Cumulative Toxicity of Residue Degradation Products of Penicillin Bacteria

[Objective] The research aimed to discuss the accumulation of toxic slag of penicillin bacteria residue degradation products and explore its ability to meet the aquaculture industry as a protein feed into development and utilization conditions.[Method] Through the sub-acute toxicity tests in mice strains,which were fed by different doses of penicillin bacteria residue degradation products （3% and 6%） under continuous observation of 15 weeks,recording a weekly mouse weight and death,and sampling executed after the test,animal liver and kidney function were blood test,taking heart,liver,spleen,kidney weighing,as well as liver and kidney pathology observed in the optical microscope.[Result] There were no significant differences （P 0.05） between the test group mice body weight,mortality and liver and kidney function and the control group within 15 weeks.Low-dose test group could be seen the liver cells,renal tubular epithelial nuclei broken,and a small number of liver and kidney cells with mild edema.High-dose test group could be seen in liver tissue of mice nuclei fragmentation and a fat droplets,the majority of liver cells,edema,and only a small number of liver cells,there were no significant changes.Renal portal area showed inflammatory cell infiltration,renal tubular epithelial cells,edema and necrosis.[Conclusion] In this experimental condition,the degradation products of penicillin bacteria residue played a mild toxcity on organ parenchymal cells in mice.

Study on degradation kinetics of epalrestat in aqueous solutions and characterization of its major degradation products under stress degradation conditions by UHPLC-PDA-MS/MS

Drug stability is closely related to drug safety and needs to be considered in the process of drug production,package and storage.To investigate the stability of epalrestat,a carboxylic acid derivative,a reversed-phase high-performance liquid chromatography(RP-HPLC)method was developed in this study and applied to analyzing the degradation kinetics of epalrestat in aqueous solutions in various conditions,such as different pH,temperatures,ionic strengths,oxidation and irradiation.The calibration curve was A=1.6×10^5C–1.3×10^3(r=0.999)with the liner range of 0.5–24μg/mL,the intra-day and inter-day precision was less than 2.0%,as was the repeatibility.The average accuracy for different concentrations was more than 98.5%,indicating that perfect recoveries were achieved.Degradation kinetic parameters such as degradation rate constants(k),activation energy(Ea)and shelf life(t0.9)under different conditions were calculated and discussed.The results indicated that the degradation behavior of epalrestat was pH-dependent and the stability of epalrestat decreased with the rised irradiation and ionic strength;however,it was more stable in neutral and alkaline conditions as well as lower temperatures.The results showed that the degradation kinetics of epalrestat followed first-order reaction kinetics.Furthermore,the degradation products of epalrestat under stress conditions were identified by UHPLC-PDA-MS/MS,with seven degradation products being detected and four of them being tentatively identified.

Degradation kinetics of larotaxel and identification of its degradation products in alkaline condition

Larotaxel, a new taxane compound prepared by partial synthesis from 10-deacetyl baccatin III, is active against tumors. In this research, a selective LC–MS method was developed and validated for the study of degradation kinetics of larotaxel, which was carried out in aqueous solutions with different pH（1.5, 3.0, 5.0, 6.5, 7.4, 9.0, 10 and 11.0） and temperature（0, 25, 37 and 45 °C）. The linear range was 0.5–25 μg/mL, the intra-and inter-day precisions were less than 7.0%, and accuracy ranged from 97.4–104.5% for each analyte. The observed rate obtained by measuring the remaining intact larotaxel was shown to follow first-order kinetics. The activation energies for degradation were 126.7 and 87.01 k J/mol at pH 1.5 and 11, respectively. Although larotaxel was stable in pH 5, 6.5 and 7.4 buffers at 37 °C for 24 h during our study, increasing or decreasing the pH of the solutions would decrease its stabilities. Moreover, three main degradation products in alkaline condition were separated by HPLC and identified by Q–TOF–MS. The three degradation products were confirmed as 10-deacetyl larotaxel, 7, 8-cyclopropyl baccatin Ⅲ and 10-deacetyl-7, 8-cyclopropyl baccatin Ⅲ.

Clinical association between coagulation indicators and bone metastasis in patients with gastric cancer

BACKGROUND Bones are one of the most common target organs for cancer metastasis.Early evaluation of bone metastasis(BM)status is clinically significant.Cancer patients often experience a hypercoagulable state.AIM To evaluate the correlation between coagulation indicators and the burden of BM in gastric cancer(GC).METHODS We conducted a single-center retrospective study and enrolled 454 patients.Clinical information including routine blood examination and coagulation markers were collected before any treatment.Patients were grouped according to the status of BM.Receiver operating characteristic curves were used to assess diagnostic performance and determine the optimal cutoff values of the above indicators.Cutoff values,sensitivity and specificity were based on the maximum Youden index.Univariate and multivariate logistic regression analyses were used to evaluate the relationships between biomarkers and BM.RESULTS Of the 454 enrolled patients,191 patients were diagnosed with BM.The receiver operating characteristic curve analysis suggested that prothrombin time(PT)Wang X et al.Coagulation indicators predict bone metastasis WJGO https://www.wjgnet.com 1254 July 15,2023 Volume 15 Issue 7[cutoff:13.25;sensitivity:0.651;specificity:0.709;area under receiver operating characteristic curve(AUC)=0.738],activated partial thromboplastin time(aPTT)(cutoff:35.15;sensitivity:0.640;specificity:0.640;AUC=0.678)and fibrin degradation products(FDP)(cutoff:2.75;sensitivity:0.668;specificity:0.801;AUC=0.768)act as novel predictors for BM.Based on multivariate logistic regression analysis,the results showed the independent correlation between PT[odds ratio(OR):3.16;95%confidence interval(CI):1.612-6.194;P=0.001],aPTT(OR:2.234;95%CI:1.157-4.313;P=0.017)and FDP(OR:3.17;95%CI:1.637-6.139;P=0.001)and BM in patients with GC.Moreover,age,carcinoembryonic antigen,erythrocyte and globulin were found to be significantly associated with BM.CONCLUSION Coagulation markers,namely PT,aPTT and FDP,might be potential predictors for screening BM in patients with GC.

Clinical significance of plasma D-dimer and von Willebrand factor levels in patients with ulcer colitis

AIM: To investigate the levels of D-dimer(DD) and von Willebrand factor(vWF) and the relationship between DD and vWF in ulcerative colitis(UC) patients. METHODS: A total of 29 plasma specimens were obtained from patients with ulcerative colitis (male 13, female 16) aged 21-47 years (33+/-11). Disease activity was assessed by Truelove-Writeria. Patients with a score of above 5 were regarded as having active colitis. Twenty healthy people(male 12, female 8) aged 19-53 years(31+/-14) served as normal controls. Blood samples were taken from an antecubital vein puncture. Blood(1.8 mL) was injected into the tubes containing sodium citrate (0.13 mmol/L). The plasma was obtained by centrifugation at 3000 r.min(-1) for 10 min, and stored at -80 degrees until assayed by ELISA. RESULTS: The mean plasma levels of DD and vWF in active UC patients were significantly higher than those of the controls (0.69+/-0.41 vs 0.27+/-0.11, P【0.01 143+/-46 vs 103+/-35, P【0.01). The mean plasma levels of DD in the patients with active disease were higher than those with inactive disease(0.69+/-0.41 vs 0.48+/-0.29 P【0.05). The levels of vWF were not different between active and inactive patients. DD levels were positively related to vWF levels( r =0.574, P【0.01). There was no significant difference between levels of DD and vWF and the scope of disease and sex of the patients. CONCLUSION: vWF is an important feature and a good marker of UC intravascular thrombus and endothelial cell dysfunction were found in UC patients and the combined test of DD and vWF is helpful to distinguish the activity of the UC patients.

Biodegradation of acetanilide herbicides acetochlor and butachlor in soil

The biodegradation of two acetanilide herbicides, acetochlor and butachlor in soil after other environmental organic matters addition were measured during 35 days laboratory incubations. The herbicides were applied to soil alone, soil SDBS (sodium dodecylbenzene sulfonate) mixtures and soil HA (humic acid) mixtures. Herbicide biodegradation kinetics were compared in the different treatment. Biodegradation products of herbicides in soil alone samples were identified by GC/MS at the end of incubation. Addition of SDBS and HA to soil decreased acetochlor biodegradation, but increased butachlor biodegradation. The biodegradation half life of acetochlor and butachlor in soil alone, soil SDBS mixtures and soil HA mixtures were 4.6d, 6.1d and 5.4d and 5.3d, 4.9d and 5.3d respectively. The biodegradation products were hydroxyacetochlor and 2 methyl 6 ethylaniline for acetochlor, and hydroxybutachlor and 2,6 diethylaniline for butachlor.

Development of forced degradation and stability indicating studies of drugs——A review

Forced degradation is a degradation of new drug substance and drug product at conditions more severe than accelerated conditions. It is required to demonstrate specificity of stability indicating methods and also provides an insight into degradation pathways and degradation products of the drug substance and helps in elucidation of the structure of the degradation products. Forced degradation studies show the chemical behavior of the molecule which in turn helps in the development of formulation and package. In addition, the regulatory guidance is very general and does not explain about the performance of forced degradation studies. Thus, this review discusses the current trends in performance of forced degradation studies by providing a strategy for conducting studies on degradation mechanisms and also describes the analytical methods helpful for development of stability indicating method.

Removal of a type of endocrine disruptors—di-n-butyl phthalate from water by ozonation

Ozonation of synthetic water containing a type of endocrine disruptor-di-n-butyl phthalate （DBP） was examined. Key impact factors such as pH, temperature, ionic strength, ozone dosage and initial DBP concentration were investigated. In addition, the activities of radicals on uncatalysed and catalysed ozonation were studied. The degradation intermediate products were followed and the kinetic of the ozonation were assessed as well. Results revealed that ozonation of DBP followed two mechanisms. Firstly, the reaction rate of direct ozonation was slower at lower pH, temperature, and ionic strength. Secondly, when these factors were increased for indirect radical reaction, higher percentage of DBP was removed with the increase of the initial ozone dosage and the decrease of the initial DBP concentration. In addition, tea-butanol, humic substances and Fe（Ⅱ） affected DBP ozonation through the radical pathway. It was determined that ozonation was restrained by adding tea-butanol for its radical inhibition effect. Furthermore, humic substances enhanced the reaction to some extent, but a slight negative effect would be encountered if the optimum dosage was exceeded. As a matter of fact, Mn（Ⅱ） affected the ozonation by ＂active sites＂ mechanism. In the experiment, three different kinds of intermediate products were produced during ozonation, but the amount of products for each one of them decreased as pH, temperature, ionic strength and initial ozone dosage increased. A kinetic equation of the reaction between ozone and DBP was obtained.

Increasing the use of biocompatible,glucose-free peritoneal dialysis solutions

A major concern inhibiting some clinicians from embracing peritoneal dialysis(PD) as the preferred first modality of dialysis is the effects of PD solutions on the peritoneal membrane. These anatomical and functional changes predispose to complications like peritonitis,encapsulating peritoneal sclerosis and ultrafiltration failure. In recent years, "biocompatible" and glucosesparing PD regimens have been developed to minimize damage to the peritoneal membrane. Can the use of these more expensive solutions be justified on current evidence? In this review of the literature, we explore how we may individualize the prescription of biocompatible PD fluid.

LC-ESI-MS分析两性霉素B降解产物

两性霉素B(amphotericin B)是一种常用的抗真菌抗生素[1],属于多烯大环内酯类化合物,化学性质不稳定,在生产和储存过程中容易发生多种降解反应,产生无活性甚至有毒性的降解物,直接影响产品质量和临床用药的安全,因此,研究该抗生素降解物和降解途径,对防止产品降解、保证产品质量非常必要.……

Fibrinogen degradation product levels on arrival for trauma patients requiring a transfusion even without head injury

BACKGROUND: There have been few reports on the clinical significance of the fibrinogen degradation product(FDP) level in trauma patients with and without head injury. We retrospectively analyzed trauma patients with or without head injury to investigate the clinical signifi cance of the FDP level.METHODS: From April 2013 to June 2015, a medical chart review was retrospectively performed for all patients with trauma. The exclusion criteria included patients who did not receive a transfusion. The patients were divided into two groups: a FDP>100 group, which included patients who had an FDP level on arrival over 100 ng/m L, and a FDP≤100 group.RESULTS: The ratio of open fractures and the prothrombin ratio in the FDP>100 group were significantly smaller than those observed in the FDP≤100 group. The average age, ratio of blunt injury, Injury Severity Score(ISS), volume of transfusion and mortality ratio in the FDP>100 group were signifi cantly greater than those in the FDP≤100 group. There was a weakly positive correlation between the FDP level and ISS(R=0.35, P=0.002), but it was not associated with the transfusion volume. The results of an analysis excluding patients with head injury showed a similar tendency.CONCLUSION: The FDP levels may be a useful biochemical parameter for the initial evaluation of the severity of trauma and mortality even in blunt traumatized patients without head injury or with stable vital signs.

Isolation and characterization of a degradation product in leflunomide and a validated selective stability-indicating HPLC-UV method for their quantification

Leflunomide （LLM） is subjected to forced degradation under conditions of hydrolysis, oxidation, dry heat, and photolysis as recommended by International Conference on Harmonization guideline Q1A（R2）. In total, four degradation products （I-IV） were formed under different conditions. Products I, II and IV were formed in alkaline hydrolytic, acidic hydrolytic and alkaline photolytic conditions. LLM and all degradation products were optimally resolved by gradient elution over a C18 column. The major degradation product （IV） formed in hydrolytic alkaline conditions was isolated through column chromatography. Based on its IH NMR, IR and mass spectral data, it was characterized as a British Pharmacopoeial impurity B. The HPLC method was found to be linear, accurate, precise, sensitive, specific, rugged and robust for quantification of LLM as well as product IV. Finally, the method was applied to stability testing of the commercially available LLM tablets.

Determination and stress studies on YK-1101,a potential histone deacetylase,by HPLC-UV and HPLC-TOF/MS methods

YK- 1101, with its structure as S-（（E）-4-（（7S, 10S,Z）-4-ethylidene-7-isopropyl-2,5,8,12- tetraoxo -9-oxa- 16-thia-3,6,13,18-tetraazabicyclo[ 13.2.1 ]octadeca- 1 （17）, 15（ 18）-dien- 10-yl）but-3-en- 1 -y l） ethanethioate, is synthesized as a potential histone deacetylase inhibitor. Its quality and stability under various stress conditions are not fully understood. In this study, a high performance liquid chromatographic （HPLC） method was established and validated for the analysis of YK-1101 bulk drug samples. The chromatographic separation was performed on a C18 column with acetonitrile and water as mobile phase in a gradient elution. Based on the established method, the stability studies of YK-1101 under various stress conditions were carried out. YK-1101 was shown to undergo degradation under basic and acidic stress conditions, while it was stable under oxidative, photolytic and thermal conditions. In addition~ a time of flight mass spectrometer （TOF/MS） was coupled to HPLC for the characterization of major degradation products produced under basic and acidic stress conditions. Their degradation pathways were also discussed.

Prolonged prothrombin time at admission predicts poor clinical outcome in COVID-19 patients

BACKGROUND Supported by the National Natural Science Foundation of China,No.The prognostic value of coagulation disorder in coronavirus disease 2019(COVID-19)patients should be demonstrated.AIM To investigate the abnormalities of coagulation parameters in the patients with COVID-19 and their prognostic values.METHODS Consecutive patients admitted in the isolation ward of Renmin Hospital of Wuhan University from January 31 to February 5,2020 with confirmed COVID-19 were included.The primary outcomes were death and survival as of March 11.Demographics,vital signs,comorbidities and laboratory tests were collected and compared between those who died and survivors.Logistic regression analysis for prognostic factors was performed.Kaplan-Meier analysis was used to compare the estimated survival rate between patients with prolonged prothrombin time and normal prothrombin time.RESULTS The total number of patients with confirmed COVID-19 who were enrolled was 213.The median age was 62 years,and 95 patients(44.6%)were men.Fifty-one patients were critical(23.9%),79 patients were severe(37.1%)and 83 patients were moderate(39%).As of March 11,2020,99 patients were discharged(46.5%),79 patients(37.1%)stayed in the hospital and 35 patients(16.2%)died.Median time to death was 6(4-8)d,while median hospital stay was 32(22-36)d in survivors(P<0.001).More men(P=0.002)and elderly patients(P<0.001)were found in the group of those who died.The respiration rate at admission was higher in the group of those who died(P<0.001).The incidences of hypertension(P=0.028),cerebrovascular disease(P<0.001),chronic kidney disease(P=0.02)and chronic obstructive pulmonary disease(P<0.001)were higher in the group of those who died.Platelet count was decreased in the group of those who died(P=0.002)whereas prothrombin time(P<0.001),activated partial thromboplastin time(P=0.033),concentration of D-dimer(P<0.001)and fibrin degradation products(P<0.001)were increased in the group of those who died.Prothrombin time[odds ratio(OR):2.19,P=0.004],respiration rate(OR:1.223,P<0.001),age(OR:1.074,P<0.001)and fibrin degradation products concentration(OR:1.02,P=0.014)were predictors of death.The survival rate was significantly lower in patients with prolonge CONCLUSION Prothrombin time,concentration of fibrin degradation products,respiration rate and age were predictive factors for clinical outcomes of COVID-19 patients.

Establishment of inherent stability of pramipexole and development of validated stability indicating LC-UV and LC-MS method

Pramipexole belongs to a class of nonergot dopamine agonist recently approved for the treatment of early and advanced Parkinson＇s disease.A validated specific stability indicating reversed-phase liquid chromatographic method has been developed for the quantitative determination of pramipexole in bulk as well as in pharmaceutical dosage forms in the presence of degradation products.Forced degradation studies were performed by exposition of drug to hydrolytic（acidic and basic）,oxidative and photolytic stress conditions,as defined under ICH guideline Q1A（R2）.Significant degradation was observed under hydrolytic,oxidative and photolytic conditions and the degradation products formed were identified by LC-MS.

Dryland agriculture and rangeland restoration priorities in Afghanistan

Afghanistan is threatened by rangeland degradation.A quantitative visual analysis of Google Earth Imagery was used to systematically locate,characterize and quantify the current extent of rangelands in Afghanistan degraded as a consequence of dryland agriculture.Climate data were used in conjunction with dryland agriculture locations to establish a climate envelope comprised by temperature and mean annual precipitation to create a geographical mask known to contain dryland agriculture.Within this mask we created a grid of 100 km2 cells that we analyzed individually to access dryland agriculture extent.Climatic limits to sustainable dryland agriculture and areas of high restoration priority were also assessed as was the distribution of rain-fed agriculture with respect to the location of traditional migration routes for extensive livestock producers.The extents of agriculture in Afghanistan,at both upper and lower elevations,correlated most closely with mean annual temperature（MAT） at the upper elevation limits,and with mean annual precipitation（MAP） at the lower elevation limits.In total,dryland agriculture comprised 38,980 km2 of former native rangeland.Conversion was highest in the northwestern,northern and northeastern provinces of Herat,Badghis,Faryab,Jawzjan,Sar-e-Pul,Samangan,Balkh,Baghlan,Kunduz,Takhar and Badakhshan,with the highest percentage of conversion occurring in Takhar.An MAP value of 〈400 mm is perceived by farmers as the current climatic limit to sustainable dryland agriculture across the northern regions of the country.Uder this MAP value,approximately 27,677 km2 of converted rangeland met the need for restoration priority.Climate projections indicate that Afghanistan will become warmer and drier in the coming decades.One consequence of this trend is that the MAP threshold of 〈400 mm to sustainable dryland agriculture will become obsolete in the coming decades.Restoration of currently converted rangelands is needed to restore critical grazing areas as is the adoption of prudent range management policies to prevent further land degradation and support a vital livestock industry.Food security is at stake as the conversion of rangelands to unsustainable rain-fed agriculture may leave large tracks of land unusable for either agriculture or livestock production.

Voltammetric Behavior of Degradation Product and Determination of Cefdinir

The electrochemical behavior of the degradation product of cefdinir（CDR） was studied in a 0.05 mol/L NaOH solution by means of linear sweep voltammetry（LSV） and cyclic voltammetry（CV）. The results indicate that the C=N bond in the oxime group was reduced. Moreover, a saturated adsorption amount of 1.32× 10^-10 mol/cm2 at Hg electrode was obtained. The adsorption coefficient β was 1.56× 10^5 L/mol. Gibbs standard energy of adsorption AGO at 25 ℃ was -29.63 kJ/mol and the number of electrons transferred n was 2. A method for the determination of CDR was proposed by differential pulse voltammetry（DPV）. The reduction peak currents of the CDR＇s degradation product were found to be linear in a concentration range of 4.0×10^-7--4.0×10^- 6 mol/L and that of 4.0× 10^-8-4.0× 10^-7 mol/L, respectively. The detection limit was found to be 3.0× 10^-8 mol/L under the optimized conditions. The applica- bility of this approach was illustrated by the determination of CDR in capsules. In addition, the mechanism about the degradation of CDR in 0.2 mol/L NaOH was discussed by UV spectrophotometry.

Characteristics and Degradation Mechanism of Fomesafen

High performance liquid chromatography(HPLC) was used to determine the degradation efficiency of bacteria 2 strain(B2 S) under different conditions, the optimum cultivation conditions for fomesafen degradation bacterium B2 S were as the followings: temperature 35℃; inoculation quantity 5%; p H 5.0; glucose content 0.5% and fomesafen concentration 10 mg · L-1. Under optimal conditions, B2 S degraded fomesafen within 72 h of fomesafen application, with a degradation rate of nearly 100%. High performance liquid chromatography-mass spectrometry(HPLC-MS) was used to analyze fomesafen degradation into microbial products. A more thorough understanding of microbial fomesafen degradation mechanisms was discussed. The pathway of fomesafen degradation by B2 S was also inferred herein.

Degradation behaviors of Nabumetone and its metabolite during UV/monochloramine process:Experimental and theoretical study

This study investigated degradation behaviors of a nonsteroidal anti-inflammatory drug Nabumetone(NMT)and its major metabolite 6-methoxy-2-naphthylacetic acid(MNA)in the coupling process of ultraviolet and monochloramine(UV/NH2Cl).The second-order rate constants of the contaminants reacting with reactive radicals(HO·,Cl·,Cl_(2)·-,and CO_(3)·^(-))were determined by laser flash photolysis experiments.HO·and Cl·contributed predominantly with 52.3%and 21.7%for NMT degradation and 60.8%and 22.3%for MNA degradation.The presence of chlorides retarded the degradation of NMT,while promoted the destruction of MNA,which was ascribed to the photosensitization effects of MNA under UV irradiation.Density functional theory(DFT)calculations revealed that radical adduct formation(RAF)was dominant pathway for both HO·and Cl·reacting with the contaminants,and hydrogen atom transfer(HAT)preferred to occur on side chains of NMT and MNA.NMT reacted with NO_(2)·through single electron transfer(SET)with the second-order rate constant calculated to be 5.35×10^(7)(mol/L)^(-1)sec^(-1),and the contribution of NO_(2)·was predicted to be 13.0%of the total rate constant of NMT in pure water,which indicated that NO_(2)·played a nonnegligible role in the degradation of NMT.The acute toxicity and developmental toxicity of NMT were enhanced after UV/NH_(2)Cl treatment,while those of MNA were alleviated.The transformation products of both NMT and MNA exhibited higher mutagenicity than their parent compounds.This study provides a deep understanding of the mechanism of radical degradation of NMT and MNA in the treatment of UV/NH2Cl.

Separation and characterization of degradation/interaction products of codeine phosphate in ibuprofen arginate/codeine phosphate combination formulation by HPLC coupled with MS analysis

A simple HPLC method was developed and validated according to the ICH guidelines to detect and quantify the related substances of codeine phosphate in the raw material and in its combination formulation with ibuprofen before and after forced degradation. These products were further identified by using HPLC-TOF/MS and MS/MS techniques. Good separations were obtained on a C18 （250 min×4.6 mm, 5 μm） column maintained at 50 ℃ with linear gradient elution by a mixture of mobile phase A （ammonium acetate （pH 6.0 regulated with acetic acid, 0.04 M）-acetonitrile （92：8, v/v）） and mobile phase B （acetonitrile） at a flow rate of 1 mL/min. UV detection was set at 245 nm. Codeine was found to be instable under oxidation with the production of mainly two stereoisomers of codeine N-oxide. A new degradation product, not reported previously, was detected under alkaline hydrolysis, which was identified as 6-hydroxy-3-methoxy-17-methyl-7,8-didehydromorphinan-5-ol and shortly named as deshydrolevomethorphandiol. The esterification of codeine by ibuprofen occurred in very small amount and only under acidic stress. These results contribute to the understanding of the degradation behavior of codeine and its interaction with ibuprofen. The developed method is sensitive and precise and could be applied for the quality control of codeine bulk drug, preparations of codeine phosphate, and its combination with ibuprofen.