Ultra high performance liquid chromatography method development for separation of omeprazole and related substances on core-shell columns using a Quality by Design approach.

An updated and improved method for analysis of omeprazole/esomeprazole and related substances on core-shell columns was developed using Fusion LC Method Development™. The method was optimized with respect to column type, column temperature, mobile phase pH level, and gradient time. Four different core-shell columns were examined to develop a method suitable for both high performance- and ultra-high performance liquid chromatography using a Quality by Design approach. The final method offers two alternative columns: Poroshell EC C18 (3.0 × 100 mm, 2.7 µm) or Poroshell HPH (3.0 × 100 mm, 2.7 µm) with the same gradient elution condition and mobile phase composition. Total run time is 18 min with 12 min of gradient elution. Phosphate buffer (15 mM, pH 7.8) is selected as the aqueous mobile phase and acetonitrile as the organic mobile phase. Column temperature is set at 40°C and ultraviolet detection at 302 nm. Furthermore, by studying parameters in a systematic way, an understanding of the effect of the input parameters enhances the method robustness and should allow for regulatory flexibility in terms of post-approval changes. Compared to the current United States Pharmacopeia method, the updated method is faster, more efficient and performs well above acceptance criteria.

Degradation caused by incompatibility between sodium stearyl fumarate (PRUV) and AZD7986 in the drug product.

During compatibility study of the AZD7986 project, a peak of 3 area% at the tail (RRT 1.03) of the active pharmaceutical ingredient (API) was discovered for all tablets containing sodium stearyl fumarate (PRUV) under humid condition (e.g. 50 °C/75% RH), regardless of choice of disintegrant or filler combination. The degradant was needed to be identified to understand the corresponding reaction mechanism and help the final formulation design. Structure elucidation was therefore done by analysis using high resolution mass spectrometry. The degradant was found to be a Michael addition product of the API and fumaric acid. Reaction between deuterated fumaric acid and the API was carried to confirm the proposed structure and reaction mechanism. Fumaric acid was a degradant product of PRUV in the presence of other excipients, revealed by the stability study. The Michael addition reaction needs facilitation by water and basic conditions. The result from this study should serve as a precaution note for projects using PRUV as one of excipients where the API could act as a nucleophile. In such cases the microenvironment should be optimised to minimize the reaction, such as pH adjustment and incorporating protection from moisture.

Monitoring of vancomycin serum concentrations and the evaluation of its safety and treatment outcomes in adult patients / 中华危重病急救医学

Objective To investigate the relationship between the serum level of vancomycin and its clinical efficacy as well as adverse reactions in adult patient so as to provide recommendations for clinical management. Methods An open observational research was performed from 1st July 2013 to 31st December 2017 in Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, which recruited the adult patients who were infected with Gram positive (G+) bacteria and treated with vancomycin. The initial dose was decided by the patient's creatinine clearance rate, and the treating dose was directed by the serum drug concentration and the patient's clinical response. By recording the associated clinical information (pathogen eradication, blood test results, adverse reactions, etc.), the clinical outcome and adverse reactions for vancomycin to treat G+bacterial infections were analyzed. Results Eighty-nine cases who meet research standards were finally recruited, with 67.42% of male patients, and an average age of (50.5±17.9) years. The most common type of infection was bloodstream infection (61.80%), followed by low respiratory infection (17.98%). Infections caused by Staphylococcus aureus accounted for 39.33%. The bacterial eradication rate was 89.89% (80/89) and the total effective rate was 77.53% (69/89). The effective rate was 80.30% (53/66) with minimum inhibitory concentration (MIC) < 2 mg/L vs. 69.57% (16/23) with MIC ≥ 2 mg/L, the difference was not statistically significant (χ2= 1.129, P = 0.288). The effective rate was 72.92% (35/48) with trough levels <10 mg/L vs. 82.93% (34/41) with trough levels ≥ 10 mg/L, the difference was not statistically significant (χ2= 1.272, P = 0.259). There were 4 cases of vancomycin associated nephrotoxicity, the incidence of nephrotoxicity was 4.49%, and the vancomycin serum trough levels were 17.22-28.53 mg/L. There were 33 cases of liver dysfunction, and elevated γ-glutamine transferase, alkaline phosphatase and aspartate aminotransferase were most common. There were 2 cases of neutropenia and 2 patients appeared rash during vancomycin period. Conclusions Treatment outcomes were similar regardless of vancomycin MIC and serum trough level. The incidence of vancomycin associated nephrotoxicity rises apparently when serum trough level is over 15 mg/L. Clinical Trial Registry Chinese Clinical Trail Registry, ChiCTR-OPC-16007920.

Core-shell column Tanaka characterization and additional tests using active pharmaceutical ingredients.

In the last decade, core-shell particles have gained more and more attention in fast liquid chromatography separations due to their comparable performance with fully porous sub-2 µm particles and their significantly lower back pressure. Core-shell particles are made of a solid core surrounded by a shell of classic fully porous material. To embrace the developed core-shell column market and use these columns in pharmaceutical analytical applications, 17 core-shell C18 columns purchased from various vendors with various dimensions (50 mm × 2.1 mm to 100 mm × 3 mm) and particle sizes (1.6-2.7 µm) were characterized using Tanaka test protocols. Furthermore, four selected active pharmaceutical ingredients were chosen as test probes to investigate the batch to batch reproducibility for core-shell columns of particle size 2.6-2.7 µm, with dimension of 100 × 3 mm and columns of particle size 1.6 µm, with dimension 100 × 2.1 mm under isocratic elution. Columns of particle size 2.6-2.7 µm were also tested under gradient elution conditions. To confirm the claimed comparable efficiency of 2.6 µm core-shell particles as sub-2 µm fully porous particles, column performances of the selected core-shell columns were compared with BEH C18 , 1.7 µm, a fully porous column material as well.

The value of MRI T1 W-SPACE in diagnosis of ischemic cerebrovascular disease / 实用放射学杂志

Objective To evaluate the feasibility of the three-dimensional brain artery vessel wall imaging technology reverse rotation angle of fast spin echo (T1 W-SPACE)in the diagnosis of ischemic cerebrovascular disease by comparing it with TOF vascular imaging in magnetic resonance. Methods Patients undergoing stroke but stable condition,including 50,patients with transient cerebral ischemia (TIA)or a history of stroke,examined by TOF-MRA and routine MRI sequence first,then followed by T1 W-SPACE.Results In 43 of 50 cases,conventional MRI sequences detectiog was positive,TOF-MRA found the vascular stenosis in 76 branches,T1 W-SPACE found the vascular stenosis in 73 branches,there was no difference between the two groups(χ2 =0.625,P >0.05);Conventional TOF-MRA cannot detect the vascular wall, T1 W-SPACE found that arterial wall thickening,plaque in 48 branches.Conclusion Compared with the TOF-MRA,T1 W-SPACE can not only detect the vessel stenosis,but also the vessel wall and plaque,and can also type on plaque from pathology angle,has im-portant clinical significance for early prevention and treatment of stroke.

A cohort study of vancomycin therapeutic drug monitoring / 中国感染与化疗杂志

Objective To evaluate the efficacy and safety of therapeutic drug monitoring (TDM ) based vancomycin dose adjustment in patients with gram‐positive infections .Methods A cohort study was designed with 128 inpatients undergoing TDM in Huashan Hospital from January 2005 to September 2014 .The clinical data of these patients were used to analyze the efficacy and safety of vancomycin therapy by Cox model and survival analysis .Results The patients undergoing TDM‐based dose adjustment had a higher daily dose and blood trough concentration ,which may lead to better bacteriological efficacy and overall efficacy .Cox proportional hazards model analysis showed that TDM‐based dose adjustment is a protective factor .No safety‐related risk factor was found .Conclusions TDM‐based vancomycin dose adjustment is important for patients to achieve better outcomes in fighting gram‐positive infections .

A multi-center clinical trial of levofloxacin 750 mg intravenous infusion for 5 days short-course treatment of community-acquired pneumonia / 中国感染与化疗杂志

Objective To compare the efficacy and safety of levofloxacin 750 mg for 5 days versus 500 mg for 7‐14 days intravenous (IV ) infusion in the treatment of community‐acquired pneumonia (CAP ) . Methods This study was a multi‐center , randomized , open‐label , non‐inferiority , controlled clinical trial .The CAP patients were randomized to receive levofloxacin 750 mg IV daily for 5 days or levofloxacin 500 mg IV daily for 7‐14 days .The clinical symptoms , laboratory tests , imaging results and microbiology data were collected and compared between the two treatment groups in terms of efficacy and safety .Results A total of 241 patients were enrolled in this clinical trial from 10 study centers .Among these patients ,223 were eligible for full analysis set (FAS) analysis ,including 111 in 750 mg group and 112 in 500 mg group .Of the 223 patients in FAS ,211 were eligible for per‐protocol set (PPS) analysis ,including 107 in 750 mg group and 104 in 500 mg group .Two hundred and forty‐one patients were included in safety set (SS) ,including 121 patients in 750 mg group and 120 in 500 mg group .The median treatment duration was 5 .0 days in 750 mg and 9 .0 days in 500 mg group .The median total dose was 3 750 mg in 750 mg group and 4 500 mg in 500 mg group .The overall efficacy rate was 86 .2% in 750 mg group and 84 .7% in 500 mg group in terms of FAS at visit 4 ,which suggested that the efficacy of 750 mg group was non‐inferior to 500 mg group .Of the 111 FAS patients in 750 mg group ,40 were bacteriological evaluable ,and 41 strains of pathogens were isolated .Forty‐nine of the 112 FAS patients in 500 mg group were bacteriological evaluable ,and 51 bacterial strains were obtained .The bacterial eradication rate was 100% in both groups .The clinical treatment efficacy rate for atypical pathogens was 100% in both groups .In 750 mg group ,the most common clinical adverse drug reactions (ADRs) were injection site adverse reactions including injection site pruritus ,pain and hyperemia .The other common ADRs were insomnia ,nausea ,skin rash .The most common drug‐related laboratory abnormalities were neutrophil percentage decreased , decreased white blood cell (WBC ) count , alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation .Most of the ADRs were mild in severity and well‐tolerated .The safety profile of the two treatments was comparable in terms of the drug‐related treatment discontinuation and the incidence of ADRs .Conclusions The short‐course regimen of levofloxacin 750 mg IV for 5 days is at least as effective and well tolerated as the long‐course regimen of 500 mg IV for 7‐14 days in treatment of CAP .

Clinical feature and antifungal susceptibility analysis of 111 cases of invasive fungal disease / 中国感染与化疗杂志

Objective To describe the clinical features of invasive fungal disease in Huashan Hospital,Fudan University from January 2004 to December 2006.Methods The medical data were reviewed retrospectively for the patients with fungal infection, which was confirmed by positive fungal culture or microscopic examination with blood,sterile body fluid,deep tissue,sputum specimen or isolation of Aspergillus spp.and Cryptococcus spp.from bronchoalveolar lavage.The proven and probable cases of invasive fungal disease were included in this analysis.Results A total of 111 patients were diagnosed as invasive fungal dis-ease,including 104 proven cases and 7 probable cases.Sixty-one cases were community-acquired and the other 50 were nosoco-mial.The most common site of infection was bloodstream (51,45.9%),followed by central nervous system (44,39.6%)and respiratory system (14,12.6%).The most common pathogens were Candida spp.(50,45%),Cryptococcus (47,42.3%) and Aspergillus spp. (12, 10.8%). The community-acquired fungal infections were mostly found in central nervous system (44,72.1%),and respiratory system (12, 19.7%),mainly caused by Cryptococcus and Aspergillus. The nosocomial fungal infections occurred primarily in blood-stream (96.0%),mainly due to Candida spp.No underlying disease or risk factor was identified in more than half of the pa-tients with community-acquired infection,while almost all the patients with nosocomial fungal infection had underlying disease and predisposing factors.Indwelling venous catheter was closely associated with nosocomial bloodstream infection.Indwelling venous catheter lasted for more than 1 week in 64.7% of the patients with Candida bloodstream infection.The same fungal strain was isolated from both the cather and blood of the same patient in 11 cases.The overall mortality of these invasive fungal diseases was 14.4% (16/111).The mortality rate was 18.0% (9/50)in the patients with nosocomial invasive fungal infection, and 11.5% (7/61)in the patients with community-acquired invasive fungal infection.Conclusions The most common site of in-vasive fungal infection is bloodstream,followed by central nervous system,and respiratory system.Majority of the fungal patho-gens are Candida spp.,Cryptococcus and Aspergillus spp.The community-acquired invasive fungal disease is primarily meningitis caused by Cryptococcus.The nosocomial invasive fungal disease is mainly bloodstream infection caused by Candida spp.

The analysis of artifacts in 64-slice spiral CT coronary angiography / 中华放射学杂志

Objective To investigate the reasons of artifacts in 64-slice spiral CT coronary angiography.Methods One hundred patients with diagnosed or suspected coronary artery disease underwent retrospectively ECG-gated 64-slice spiral CT coronary angiogruphy.Maximum intensity projection(MIP),muhiplanar reformation(MPR)and volume rendering technique(VRT)were reconstructed.The reasons of artifacts were assessed by two experienced radiologists.Results A total of 1347 segments(1347/1500,89.8%)were reviewed,the artifacts were found in 192 segments(14.2%).Breath movement was the moat common artifact(124/192).and the other reasons included fast rate and irregular rhythm of the heart beat (42/192).while the phase mismatch was the third reason(22/192).Conclusions The common artifacts of 64-slice spiral CT coronary angiography includes breath movement,fast rate and irregular rhythm of heart beat and phage mismatch.Breath-holding control,low rate and regular rhythm of heart beat,muhiphage reconstruction are suggested for the accurate diagnosis.

Bloodstream infection - the pathogenic research and clinical investigation / 中华传染病杂志

Objectives To identify the spectrum of pathogens causing bloodstream infection and their resistance profiles. Methods We examined records with positive blood culture from Jan. 1998 to Mar. 2003 in a teaching hospital in Shanghai. The contaminants were excluded according to the CDC definition of bloodstream infection. Bacteria were collected from April 1, 2002 to March 31, 2003 and MIC to the most commonly used antimicrobial agents was performed. Results 276 episodes occurred during the study period. Of all the BSI episodes, about 74.3% BSI were hospital-acquired and 37.3% were community-acquired. Gram-positive organisms accounted for 38% of isolates, while gram-negative for 44.2% and fungus for 13.8%. The commonest pathogens causing bloodstream infection in hospital-acquired BSI were coagulase-negative staphylococcus (16.9%) and Escherichia coli (16.6%), followed by Candida species (14.1%), Staphylococcus aureus (13.7%) and Klebsiella pneumoniae (13.2%). Streptococcus spp., Escherichia coli, coagulase-negative staphylococcus and Staphylococcus aureus are the leading pathogens causing community-acquired bloodstream infection, which accounted for 16.9%, 15.5%, 15.5%, 11.3% respectively. Susceptibility tests in vitro shows that methicillin resistance in S. aureus was 56%, while in coagulase-negative staphylococcus was 88%. Among the prevalent Gram-negative BSI isolates, resistance rates for most of the antimi-crobial agents were high. However, it is encouraging to note that the carbapenems retained potency against almost all the Enterobacteriaceae, including those resistant to the third-generation cephalosporins and extended-broad-spectrum penicillins. The crude mortality rate of BSI was 24.4%. Conclusion The rate of Coagulase-negative staphylococcus, Klebsiella pneumoniae and fungus in BSI have increased in the past years. Enterobacteriaceae, acinetobacter spp and fungus are more common in hospital-acquired BSI than community-acquired BSI.

Multidimensional Thoughts on "Life" and "Death" from the Perspective of Life Science Technology / 中国医学伦理学

The natural process of life and death has been profoundly and widely involved and increasingly manipulated by the fast developed technology of life science,which could change the human beings' state of life as well as the state of death.Thus,human beings are motivated to think multidimensionally on life and death from the perspective of science,such as the weakening of sacredness of life,the technology employed in life,the socialization of lifestyles,the exploration of the nature of death,the pluralism of different ways of death and the systematization in the education of death.These considerations will no doubt contribute to the mutual promotion of the development of morality and the advancement of life science technology.

Research on the Incentive Mechanism of Human Organ Donation / 中国医学伦理学

The lack of organs has been an crucial limiting factor for Chinese organ transplantation,thus it is in urgent need to effectively increase the number of donor organs.This article holds that,besides through publicity and education to promote unpaid voluntary organ donation,some incentive mechanisms are also required to serve as useful complements.Therefore,organs' origin can be expanded to a certain extent,and the intense supply and demand in organ transplantation can also be eased.Unifying organ transplantation practice in China,this paper explains the necessity of organ donation incentive mechanisms from both theoretical and practical significances,reveals the main elements of the incentive mechanisms,and explores the realization means.