was effective in vitro against T. whipplei both intracellularly and in axenic medium. This is the first evidence of the direct efficacy of pentamidine against T. whipplei grown in axenic medium and in cells. Since pentamidine has been widely used in humans, we believe that it could be an alternative drug for the treatment of this chronic disease that should be further studied in clinical trials.     

2012—2020年泰达国际心血管病医院心血管疾病患者血流感染病原菌分布和耐药性分析

目的 分析泰达国际心血管病医院心血管疾病患者发生血流感染的病原菌分布及耐药特征,为临床合理应用抗菌药物提供依据.方法 对2012年1月—2020年12月泰达国际心血管病医院血流感染病原菌的分布及耐药性进行回顾性分析.结果 共检出病原菌234株,其中革兰阴性菌133株,构成比为56.8％,主要为大肠埃希菌、肺炎克雷伯菌和...     

不同产地五倍子体外抗菌作用研究

目的 考察五倍子不同产地（河北曲阳、浙江嘉兴、湖南桑植、陕西西乡、云南凤县）的体外抗菌作用。方法 五倍子醇提浸膏用倍半稀释法稀释成不同浓度药液,采用管碟法测定各产地五倍子的最小抑菌浓度（MIC）。结果 河北、浙江、湖南、陕西、云南所产五倍子醇提浸膏对金黄色葡萄球菌的MIC依次为6.25、1.562 5、1.562 5、3.125、0.781 25 mg/L;对大肠杆菌的MIC依次为3.125、12.5、6.25、6.25、3.125 mg/L;对白色念珠菌的MIC依次为6.25、1.562 5、3.125、1.562 5、3.125 mg/L;对绿脓杆菌的MIC依次为12.5、6.25、6.25、6.25、3.125 mg/L。结论 河北、浙江、陕西、云南、湖南所产五倍子均有抑菌作用,其中云南产五倍子醇提物对金黄色葡萄球菌、大肠杆菌、绿脓杆菌抑菌作用最强,陕西、浙江产五倍子醇提物对白色念球菌的抑菌作用强。     

Another look at differences in the susceptibility of Escherichia coli and Klebsiella pneumoniae to cephalothin and cefazolin

The significance of in vitro susceptibility tests on Enterobacteriaceae to cephalothin and cefazolin has not been exactly defined in the guidelines of the National Committee for Clinical Laboratory Standards. In the hope of clarifying this confusion, we provide additional information from an ancillary study of the Taiwan Surveillance of Antimicrobial Resistance 1998 (TSAR I). There were 505 Escherichia coli and 227 Klebsiella pneumoniae isolates susceptible to cephalothin, reported by 42 participating hospitals. The susceptibility of these isolates were re-tested at the Microbial Infections Reference Laboratory using cefazolin, with the result that 72% of the 252 cephalothin-resistant E. coli isolates and 24% of the 41 cephalothin-resistant K. pneumoniae isolates were found to be susceptible to cefazolin. We further surveyed the availability of cephalothin and cefazolin in Pharmacy Departments; all of the TSAR I hospitals had cefazolin available in their pharmacies. The resistance rate of E. coli was significantly lower for 12 hospitals that had cefazolin in both pharmacy and laboratory compared with 11 hospitals that had cefazolin available in pharmacy but cephalothin in laboratory. In addition, for all the hospitals that had cephalothin available for clinical use, the resistance rate was twice as low in two hospitals reporting cefazolin susceptibility as in the seven hospitals reporting cephalothin susceptibility. Our findings suggest that inappropriate selection of cephalothin and cefazolin for susceptibility testing contribute to inaccurate indications of in vivo activity for first generation cephalosporins in the treatment of E. coli infections.     

明目蒺藜丸联合聚乙烯醇滴眼液治疗干眼症的临床研究

目的 制备他达拉非片并考察其体内外释药特性。方法 以溶出度为评价指标,筛选他达拉非片各辅料用量及包衣增重。用相似因子（f₂）法比较自制制剂与参比制剂在0.5% SDS溶液、含0.5% SDS的0.1 mol/L的盐酸溶液、含0.5% SDS的pH 4.5醋酸钠缓冲液、含0.5% SDS的pH 6.8磷酸盐缓冲液中溶出曲线的相似性。比较二者在Beagle犬体内的药动学特征。结果 他达拉非片处方为他达拉非20 mg、乳糖50M 227.625 mg、羟丙基纤维素L 10.5 mg、交联羧甲基纤维素钠19.6 mg、SDS 0.525 mg、微晶纤维素M102 70 mg、硬脂酸镁1.75 mg,包衣增质量范围2%～4%。自制与参比制剂在4种溶出介质中的f₂均大于65,二者体外溶出行为相似。2种制剂在Beagle体内的药动学参数AUC_0~t、C_max、t_max均无显著性差异,自制他达拉非片的相对生物利用度为（101.67±8.99）%。结论 成功制备他达拉非片,其体外溶出和体内药动学行为与参比制剂相似。     

Molluscicidal activity of cardiac glycosides from Nerium indicum against Pomacea canaliculata and its implications for the mechanisms of toxicity

Cardiac glycosides from fresh leaves of Nerium indicum were evaluated for its molluscicidal activity against Pomacea canaliculata (golden apple snail: GAS) under laboratory conditions. The results showed that LC₅₀ value of cardiac glycosides against GAS was time dependent and the LC₅₀ value at 96 h was as low as 3.71 mg/L, which was comparable with that of metaldehyde at 72 h (3.88 mg/L). These results indicate that cardiac glycosides could be an effective molluscicide against GAS. The toxicological mechanism of cardiac glucosides on GAS was also evaluated through changes of selected biochemical parameters, including cholinesterase (ChE) and esterase (EST) activities, glycogen and protein contents in hepatopancreas tissues of GAS. Exposure to sublethal concentrations of cardiac glycosides, GAS showed lower activities of EST isozyme in the later stages of the exposure period as well as drastically decreased glycogen content, although total protein content was not affected at the end of 24 and 48 h followed by a significant depletion at the end of 72 and 96 h. The initial increase followed by a decline of ChE activity was also observed during the experiment. These results suggest that cardiac glycosides seriously impair normal physiological metabolism, resulting in fatal alterations in major biochemical constituents of hepatopancreas tissues of P. canaliculata.