905株革兰阴性杆菌对氟哌酸耐药性的观察

本文就氟哌酸广泛应用于临床后,对近三年来从各种标本中分离出的905株革兰阴性杆菌吋氟哌酸的耐药性进行了观察研究,发现其敏感率呈逐年下降趋势,敏感率依次为93.39%、85.56%、79.38%,同时耐药性逐年升高,耐药率依次为4.96%、8.45%、17.27%。     

Medicinal chemistry of oxazines as promising agents in drug discovery

Oxazines have brought much synthetic interest due to their extensive biological activities. These are the important category of heterocycles, which may be formally derived from benzene and its reduction products by convenient substitution of carbon (and hydrogen) atoms by nitrogen and oxygen. In the last few decades, oxazine derivatives have documented as worthy synthetic intermediates and also blessed with notable sedative, analgesic, anticonvulsant, antipyretic, antimicrobial, antitubercular, antimalarial, antioxidant, and anticancer activities. Nowadays, it is important to develop new classes of compounds with more effective mechanisms due to drug resistance activity in which the ability of drug to effectively treat disease can be reduced. The aim of the article is to collect and make a more generalized review on the synthesis of oxazine derivatives and their pharmaceutical and biological activities. We hope this review will provide ample references for the researchers concerned with azines in generally and oxazines in particular.     

Synthesis and antimicrobial evaluation of piperic acid amides and their lower homologues

Seven piperic acid amides along with their lower homologs (12) were synthesized using HATU-DIPEA coupling reagent. All the synthesized derivatives were evaluated for their antibacterial activities against Staphylococcus aureus, Pseudomonas aeruginosa, and vancomycin-resistant P. aeruginosa. They were found to be more active on P. aeruginosa than on S. aureus. However, they did not exhibit potent activity on Vancomycin resistant P. aeruginosa. Among the tested compounds, methylenedioxycinnamic acid amide of anthranilic acid (MDCA-AA, 2a) was found to be most active against S. aureus with MIC of 3.125 μg/ml. The PAS and INH amides of piperic acid were screened against Mycobacterium tuberculosis H37R_a strain. They were found to be most active among all the tested compounds but were found to be less active than the standard drug, isoniazid.     

Opportunities and challenges of using five-membered ring compounds as promising antitubercular agents

Tuberculosis (TB), a chronic infectious disease, is one of the greatest risks to human beings and 10 million people were diagnosed with TB and 1.6 million died from this disease in 2017. In addition, with the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), the TB situation has become even worse, which has aggravated the mortality and spread of this disease. To overcome this problem, research into novel antituberculosis agents with enhanced activities against MDR-TB, reduced toxicity, and shortened duration of therapy is of great importance. Fortunately, many novel potential anti-TB drug candidates with five-membered rings, which are most likely to be effective against sensitive and resistant strains, have recently entered clinical trials. Different five-membered rings such as furans, pyranoses, thiazoles, pyrazolines, imidazoles, oxazolidinone, thiazolidins, isoxazoles, triazoles, oxadiazoles, thiadiazoles, and tetrazoles have been designed, prepared, and evaluated for their antimycobacterial activity against Mycobacterium tuberculosis. In this article, we highlight the recent advances made in the discovery of novel five-membered ring compounds and focus on their antitubercular activities, toxicity, structure–activity relationships, and mechanisms of action.     

Usnic acid and its derivatives for pharmaceutical use: a patent review (2000–2017)

Introduction: Usnic acid (UA) is a lichen-derived secondary metabolite with a unique dibenzofuran skeleton and is commonly found in lichenized fungi of the genera Usnea and Cladonia. Usnic acid has been incorporated for years in cosmetics, perfumery, and traditional medicines. It has a wide range of bioactivities, including antimicrobial, antiviral, anticancer, anti-inflammatory properties.

Areas covered: This review covers patents on therapeutic activities of UA and its synthetic derivatives published during the period 2000–2017.

Expert opinion: UA demonstrates excellent anticancer and antimicrobial properties. However, its application was withdrawn due to acute liver toxicity reported with chronic consumption. The broad spectrum of its biological activity indicates high the variability of UA’s binding preferences. The main idea to be addressed in the future should include the synthesis of UA derivatives because these might possess increased bioactivity, bioavailability and decreased toxicity. It is noteworthy that UA derivatives possessed better antibacterial, antitubercular, and anticancer activity than the parent compound . Most importantly, UA and its analogs (to a greater extent than UA) can be useful in cancer drug treatment. They have the potential for joint application with other anticancer drugs in order to overcome drug resistance.     

UFLC method development and validation of a novel triethylamine containing thiophene S006‐830 ‐ an antitubercular molecule and its application to pharmacokinetic and bioavailability studies in SD rats

A sensitive and selective ultra fast liquid chromatography (UFLC) method has been developed and validated for the determination of a potent and novel antitubercular compound S006‐830 in Sprague Dawley (SD) rat plasma. Samples were extracted and processed by protein precipitation method using acetonitrile. Chromatographic separation was achieved on a Phenomenex, Luna C‐18 column (3μm, 100mm x 2mm i.d.) under isocratic condition. Detection was performed on UFLC‐NEXERA system (LC‐30AD, Shimadzu, Kyoto, Japan) with a degasser (DGU‐20A), auto‐injector (SIL‐30AC), fixed with a 100‐μL loop. Method was found sensitive and reproducible over a linearity range of 15.6‐2000 ng/mL. Recovery of S006‐830 and internal standard was found >90% for spiked matrix control and standard quality control plasma samples. This validated method was successfully applied to generate pharmacokinetic profile of S006‐830 in SD rats. Oral dose proportionality studies were conducted at 100, 50, 25 mg/Kg dose levels, while an IV study was conducted at 25 mg/Kg dose. There was dose dependent increase in AUC and C_max indicating S006‐830 to exhibit linear pharmacokinetics. S006‐830 exhibited favorable bioavailability in the range of 45‐55%. Copyright © 2014 John Wiley & Sons, Ltd.     

Spray-dried fucoidan microparticles for pulmonary delivery of antitubercular drugs

Pulmonary tuberculosis accounts for 80% of cases and the delivery of antitubercular drugs into the lungs allows targeting the infected organ and, possibly, reducing systemic drug toxicity. This work aimed at using fucoidan as matrix of inhalable microparticles that associate two first-line antitubercular drugs, for an application in pulmonary tuberculosis therapy. Fucoidan is composed of fucose and sulphated sugar residues, moieties described as being recognised by surface receptors of alveolar macrophages, which host mycobacteria. Inhalable fucoidan microparticles loaded with antitubercular drugs were successfully produced with high association efficiencies of either isoniazid (95%) or rifabutin (81%). The microparticles evidenced no cytotoxicity on lung epithelial cells (A549). However, rifabutin-loaded microparticles showed a certain degree of toxicity on macrophage-like cells (THP-1) at the highest tested concentration (1?mg/mL). Furthermore, microparticles showed favourable aerodynamic properties for deep lung delivery (MMAD 2.0–3.8?µm) and, thus, show potential for an application as inhalable tuberculosis therapy.     

新型尿苷肽类化合物Sansanmycin P的提取分离、结构鉴定及活性研究

目的从放线菌 Streptomyces sp SS 发酵液中分离新型活性尿苷肽类似物。方法发酵液经 D4006大孔吸附树脂、DEAE-葡聚糖凝胶及制备液相分离纯化,获得单一化合物;根据 UV、MS、MS/MS、1D 和2D NMR 确定化合物结构,并进行抗菌活性研究。结果分离纯化得到1个 N-末端含有1-甲基-6-羟基四氢异喹啉的尿苷肽类化合物 Sansanmycin P。初步体外抗菌活性,抗铜绿假单胞菌 MIC 〉32μg/ml,抗结核杆菌 MIC 〉32μg/ml。结论 Sansanmycin P 为全新结构 Sansanmycins 类似物,具有一定抗结核杆菌和铜绿假单胞菌活性。     

Delamanid when other anti-tuberculosis-treatment regimens failed due to resistance or tolerability

Introduction: The limited availability of effective drugs causes difficulties in the management of multidrug-resistant tuberculosis (MDR-TB) and novel therapeutic agents are needed. Delamanid, a new nitro-hydro-imidazooxazole derivative, inhibits mycolic acid synthesis. This review covers the efficacy and safety of delamanid for MDR-TB.

Area covered: This paper reviews the pharmacological profile of delamanid and the results of clinical trials evaluating its efficacy for treating MDR-TB in combination with other anti-TB drugs. The drug’s safety and tolerability profiles are also considered.

Expert opinion: Delamanid showed potent activity against drug-susceptible and -resistant Mycobacterium tuberculosis in both in vitro and in vivo studies. In clinical trials, the drug showed significant early bactericidal activity in pulmonary TB patients, and increased culture conversion after 2 months of treatment in combination with an optimized background regimen in MDR-TB patients. In addition, decreased mortality was observed in MDR-TB patients who received > 6 months of delamanid treatment. The drug was generally tolerable, but QT prolongation should be monitored carefully using electrocardiograms and potassium levels. Therefore, delamanid could be used as part of an appropriate combination regimen for pulmonary MDR-TB in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.     

Diagnosis and treatment of spinal tuberculosis after liver transplantation

BACKGROUND:Spinal tuberculosis is a common disease in orthopedic clinical practice;however,it is seldom reported after organ transplantation.The aim of this study was to investigate the diagnosis and treatment of spinal tuberculosis after organ transplantation. METHOD:Two cases were diagnosed as spinal tuberculosis after liver transplantation and were treated with socarboxazide,rifampicin,streptomycin and ethambutol for more than one year. RESULTS:After treatment with anti-tuberculosis drugs for several mon...