In this work,we have applied molybdenum(Mo)and titanium(Ti)co-doping to solve the degradation of Ni-rich cathodes.The modified cathode,i.e.,Li(Ni_(0.89)Co_(0.05)Mn_(0.05)Mo_(0.005)Ti_(0.005))O_(2) holds a stable struc...In this work,we have applied molybdenum(Mo)and titanium(Ti)co-doping to solve the degradation of Ni-rich cathodes.The modified cathode,i.e.,Li(Ni_(0.89)Co_(0.05)Mn_(0.05)Mo_(0.005)Ti_(0.005))O_(2) holds a stable structure with expanded crystal lattice distance which improves Li ion diffusion kinetics.The dopants have suppressed the growth of primary particles,formed a coating on the surface,and promoted the elongated morphology.Moreover,the mechanical strength of these particles has increased,as confirmed by the nanoindentation test,which can help suppress particle cracking.The detrimental H2-H3 phase transition has been postponed by 90 mV allowing the cathode to operate at a higher voltage.A better cycling stability over 100 cycles with 69%capacity retention has been observed.We believe this work points out a way to improve the cycling performance,Coulombic efficiency and capacity retention in Ni-rich cathodes.展开更多
AIM:To review literature on efficacy and safety of octreotide-long-acting repeatable(LAR)used at doses higher than the Food and Drug Administration(FDA)-approved 30 mg/mo for treatment of neuroendocrine tumors(NETs).M...AIM:To review literature on efficacy and safety of octreotide-long-acting repeatable(LAR)used at doses higher than the Food and Drug Administration(FDA)-approved 30 mg/mo for treatment of neuroendocrine tumors(NETs).METHODS:We searched Pub Med and Cochrane Library from 1998-2012,5 conferences(American Society of Clinical Oncology,Endocrine Society,European Neuroendocrine Tumor Society,European Society for Medical Oncology,North American Neuroendocrine Tumor Society)from 2000-2013 using Me SH and keyterms including neuroendocrine tumors,carcinoid tumor,carcinoma,neuroendocrine,and octreotide.Bibliographies of accepted articles were also searched.Two reviewers reviewed titles,abstracts,and full-length articles.Studies that reported data on efficacy and safety of≥30 mg/mo octreotide-LAR for NETs in human subjects,published in any language were included in the review.RESULTS:The search identified 1086 publications,of which 238 underwent full-text review(20 were translated into English);17 were included in the review.Studies varied in designs,subjects,octreotide-LAR regimens,and definition of outcomes.Eleven studies reported use of higher doses to control symptoms and tumor progression,although symptom severity and formal quality-of-life analysis were not quantitatively measured.Ten studies reported efficacy,describing 260 subjects with doses ranging from 40 mg/mo or 30 mg/3 wk up to 120 mg/mo.Eight studies reported expert clinical opinion that supported dose escalation of octreotide-LAR up to 60 mg/mo for symptom control and suggested increased doses may be effective at preventing tumor progression.Eight studies reported safety;there was no evidence of increased toxicity associated with doses of octreotide-LAR>30 mg/mo.CONCLUSION:As reported in this review,octreotide-LAR at doses>30 mg/mo is being prescribed for symptom and tumor control in NET patients.Furthermore,expert clinical opinion provided support for escalation of somatostatin analogs for refractory hormonal symptoms.展开更多
A liquid chromatography （HPLC） method with UV detection was developed for determination of sodium hyaluronate in pharmaceutical formulation. Sodium hyaluronate is a polymer of disaccharides, composed of D-glucuronic...A liquid chromatography （HPLC） method with UV detection was developed for determination of sodium hyaluronate in pharmaceutical formulation. Sodium hyaluronate is a polymer of disaccharides, composed of D-glucuronic acid and D-N-acetylglucosamine, linked via alternating 13-1, 4 and D-l, 3 glycosidic bonds. Being a polymer compound it lacks a UV absorbing chromophore. In the absence of a UV absorbing chromophore and highly polar nature of compound, the analysis becomes a major challenge. To overcome these problems a novel method for the determination of sodium hyaluronate was developed and validated based on size exclusion liquid chromatography （SEC） with UV detection. An isocratic mobile phase consisting of buffer 0.05 M potassium dihydrogen phosphate, pH adjusted to 7.0 using potassium hydroxide （10%） was used. Chromatography was carried out at 25 ~C on a BioSep SEC $2000, 300 mm ~ 7.8 mm column. The detection was carded out using variable wavelength UV-vis detector set at 205 nm. The compounds were eluted isocratically at a steady flow rate of 1.0 mL/min. Sodium hyaluronate retention time was about 4.9 min with an asymmetry factor of 1.93. A calibration curve was obtained from 1 to 38 g/mL （r〉0.9998）. Within-day % RSD was 1.0 and between-day % RSD was 1.10. Specificity/selectivity experiments revealed the absence of interference from excipients, recovery from spiked samples for sodium hyaluronate was 99-102. The developed method was applied to the determination of sodium hyaluronate in pharmaceutical drug substance and product.展开更多
A rapid GC-FID method was developed to simultaneously determine residual levels of triethylamine(TEA), 1,1,3,3-tetramethylguanidine(TMG), and diisopropylamine(DIPA) in the synthetic route of an active pharmaceutical i...A rapid GC-FID method was developed to simultaneously determine residual levels of triethylamine(TEA), 1,1,3,3-tetramethylguanidine(TMG), and diisopropylamine(DIPA) in the synthetic route of an active pharmaceutical ingredient(API). Due to the severe absorption of amines on GC stationary phases,GC columns with various stationary phases were evaluated for optimal peak shape and reproducibility.The final conditions used the Agilent CP-Volamine column to resolve the three amines in 12 min. Various inlet liners were also screened to further improve the sensitivity of the analysis. The Restek Siltek~? liner was selected to achieve the desired detectability for the method. The quantitation limits were 4, 3, and 4 mg/mL for TEA, DIPA, and TMG in the presence of API, respectively. All three amines showed good linearity(r > 0.999) and recoveries(> 90%) over the concentration range of 3 to 16 mg/mL. The testing of residual amines was initially performed at the penultimate stage of the synthesis. However, this work demonstrates that TMG can act as a proton sponge to react with salicylic acid, the counter ion of the penultimate, to form a volatile component that elutes at a different retention time. Consequently, in the final method, these three amines were monitored in the final API to circumvent the matrix interference.Key parameters of the method were qualified per method validation requirements in ICH guidelines. The method was successfully applied for batch testing during development and implemented as an inprocess control procedure at manufacturing sites.展开更多
A new impurity was detected during high performance liquid chromatographic （HPLC） analysis of eslicarbazepine acetate active pharmaceutical ingredient. The structure of unknown impurity was postulated based on liqui...A new impurity was detected during high performance liquid chromatographic （HPLC） analysis of eslicarbazepine acetate active pharmaceutical ingredient. The structure of unknown impurity was postulated based on liquid chromatography mass spectrometry using electrospray ionization and ion trap analyzer （LC/ESI-IT/MS） analysis. Proposed structure of impurity was unambiguously confirmed by synthesis followed by characterization using 1H, 13C nuclear magnetic resonance spectrometry （NMR）, 1H-1H correlation spectro-scopy （COSY） and infrared spectroscopy （IR）. Based on the spectroscopic and spectrometric data, unknown impurity was characterized as 5-carbamoyl-10,11-dihydro-5H-dibenzo[b,f]azepin-10-yl propionate.展开更多
AIM To examine healthcare resource utilizationpatterns and costs accrued by carcinoid syndrome （CS）patients with and without diarrhea.METHODS： We conducted a retrospective cohort studyusing MarketScan data from 1/1...AIM To examine healthcare resource utilizationpatterns and costs accrued by carcinoid syndrome （CS）patients with and without diarrhea.METHODS： We conducted a retrospective cohort studyusing MarketScan data from 1/1/2002-12/31/2012.Newly diagnosed CS patients had 1 medical claim forCS （ICD-9-CM code 259.2） plus either ≥ 1 additionalclaim for CS or for carcinoid tumors （ICD-9-CM 209.x）, and had no evidence of CS for 1 year prior to index CS diagnosis, in commercially-insured patients 〈 65years old. Patients were required to have continuousenrollment one year prior and after index date （firstclaim with CS diagnosis in the ID period）. We identifiedpatients with evidence of non-infectious diarrhea （ICD-9-CM codes 564.5 and 787.91） within one year from theindex date. Overall and CS-related healthcare resourceutilization and costs were compared between patientswith and without non-infectious diarrhea during theone year period after the index date.RESULTS： There were 2822 newly diagnosed CSpatients; 534 （18.9%） had evidence of non-infectiousdiarrhea. Compared to patients without non-infectiousdiarrhea, non-infectious diarrhea patients morecommonly had at ≥ 1 CS-related hospitalization（13.7% vs 7.2%）, ≥ 1 CS-related ED visit （11.0% vs4.4%）, and CS-related office visits in one year （6.9 vs4.1; all p 〈 0.001）. After adjusting for demographics,region, number of chronic conditions and the CharlsonComorbidity Index, the proportions of patients withany and with CS-related hospitalizations were 9.7%and 6.8% higher, respectively, among non-infectiousdiarrhea patients compared to those with without noninfectiousdiarrhea （p 〈 0.001）. Unadjusted costs weresignificantly higher among non-infectious diarrheapatients vs those without non-infectious diarrhea. Thenon-infectious diarrhea group was also more costly,with adjusted mean annual costs of $81610, comparedto $51719 in the group without non-infectious diarrhea（p 〈 0.001）.CONCLUSION： Diarrhea is burdensome and costlyin CS patients. Reduction of CS-related healthcareexpenditures may be achievable through preventivetreatment and appropriate management of diarrhea inCS.展开更多
The present study deals with the forced degradation behavior of dexlansoprazole under International Conference on Harmonisation(ICH)prescribed stress conditions. The drug was found to be more labile under acid,base,ne...The present study deals with the forced degradation behavior of dexlansoprazole under International Conference on Harmonisation(ICH)prescribed stress conditions. The drug was found to be more labile under acid,base,neutral,oxidative hydrolysis and thermal stress,while it was moderately stable under photolytic conditions. The known and unknown degradation products were separated on a C-18 column using a stabilityindicating method. Liquid chromatography-mass spectrometry(LC-MS)analysis was performed for all the degradation studies. Isolation and structure characterization of oxidation degradation products were executed using sophisticated tools,viz. preparative high performance liquid chromatography(HPLC),liquid chromatographymass spectrometry / time of flight(LC-MS / TOF),liquid chromatography-tandem mass spectrometry(LC-MS /MS),and nuclear magnetic resonance(NMR). This study demonstrates an ample methodology of degradation studies and structure elucidation of unknown degradation products of dexlansoprazole,which helps in the development and stability study of active pharmaceutical ingredients and formulated products.展开更多
AIM To describe real-world treatment patterns of gastrointestinal neuroendocrine tumors(GI NET).METHODS In this retrospective cohort study,we used 2009-2014 data from 2 United States commercial claims databases to exa...AIM To describe real-world treatment patterns of gastrointestinal neuroendocrine tumors(GI NET).METHODS In this retrospective cohort study,we used 2009-2014 data from 2 United States commercial claims databases to examine newly pharmacologically treated patients using tabular and graphical techniques.Treatments included somatostatin analogues(SSA),cytotoxic chemotherapy(CC),targeted therapy(TT),interferon(IF)and combinations.We identified patients at least 18 years of age,with≥1 inpatient or≥2 outpatient claims for GI NET who initiated pharmacologic treatment from 7/1/09-6/30/14.A 6 mo clean period prior to first treatment ensured patients were newly treated.Patients were followed until end of enrollment or the study end date,whichever was first.RESULTS We identified 2258 newly treated GI NET patients:mean(SD)age was 55.6 years(SD=9.7),47.2%of the patients were between 55 and 64 years,and 48.8%were female.All regions of the United States were represented.59.6%started first-line therapy with SSA monotherapy(964 with octreotide LAR,380 with octreotide SA,and 1 with lanreotide),33.3%CC,3.6%TT,and 0.5%IF.The remainder received combinations.Mean follow up was 576 d.Overall mean first-line therapy duration was 361 d(449 d for SSA,215 for CC,267 for TT).58.9%of patients had no pharmacological treatment beyond first line.The most common secondline was combination therapy with SSA.In graphical pattern analysis,there was no clear pattern visible after first line therapy.CONCLUSION In this study,60%of patients initiated treatment with SSA alone or in combination.The relatively long time to discontinuation suggests possible sustained effectiveness and tolerability.展开更多
Silicon is a promising anode material for rechargeable Li-ion battery (LIB) due to its high energy density and relatively low operating voltage. However, silicon based electrodes suffer from rapid capacity degradation...Silicon is a promising anode material for rechargeable Li-ion battery (LIB) due to its high energy density and relatively low operating voltage. However, silicon based electrodes suffer from rapid capacity degradation during electrochemical cycling. The capacity decay is predominantly caused by (i) cracking due to large volume variations during lithium insertion/extraction and (ii) surface degradation due to excessive solid electrolyte interface (SEI) formation. In this work, we demonstrate that coating of a-Si thin film with a Li-active, nanoporous SiOx layer can result in exceptional electrochemical performance in Li-ion battery. The SiOx layer provides improved cracking resistance to the thin film and prevent the active material loss due to excessive SEI formation, benefiting the electrode cycling stability. Half-cell experiments using this anode material show an initial reversible capacity of 2173 mAh g^-1 with an excellent coulombic efficiency of 90.9%. Furthermore, the electrode shows remarkable capacity retention of ~97% after 100 cycles at C/2 charging rate. The proposed anode architecture is free from Liinactive binders and conductive additives and provides mechanical stability during the charge/discharge process.展开更多
Osteoarthritis(OA)is a debilitating degenerative disease affecting multiple joint tissues,including cartilage,bone,synovium,and adipose tissues.OA presents diverse clinical phenotypes and distinct molecular endotypes,...Osteoarthritis(OA)is a debilitating degenerative disease affecting multiple joint tissues,including cartilage,bone,synovium,and adipose tissues.OA presents diverse clinical phenotypes and distinct molecular endotypes,including inflammatory,metabolic,mechanical,genetic,and synovial variants.Consequently,innovative technologies are needed to support the development of effective diagnostic and precision therapeutic approaches.Traditional analysis of bulk OA tissue extracts has limitations due to technical constraints,causing challenges in the differentiation between various physiological and pathological phenotypes in joint tissues.This issue has led to standardization difficulties and hindered the success of clinical trials.Gaining insights into the spatial variations of the cellular and molecular structures in OA tissues,encompassing DNA,RNA,metabolites,and proteins,as well as their chemical properties,elemental composition,and mechanical attributes,can contribute to a more comprehensive understanding of the disease subtypes.Spatially resolved biology enables biologists to investigate cells within the context of their tissue microenvironment,providing a more holistic view of cellular function.Recent advances in innovative spatial biology techniques now allow intact tissue sections to be examined using various-omics lenses,such as genomics,transcriptomics,proteomics,and metabolomics,with spatial data.This fusion of approaches provides researchers with critical insights into the molecular composition and functions of the cells and tissues at precise spatial coordinates.Furthermore,advanced imaging techniques,including high-resolution microscopy,hyperspectral imaging,and mass spectrometry imaging,enable the visualization and analysis of the spatial distribution of biomolecules,cells,and tissues.Linking these molecular imaging outputs to conventional tissue histology can facilitate a more comprehensive characterization of disease phenotypes.This review summarizes the recent advancements in the molecular imaging modalities and methodologies for in-depth spatial analysis.It explores their applications,challenges,and potential opportunities in the field of OA.Additionally,this review provides a perspective on the potential research directions for these contemporary approaches that can meet the requirements of clinical diagnoses and the establishment of therapeutic targets for OA.展开更多
In this study,using mesoporous silica for the solubility enhancement of poorly watersoluble drug was investigated.Although the incorporating drug into mesoporous silica is generally performed through the solvent meth...In this study,using mesoporous silica for the solubility enhancement of poorly watersoluble drug was investigated.Although the incorporating drug into mesoporous silica is generally performed through the solvent method,the new melting method was proposed in the present study.Fenofibrate,a poorly water-soluble drug,was incorporated into mesoporous silica by solvent method and melting method.The obtained samples were observed by SEM and their physicochemical properties were evaluated by PXRD and DSC measurement.The dissolution and supersaturated property were also investigated.The results from SEM,PXRD and DSC measurement showed that drug could be loaded into pore via the melting method as well as by the solvent method.The drug loaded quantity depended on the pore volume.Drug up to 33%could be incorporated into mesoporous silica and existed in amorphous state.When drug was overloaded or difficulty in incorporation into pore was found,recrystallization of drug occurred at the outer surface of mesoporous silica.From the dissolution test,samples prepared by solvent method and melting method gave the supersaturated drug concentration which sample from melting method showed superior dissolution to the one from solvent method.From this study,drug was efficiently incorporated into mesoporous silica by the melting method which is a simple and solvent-free process,and the aqueous solubility enhancement of poorly watersoluble drug was achieved.展开更多
The unsatisfactory rate capability and poor cycling stability at high rate of sodium-ion batteries(SIBs) have impeded their practical applications. Herein, a Na_(3)V_(2)(PO_(4))_(3)/Na_(3)V_(3)(PO_(4))_(4) multiphase ...The unsatisfactory rate capability and poor cycling stability at high rate of sodium-ion batteries(SIBs) have impeded their practical applications. Herein, a Na_(3)V_(2)(PO_(4))_(3)/Na_(3)V_(3)(PO_(4))_(4) multiphase cathode materials for high-rate and long cycling SIBs was successfully synthesized by regulation the stoichiometric ratio of raw materials. The combined experiment and simulation results show that the multiphase materials consisted of NASICON structural phase Na3V2(PO4)3 and layered structure phase Na_(3)V_(3)(PO_(4))_(4), possess abundant phase boundaries. Electrochemical experiments demonstrate that the multiphase materials maintain a remarkable reversible capacity of 69.0 mA h g^(-1) even at an ultrahigh current density of 100 C with a high capacity retention of 81.25 % even after 10,000 cycles. Na_(3)V_(2)(PO_(4))_(3)/Na_(3)V_(3)(PO_(4))_(4) electrode exhibits a higher working voltage, superior rate capability and better cycling stability than Na_(3)V_(2)(PO_(4))_(3) electrode, which indicates that the introduction of second phase can be an effective strategy for the development of novel cathode materials for SIBs.展开更多
A selective, precise and stability-indicating, high performance liquid chromatographic method was developed for the analysis of active ingredient sodium Picosulfate and forced degradation behavior was studied. The cur...A selective, precise and stability-indicating, high performance liquid chromatographic method was developed for the analysis of active ingredient sodium Picosulfate and forced degradation behavior was studied. The current article describes forced degradation behavior of the Sodium Picosulfate drug substance in detail by analyzing 15 process related/degradants in a single HPLC method under ICH recommended stressed conditions. Mobile phase comprised of 0.01 M of Disodium hydrogen phosphate and 0.01 M of potassium phosphate monobasic buffer and 1 mL of triethyl amine in 1000 mL water adjusted to pH 7.5 with 10% phosphoric acid. Acetonitrile was used as Mobile Phase B. The separation was achieved on a gradient method. The reversed phase chromatography was performed in Hypersil BDS C18 5.0 μm, 4.6 × 250 mm column maintained at temperature 35°C. Injection volume was 60 μL. Milli-Q water used as diluent. The mobile phase was pumped at 0.9 mL/min<sup>-1</sup>. The eluted compounds were monitored at 220 nm. Secondary wavelength of the 263 nm was studied to check any further degradants during the forced degradation studies. New additional degradants Sodium Picosulfate Benzyl alcohol Impurity and N oxide degradations were discussed and studied during the forced degradation to understand the chemical stability of the drug substance.展开更多
AIM:To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors(PNETs)and provide consensus treatment recommendations.METHODS:Systemic treatment options for p...AIM:To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors(PNETs)and provide consensus treatment recommendations.METHODS:Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs,angiogenesis inhibitors,inhibitors of mammalian target of rapamycinand cytotoxic agents.At this time,there is little data to guide treatment selection and sequence.We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations.Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process.After studying the literature,a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale.Ratings were done both before and after an extended discussion of the evidence.Quantitative measurements of agreement were made and consensus statements developed from the second round ratings.RESULTS:Specialties represented were medical and surgical oncology,interventional radiology,and gastroenterology.Panelists had practiced for a mean of15.5 years(range:6-33).Among 202 rated scenarios,disagreement decreased from 13.2%(26 scenarios)before the face-to-face discussion of evidence to 1%(2)after.In the final ratings,46.5%(94 scenarios)were rated inappropriate,21.8%(44)were uncertain,and30.7%(62)were appropriate.Consensus statements from the scenarios included:(1)it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic;(2)it is appropriate to use everolimus,sunitinib,or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors;and(3)beyond first line,these same agents can be used.In patients with uncontrolled secretory symptoms,octreotide LAR doses can be titrated up to 60 mg every4 wk or up to 40 mg every 3 or 4 wk.CONCLUSION:Using the Delphi process allowed physician experts to systematically obtain a consensus on the appropriateness of a variety of medical therapies in patients with PNETs.展开更多
A simple, rapid, precise, accurate, rugged and robust stability-indicating ultra-fast high performance liquid chromatographic (UHPLC) method has been developed for the estimation of related compounds (imp-A, imp-B, im...A simple, rapid, precise, accurate, rugged and robust stability-indicating ultra-fast high performance liquid chromatographic (UHPLC) method has been developed for the estimation of related compounds (imp-A, imp-B, imp-C, imp-D and imp-E) in Naproxen and also the assay of Naproxen from bulk drug samples. The stability indicating capability of the method was proven by subjecting the samples to stress conditions such as acid, base, oxidation, photolysis and thermal degradation. The efficient chromatographic separation was achieved using mobile phase solution A prepared as buffer solution 10 mM monobasic potassium phosphate pH 4.0 ± 0.05 adjusted with diluted ortho phosphoric acid solution and solution B acetonitrile with linear gradient elution on poroshell 120 EC-C18 shot column (50 mm × 4.6 mm, 2.7 μm) and UV detection at 235 nm at a flow rate 1.0 mL/min, column oven temperature was set to 25?C. The above are all known impurities and degradation impurities are well resolved with Naproxen peak and these are eluted within a 10 min runtime of HPLC. The photo diode array detector was used for peak homogeneity testing during stress study experiments and the overall mass balance was found to be 99.2% to 100.2% in all stress conditions. The linear calibration range was found to be 0.05 μg/mL to 0.75 μg/mL for related compounds and 50 μg/mL to 150 μg/mL for Naproxen and the accuracy of the method was found to be 91.5% to 98.5% recovery for the related substance method and 95.4% to 97.4% recovery for the assay method. The Naproxen and related compounds were found to be stable up to 48 hours and the method validation data show excellent results for precision, linearity, specificity, limit of detection, limit of quantitation and robustness. The present method can be successfully used for routine QC and stability studies and it will help to reduce the analysis cost, time and effluent load compared to conventional HPLC methods.展开更多
INTRODUCTION Gender dysphoria(GD),or gender identity disorder,is defined as persistent distress stemming from the incongruence between one's assigned sex at birth and gender identity.'GD has traditionally been...INTRODUCTION Gender dysphoria(GD),or gender identity disorder,is defined as persistent distress stemming from the incongruence between one's assigned sex at birth and gender identity.'GD has traditionally been introduced as a rare condition predominant in assigned males at birth(AMABs).2 However,recent studies have shown an upward trend in assigned females at birth(AFABs)with a dramatic reversal of the AMAB:AFAB ratio-.5-The actual AMAB:AFAB ratio varies by age group and study population.4-Questions have been raised concerning the increasing number of youth who seek professional care for GD,especially adolescent AFABs.展开更多
Increased expression of matrix metalloproteinase-1(MMP-1)has been observed in the lesions of atherosclerosis and aneurysms;however,it is not fully understood whether macrophage-derived MMP-1 affects these diseases.To ...Increased expression of matrix metalloproteinase-1(MMP-1)has been observed in the lesions of atherosclerosis and aneurysms;however,it is not fully understood whether macrophage-derived MMP-1 affects these diseases.To investigate whether macrophage-derived MMP-1 participates in the development of vascular diseases,we generated transgenic(Tg)rabbits expressing human MMP-1 in the monocyte/macrophage lineage under the control of the human scavenger receptor enhancer/promoter.Tg rabbits exhibited no visible abnormalities throughout their bodies.Western blotting analysis revealed that the amount of MMP-1 proteins in the conditioned media secreted from peritoneal macrophages of Tg rabbits was up to 3-fold higher than that in non-Tg rabbits.For the first experiment,Tg and non-Tg rabbits were fed a cholesterol diet for 16 weeks,and aortic and coronary atherosclerosis were evaluated.The gross lesion area of aortic atherosclerosis in Tg rabbits was not significantly different from that in non-Tg rabbits,but Tg rabbits had marked destruction of the medial elastic lamina of the aortic lesions on microscopic examination.For the second experiment,we generated aortic aneurysms by incubating with elastase.Compared with non-Tg rabbits,Tg rabbits exhibited a significantly greater aortic dilation.Increased macrophage-derived MMP-1 led to increased medial destruction in both aortic atherosclerosis and aneurysms.These results demonstrate that MMP-1 plays a different role in the pathogenesis of atherosclerosis and aneurysms.展开更多
Carnuba wax consists chiefly of myricyl cerotate (M<sub>W</sub> 817.4) and small quantities of free cerotic acid (C<sub>26</sub>H<sub>52</sub>O<sub>2</sub>, Mw 396.7) an...Carnuba wax consists chiefly of myricyl cerotate (M<sub>W</sub> 817.4) and small quantities of free cerotic acid (C<sub>26</sub>H<sub>52</sub>O<sub>2</sub>, Mw 396.7) and myricyl alcohol (C<sub>30</sub>H<sub>62</sub>O, mp 90°C). Of the two common extraction solvents, ethyl ether or petroleum ether, Lewkowitsch prefers the former. Concerning separation of phases, he advocates addition of small amounts of alcohol or caustic, and he also states that formation of a flocculant layer between the aqueous layer and the solvent does not interfere with the correct estimation of the unsaponifiable matter. These statements were not corroborated in the hands of this chemist. The “Unsaponifiable Matter” in oils or and fats, which consist mainly of hydrocarbons, sterols and aliphatic alcohols of high molecular mass that are not saponifiable by alkali hydroxides but are soluble in the ordinary fat solvents, and to products of saponification that are soluble in such solvents. Carnuba wax, a rather expensive wax, may be adulterated with less expensive paraffin by dishonest merchants. ASTM has a method for determining paraffinic material in carnuba wax. It uses heptanes at its boiling point to dissolve the wax, apply it to a silica gel column, and elute only the nonpolar (i.e. alkane) material. The method has the disadvantage of using a large volume of haptane, nor is it called for by either US Pharmacopeia/National Formulary (USP/NF) or Food Chemicals Codex (FCC). The test for unsaponifiable matter on pure carnuba wax will yield a result of 50.0% - 55.0%, while a higher result will betray the presence of paraffin adulterants.展开更多
Macitentan (MAC) is a pulmonary arterial hypertension (PAH) drug marketed as a tablet and often has stability issues in the final dosage form. Quantitative determination of MAC and its associated impurities in tablet ...Macitentan (MAC) is a pulmonary arterial hypertension (PAH) drug marketed as a tablet and often has stability issues in the final dosage form. Quantitative determination of MAC and its associated impurities in tablet dosage form has not been previously reported. This study quantified impurities present in Macitentan tablets using a binary solvent-based gradient elution method using reversed phase-high performance liquid chromatography.The developed method w as validated per International Conference on Harmonization (ICH) guidelines and the drug product w as subjected to forced degradation studies to evaluate stability. The developed method efficiently separated the drug and impurities (48 min) w ithout interference from solvents,excipients,or other impurities. The developed method met all guidelines in all characteristics w ith recoveries ranging from 85%-115%,linearity w ith r 2≥0. 996 6,and substantial robustness. The stability-indicating nature of the method w as evaluated using stressed conditions (hydrolysis:1 N HCl at 80℃/15 min; 1 N NaOH at 25℃/45 min; humidity stress (90%relative humidity) at 25℃for 24 h,oxidation:at 6%(v/v) H2O2,80℃/15 min,thermolysis:at105℃/16 h and photolysis:UV light at 200 Wh/m2; Fluorescent light at 1. 2 million luxh). Forced degradation experiments show ed that the developed method w as effective for impurity profiling. All stressed samples w ere assayed and mass balance w as> 96%. Forced degradation results indicated that MAC tablets w ere sensitive to hydrolysis (acid and alkali) and thermal conditions. The developed method is suitable for both assay and impurity determination,w hich is applicable to the pharmaceutical industry.展开更多
基金support from Queensland University of Technology,Brisbane,Queensland,Australiafinancial support from ARC Discovery Project(DP210103266).
文摘In this work,we have applied molybdenum(Mo)and titanium(Ti)co-doping to solve the degradation of Ni-rich cathodes.The modified cathode,i.e.,Li(Ni_(0.89)Co_(0.05)Mn_(0.05)Mo_(0.005)Ti_(0.005))O_(2) holds a stable structure with expanded crystal lattice distance which improves Li ion diffusion kinetics.The dopants have suppressed the growth of primary particles,formed a coating on the surface,and promoted the elongated morphology.Moreover,the mechanical strength of these particles has increased,as confirmed by the nanoindentation test,which can help suppress particle cracking.The detrimental H2-H3 phase transition has been postponed by 90 mV allowing the cathode to operate at a higher voltage.A better cycling stability over 100 cycles with 69%capacity retention has been observed.We believe this work points out a way to improve the cycling performance,Coulombic efficiency and capacity retention in Ni-rich cathodes.
基金Supported by Novartis Pharmaceuticals Corporation,One Health Plaza,East Hanover,NJ 07936-1080,United States
文摘AIM:To review literature on efficacy and safety of octreotide-long-acting repeatable(LAR)used at doses higher than the Food and Drug Administration(FDA)-approved 30 mg/mo for treatment of neuroendocrine tumors(NETs).METHODS:We searched Pub Med and Cochrane Library from 1998-2012,5 conferences(American Society of Clinical Oncology,Endocrine Society,European Neuroendocrine Tumor Society,European Society for Medical Oncology,North American Neuroendocrine Tumor Society)from 2000-2013 using Me SH and keyterms including neuroendocrine tumors,carcinoid tumor,carcinoma,neuroendocrine,and octreotide.Bibliographies of accepted articles were also searched.Two reviewers reviewed titles,abstracts,and full-length articles.Studies that reported data on efficacy and safety of≥30 mg/mo octreotide-LAR for NETs in human subjects,published in any language were included in the review.RESULTS:The search identified 1086 publications,of which 238 underwent full-text review(20 were translated into English);17 were included in the review.Studies varied in designs,subjects,octreotide-LAR regimens,and definition of outcomes.Eleven studies reported use of higher doses to control symptoms and tumor progression,although symptom severity and formal quality-of-life analysis were not quantitatively measured.Ten studies reported efficacy,describing 260 subjects with doses ranging from 40 mg/mo or 30 mg/3 wk up to 120 mg/mo.Eight studies reported expert clinical opinion that supported dose escalation of octreotide-LAR up to 60 mg/mo for symptom control and suggested increased doses may be effective at preventing tumor progression.Eight studies reported safety;there was no evidence of increased toxicity associated with doses of octreotide-LAR>30 mg/mo.CONCLUSION:As reported in this review,octreotide-LAR at doses>30 mg/mo is being prescribed for symptom and tumor control in NET patients.Furthermore,expert clinical opinion provided support for escalation of somatostatin analogs for refractory hormonal symptoms.
文摘A liquid chromatography （HPLC） method with UV detection was developed for determination of sodium hyaluronate in pharmaceutical formulation. Sodium hyaluronate is a polymer of disaccharides, composed of D-glucuronic acid and D-N-acetylglucosamine, linked via alternating 13-1, 4 and D-l, 3 glycosidic bonds. Being a polymer compound it lacks a UV absorbing chromophore. In the absence of a UV absorbing chromophore and highly polar nature of compound, the analysis becomes a major challenge. To overcome these problems a novel method for the determination of sodium hyaluronate was developed and validated based on size exclusion liquid chromatography （SEC） with UV detection. An isocratic mobile phase consisting of buffer 0.05 M potassium dihydrogen phosphate, pH adjusted to 7.0 using potassium hydroxide （10%） was used. Chromatography was carried out at 25 ~C on a BioSep SEC $2000, 300 mm ~ 7.8 mm column. The detection was carded out using variable wavelength UV-vis detector set at 205 nm. The compounds were eluted isocratically at a steady flow rate of 1.0 mL/min. Sodium hyaluronate retention time was about 4.9 min with an asymmetry factor of 1.93. A calibration curve was obtained from 1 to 38 g/mL （r〉0.9998）. Within-day % RSD was 1.0 and between-day % RSD was 1.10. Specificity/selectivity experiments revealed the absence of interference from excipients, recovery from spiked samples for sodium hyaluronate was 99-102. The developed method was applied to the determination of sodium hyaluronate in pharmaceutical drug substance and product.
文摘A rapid GC-FID method was developed to simultaneously determine residual levels of triethylamine(TEA), 1,1,3,3-tetramethylguanidine(TMG), and diisopropylamine(DIPA) in the synthetic route of an active pharmaceutical ingredient(API). Due to the severe absorption of amines on GC stationary phases,GC columns with various stationary phases were evaluated for optimal peak shape and reproducibility.The final conditions used the Agilent CP-Volamine column to resolve the three amines in 12 min. Various inlet liners were also screened to further improve the sensitivity of the analysis. The Restek Siltek~? liner was selected to achieve the desired detectability for the method. The quantitation limits were 4, 3, and 4 mg/mL for TEA, DIPA, and TMG in the presence of API, respectively. All three amines showed good linearity(r > 0.999) and recoveries(> 90%) over the concentration range of 3 to 16 mg/mL. The testing of residual amines was initially performed at the penultimate stage of the synthesis. However, this work demonstrates that TMG can act as a proton sponge to react with salicylic acid, the counter ion of the penultimate, to form a volatile component that elutes at a different retention time. Consequently, in the final method, these three amines were monitored in the final API to circumvent the matrix interference.Key parameters of the method were qualified per method validation requirements in ICH guidelines. The method was successfully applied for batch testing during development and implemented as an inprocess control procedure at manufacturing sites.
文摘A new impurity was detected during high performance liquid chromatographic （HPLC） analysis of eslicarbazepine acetate active pharmaceutical ingredient. The structure of unknown impurity was postulated based on liquid chromatography mass spectrometry using electrospray ionization and ion trap analyzer （LC/ESI-IT/MS） analysis. Proposed structure of impurity was unambiguously confirmed by synthesis followed by characterization using 1H, 13C nuclear magnetic resonance spectrometry （NMR）, 1H-1H correlation spectro-scopy （COSY） and infrared spectroscopy （IR）. Based on the spectroscopic and spectrometric data, unknown impurity was characterized as 5-carbamoyl-10,11-dihydro-5H-dibenzo[b,f]azepin-10-yl propionate.
基金Supported by Novartis Pharmaceuticals CorporationOne Health Plaza+2 种基金East HanoverNJ 07936-1080United States
文摘AIM To examine healthcare resource utilizationpatterns and costs accrued by carcinoid syndrome （CS）patients with and without diarrhea.METHODS： We conducted a retrospective cohort studyusing MarketScan data from 1/1/2002-12/31/2012.Newly diagnosed CS patients had 1 medical claim forCS （ICD-9-CM code 259.2） plus either ≥ 1 additionalclaim for CS or for carcinoid tumors （ICD-9-CM 209.x）, and had no evidence of CS for 1 year prior to index CS diagnosis, in commercially-insured patients 〈 65years old. Patients were required to have continuousenrollment one year prior and after index date （firstclaim with CS diagnosis in the ID period）. We identifiedpatients with evidence of non-infectious diarrhea （ICD-9-CM codes 564.5 and 787.91） within one year from theindex date. Overall and CS-related healthcare resourceutilization and costs were compared between patientswith and without non-infectious diarrhea during theone year period after the index date.RESULTS： There were 2822 newly diagnosed CSpatients; 534 （18.9%） had evidence of non-infectiousdiarrhea. Compared to patients without non-infectiousdiarrhea, non-infectious diarrhea patients morecommonly had at ≥ 1 CS-related hospitalization（13.7% vs 7.2%）, ≥ 1 CS-related ED visit （11.0% vs4.4%）, and CS-related office visits in one year （6.9 vs4.1; all p 〈 0.001）. After adjusting for demographics,region, number of chronic conditions and the CharlsonComorbidity Index, the proportions of patients withany and with CS-related hospitalizations were 9.7%and 6.8% higher, respectively, among non-infectiousdiarrhea patients compared to those with without noninfectiousdiarrhea （p 〈 0.001）. Unadjusted costs weresignificantly higher among non-infectious diarrheapatients vs those without non-infectious diarrhea. Thenon-infectious diarrhea group was also more costly,with adjusted mean annual costs of $81610, comparedto $51719 in the group without non-infectious diarrhea（p 〈 0.001）.CONCLUSION： Diarrhea is burdensome and costlyin CS patients. Reduction of CS-related healthcareexpenditures may be achievable through preventivetreatment and appropriate management of diarrhea inCS.
基金the management of Dr. Reddy’s Laboratories Ltd. for supporting this work
文摘The present study deals with the forced degradation behavior of dexlansoprazole under International Conference on Harmonisation(ICH)prescribed stress conditions. The drug was found to be more labile under acid,base,neutral,oxidative hydrolysis and thermal stress,while it was moderately stable under photolytic conditions. The known and unknown degradation products were separated on a C-18 column using a stabilityindicating method. Liquid chromatography-mass spectrometry(LC-MS)analysis was performed for all the degradation studies. Isolation and structure characterization of oxidation degradation products were executed using sophisticated tools,viz. preparative high performance liquid chromatography(HPLC),liquid chromatographymass spectrometry / time of flight(LC-MS / TOF),liquid chromatography-tandem mass spectrometry(LC-MS /MS),and nuclear magnetic resonance(NMR). This study demonstrates an ample methodology of degradation studies and structure elucidation of unknown degradation products of dexlansoprazole,which helps in the development and stability study of active pharmaceutical ingredients and formulated products.
基金Supported by Novartis Pharmaceuticals,One Health Plaza,East Hanover,No.NJ 07936-1080,United State
文摘AIM To describe real-world treatment patterns of gastrointestinal neuroendocrine tumors(GI NET).METHODS In this retrospective cohort study,we used 2009-2014 data from 2 United States commercial claims databases to examine newly pharmacologically treated patients using tabular and graphical techniques.Treatments included somatostatin analogues(SSA),cytotoxic chemotherapy(CC),targeted therapy(TT),interferon(IF)and combinations.We identified patients at least 18 years of age,with≥1 inpatient or≥2 outpatient claims for GI NET who initiated pharmacologic treatment from 7/1/09-6/30/14.A 6 mo clean period prior to first treatment ensured patients were newly treated.Patients were followed until end of enrollment or the study end date,whichever was first.RESULTS We identified 2258 newly treated GI NET patients:mean(SD)age was 55.6 years(SD=9.7),47.2%of the patients were between 55 and 64 years,and 48.8%were female.All regions of the United States were represented.59.6%started first-line therapy with SSA monotherapy(964 with octreotide LAR,380 with octreotide SA,and 1 with lanreotide),33.3%CC,3.6%TT,and 0.5%IF.The remainder received combinations.Mean follow up was 576 d.Overall mean first-line therapy duration was 361 d(449 d for SSA,215 for CC,267 for TT).58.9%of patients had no pharmacological treatment beyond first line.The most common secondline was combination therapy with SSA.In graphical pattern analysis,there was no clear pattern visible after first line therapy.CONCLUSION In this study,60%of patients initiated treatment with SSA alone or in combination.The relatively long time to discontinuation suggests possible sustained effectiveness and tolerability.
基金financial support from ARC Discovery Projects (DP150101717 and DP180102003)
文摘Silicon is a promising anode material for rechargeable Li-ion battery (LIB) due to its high energy density and relatively low operating voltage. However, silicon based electrodes suffer from rapid capacity degradation during electrochemical cycling. The capacity decay is predominantly caused by (i) cracking due to large volume variations during lithium insertion/extraction and (ii) surface degradation due to excessive solid electrolyte interface (SEI) formation. In this work, we demonstrate that coating of a-Si thin film with a Li-active, nanoporous SiOx layer can result in exceptional electrochemical performance in Li-ion battery. The SiOx layer provides improved cracking resistance to the thin film and prevent the active material loss due to excessive SEI formation, benefiting the electrode cycling stability. Half-cell experiments using this anode material show an initial reversible capacity of 2173 mAh g^-1 with an excellent coulombic efficiency of 90.9%. Furthermore, the electrode shows remarkable capacity retention of ~97% after 100 cycles at C/2 charging rate. The proposed anode architecture is free from Liinactive binders and conductive additives and provides mechanical stability during the charge/discharge process.
基金the NHMRC Investigator grant fellowship (APP1176298)the EMCR grant from the Centre for Biomedical Technologies (QUT)+4 种基金the QUT Postgraduate Research Award (QUTPRA)QUT HDR TOP-UP scholarshipQUT HDR Tuition Fee Sponsorshipfunding support from the Academy of Finland (315820)the Jane and Aatos Erkko Foundation (190001).
文摘Osteoarthritis(OA)is a debilitating degenerative disease affecting multiple joint tissues,including cartilage,bone,synovium,and adipose tissues.OA presents diverse clinical phenotypes and distinct molecular endotypes,including inflammatory,metabolic,mechanical,genetic,and synovial variants.Consequently,innovative technologies are needed to support the development of effective diagnostic and precision therapeutic approaches.Traditional analysis of bulk OA tissue extracts has limitations due to technical constraints,causing challenges in the differentiation between various physiological and pathological phenotypes in joint tissues.This issue has led to standardization difficulties and hindered the success of clinical trials.Gaining insights into the spatial variations of the cellular and molecular structures in OA tissues,encompassing DNA,RNA,metabolites,and proteins,as well as their chemical properties,elemental composition,and mechanical attributes,can contribute to a more comprehensive understanding of the disease subtypes.Spatially resolved biology enables biologists to investigate cells within the context of their tissue microenvironment,providing a more holistic view of cellular function.Recent advances in innovative spatial biology techniques now allow intact tissue sections to be examined using various-omics lenses,such as genomics,transcriptomics,proteomics,and metabolomics,with spatial data.This fusion of approaches provides researchers with critical insights into the molecular composition and functions of the cells and tissues at precise spatial coordinates.Furthermore,advanced imaging techniques,including high-resolution microscopy,hyperspectral imaging,and mass spectrometry imaging,enable the visualization and analysis of the spatial distribution of biomolecules,cells,and tissues.Linking these molecular imaging outputs to conventional tissue histology can facilitate a more comprehensive characterization of disease phenotypes.This review summarizes the recent advancements in the molecular imaging modalities and methodologies for in-depth spatial analysis.It explores their applications,challenges,and potential opportunities in the field of OA.Additionally,this review provides a perspective on the potential research directions for these contemporary approaches that can meet the requirements of clinical diagnoses and the establishment of therapeutic targets for OA.
文摘In this study,using mesoporous silica for the solubility enhancement of poorly watersoluble drug was investigated.Although the incorporating drug into mesoporous silica is generally performed through the solvent method,the new melting method was proposed in the present study.Fenofibrate,a poorly water-soluble drug,was incorporated into mesoporous silica by solvent method and melting method.The obtained samples were observed by SEM and their physicochemical properties were evaluated by PXRD and DSC measurement.The dissolution and supersaturated property were also investigated.The results from SEM,PXRD and DSC measurement showed that drug could be loaded into pore via the melting method as well as by the solvent method.The drug loaded quantity depended on the pore volume.Drug up to 33%could be incorporated into mesoporous silica and existed in amorphous state.When drug was overloaded or difficulty in incorporation into pore was found,recrystallization of drug occurred at the outer surface of mesoporous silica.From the dissolution test,samples prepared by solvent method and melting method gave the supersaturated drug concentration which sample from melting method showed superior dissolution to the one from solvent method.From this study,drug was efficiently incorporated into mesoporous silica by the melting method which is a simple and solvent-free process,and the aqueous solubility enhancement of poorly watersoluble drug was achieved.
基金the financial support of this work by the Science, Technology, and Innovation Commission of Shenzhen Municipality (JCYJ20180508151856806 and JCYJ20180306171121424)the Key R&D Program of Shanxi (No. 2019ZDLGY04-05)+3 种基金the National Natural Science Foundation of Shaanxi (No.2019JLZ-01No.2019JLM-29 and No.2020JQ-189)the Research Fund of the State Key Laboratory of Solidification Processing (NPU), China (No.2019-TS-06)China Postdoctoral Science Foundation (No.2018M641015)。
文摘The unsatisfactory rate capability and poor cycling stability at high rate of sodium-ion batteries(SIBs) have impeded their practical applications. Herein, a Na_(3)V_(2)(PO_(4))_(3)/Na_(3)V_(3)(PO_(4))_(4) multiphase cathode materials for high-rate and long cycling SIBs was successfully synthesized by regulation the stoichiometric ratio of raw materials. The combined experiment and simulation results show that the multiphase materials consisted of NASICON structural phase Na3V2(PO4)3 and layered structure phase Na_(3)V_(3)(PO_(4))_(4), possess abundant phase boundaries. Electrochemical experiments demonstrate that the multiphase materials maintain a remarkable reversible capacity of 69.0 mA h g^(-1) even at an ultrahigh current density of 100 C with a high capacity retention of 81.25 % even after 10,000 cycles. Na_(3)V_(2)(PO_(4))_(3)/Na_(3)V_(3)(PO_(4))_(4) electrode exhibits a higher working voltage, superior rate capability and better cycling stability than Na_(3)V_(2)(PO_(4))_(3) electrode, which indicates that the introduction of second phase can be an effective strategy for the development of novel cathode materials for SIBs.
文摘A selective, precise and stability-indicating, high performance liquid chromatographic method was developed for the analysis of active ingredient sodium Picosulfate and forced degradation behavior was studied. The current article describes forced degradation behavior of the Sodium Picosulfate drug substance in detail by analyzing 15 process related/degradants in a single HPLC method under ICH recommended stressed conditions. Mobile phase comprised of 0.01 M of Disodium hydrogen phosphate and 0.01 M of potassium phosphate monobasic buffer and 1 mL of triethyl amine in 1000 mL water adjusted to pH 7.5 with 10% phosphoric acid. Acetonitrile was used as Mobile Phase B. The separation was achieved on a gradient method. The reversed phase chromatography was performed in Hypersil BDS C18 5.0 μm, 4.6 × 250 mm column maintained at temperature 35°C. Injection volume was 60 μL. Milli-Q water used as diluent. The mobile phase was pumped at 0.9 mL/min<sup>-1</sup>. The eluted compounds were monitored at 220 nm. Secondary wavelength of the 263 nm was studied to check any further degradants during the forced degradation studies. New additional degradants Sodium Picosulfate Benzyl alcohol Impurity and N oxide degradations were discussed and studied during the forced degradation to understand the chemical stability of the drug substance.
基金Supported by Grants from Novartis Pharmaceuticals Corporation,One Health Plaza,East Hanover,NJ 07936-1080,United States
文摘AIM:To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors(PNETs)and provide consensus treatment recommendations.METHODS:Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs,angiogenesis inhibitors,inhibitors of mammalian target of rapamycinand cytotoxic agents.At this time,there is little data to guide treatment selection and sequence.We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations.Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process.After studying the literature,a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale.Ratings were done both before and after an extended discussion of the evidence.Quantitative measurements of agreement were made and consensus statements developed from the second round ratings.RESULTS:Specialties represented were medical and surgical oncology,interventional radiology,and gastroenterology.Panelists had practiced for a mean of15.5 years(range:6-33).Among 202 rated scenarios,disagreement decreased from 13.2%(26 scenarios)before the face-to-face discussion of evidence to 1%(2)after.In the final ratings,46.5%(94 scenarios)were rated inappropriate,21.8%(44)were uncertain,and30.7%(62)were appropriate.Consensus statements from the scenarios included:(1)it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic;(2)it is appropriate to use everolimus,sunitinib,or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors;and(3)beyond first line,these same agents can be used.In patients with uncontrolled secretory symptoms,octreotide LAR doses can be titrated up to 60 mg every4 wk or up to 40 mg every 3 or 4 wk.CONCLUSION:Using the Delphi process allowed physician experts to systematically obtain a consensus on the appropriateness of a variety of medical therapies in patients with PNETs.
文摘A simple, rapid, precise, accurate, rugged and robust stability-indicating ultra-fast high performance liquid chromatographic (UHPLC) method has been developed for the estimation of related compounds (imp-A, imp-B, imp-C, imp-D and imp-E) in Naproxen and also the assay of Naproxen from bulk drug samples. The stability indicating capability of the method was proven by subjecting the samples to stress conditions such as acid, base, oxidation, photolysis and thermal degradation. The efficient chromatographic separation was achieved using mobile phase solution A prepared as buffer solution 10 mM monobasic potassium phosphate pH 4.0 ± 0.05 adjusted with diluted ortho phosphoric acid solution and solution B acetonitrile with linear gradient elution on poroshell 120 EC-C18 shot column (50 mm × 4.6 mm, 2.7 μm) and UV detection at 235 nm at a flow rate 1.0 mL/min, column oven temperature was set to 25?C. The above are all known impurities and degradation impurities are well resolved with Naproxen peak and these are eluted within a 10 min runtime of HPLC. The photo diode array detector was used for peak homogeneity testing during stress study experiments and the overall mass balance was found to be 99.2% to 100.2% in all stress conditions. The linear calibration range was found to be 0.05 μg/mL to 0.75 μg/mL for related compounds and 50 μg/mL to 150 μg/mL for Naproxen and the accuracy of the method was found to be 91.5% to 98.5% recovery for the related substance method and 95.4% to 97.4% recovery for the assay method. The Naproxen and related compounds were found to be stable up to 48 hours and the method validation data show excellent results for precision, linearity, specificity, limit of detection, limit of quantitation and robustness. The present method can be successfully used for routine QC and stability studies and it will help to reduce the analysis cost, time and effluent load compared to conventional HPLC methods.
文摘INTRODUCTION Gender dysphoria(GD),or gender identity disorder,is defined as persistent distress stemming from the incongruence between one's assigned sex at birth and gender identity.'GD has traditionally been introduced as a rare condition predominant in assigned males at birth(AMABs).2 However,recent studies have shown an upward trend in assigned females at birth(AFABs)with a dramatic reversal of the AMAB:AFAB ratio-.5-The actual AMAB:AFAB ratio varies by age group and study population.4-Questions have been raised concerning the increasing number of youth who seek professional care for GD,especially adolescent AFABs.
基金supported in part by research grants from JSPS KAKENHI(JP26460486 to MN and JP15H04718 to JF)NIH grants(R01HL117491and RO1HL129778 to YEC)
文摘Increased expression of matrix metalloproteinase-1(MMP-1)has been observed in the lesions of atherosclerosis and aneurysms;however,it is not fully understood whether macrophage-derived MMP-1 affects these diseases.To investigate whether macrophage-derived MMP-1 participates in the development of vascular diseases,we generated transgenic(Tg)rabbits expressing human MMP-1 in the monocyte/macrophage lineage under the control of the human scavenger receptor enhancer/promoter.Tg rabbits exhibited no visible abnormalities throughout their bodies.Western blotting analysis revealed that the amount of MMP-1 proteins in the conditioned media secreted from peritoneal macrophages of Tg rabbits was up to 3-fold higher than that in non-Tg rabbits.For the first experiment,Tg and non-Tg rabbits were fed a cholesterol diet for 16 weeks,and aortic and coronary atherosclerosis were evaluated.The gross lesion area of aortic atherosclerosis in Tg rabbits was not significantly different from that in non-Tg rabbits,but Tg rabbits had marked destruction of the medial elastic lamina of the aortic lesions on microscopic examination.For the second experiment,we generated aortic aneurysms by incubating with elastase.Compared with non-Tg rabbits,Tg rabbits exhibited a significantly greater aortic dilation.Increased macrophage-derived MMP-1 led to increased medial destruction in both aortic atherosclerosis and aneurysms.These results demonstrate that MMP-1 plays a different role in the pathogenesis of atherosclerosis and aneurysms.
文摘Carnuba wax consists chiefly of myricyl cerotate (M<sub>W</sub> 817.4) and small quantities of free cerotic acid (C<sub>26</sub>H<sub>52</sub>O<sub>2</sub>, Mw 396.7) and myricyl alcohol (C<sub>30</sub>H<sub>62</sub>O, mp 90°C). Of the two common extraction solvents, ethyl ether or petroleum ether, Lewkowitsch prefers the former. Concerning separation of phases, he advocates addition of small amounts of alcohol or caustic, and he also states that formation of a flocculant layer between the aqueous layer and the solvent does not interfere with the correct estimation of the unsaponifiable matter. These statements were not corroborated in the hands of this chemist. The “Unsaponifiable Matter” in oils or and fats, which consist mainly of hydrocarbons, sterols and aliphatic alcohols of high molecular mass that are not saponifiable by alkali hydroxides but are soluble in the ordinary fat solvents, and to products of saponification that are soluble in such solvents. Carnuba wax, a rather expensive wax, may be adulterated with less expensive paraffin by dishonest merchants. ASTM has a method for determining paraffinic material in carnuba wax. It uses heptanes at its boiling point to dissolve the wax, apply it to a silica gel column, and elute only the nonpolar (i.e. alkane) material. The method has the disadvantage of using a large volume of haptane, nor is it called for by either US Pharmacopeia/National Formulary (USP/NF) or Food Chemicals Codex (FCC). The test for unsaponifiable matter on pure carnuba wax will yield a result of 50.0% - 55.0%, while a higher result will betray the presence of paraffin adulterants.
基金the management of Sinotherapeutics Inc. for supporting this study
文摘Macitentan (MAC) is a pulmonary arterial hypertension (PAH) drug marketed as a tablet and often has stability issues in the final dosage form. Quantitative determination of MAC and its associated impurities in tablet dosage form has not been previously reported. This study quantified impurities present in Macitentan tablets using a binary solvent-based gradient elution method using reversed phase-high performance liquid chromatography.The developed method w as validated per International Conference on Harmonization (ICH) guidelines and the drug product w as subjected to forced degradation studies to evaluate stability. The developed method efficiently separated the drug and impurities (48 min) w ithout interference from solvents,excipients,or other impurities. The developed method met all guidelines in all characteristics w ith recoveries ranging from 85%-115%,linearity w ith r 2≥0. 996 6,and substantial robustness. The stability-indicating nature of the method w as evaluated using stressed conditions (hydrolysis:1 N HCl at 80℃/15 min; 1 N NaOH at 25℃/45 min; humidity stress (90%relative humidity) at 25℃for 24 h,oxidation:at 6%(v/v) H2O2,80℃/15 min,thermolysis:at105℃/16 h and photolysis:UV light at 200 Wh/m2; Fluorescent light at 1. 2 million luxh). Forced degradation experiments show ed that the developed method w as effective for impurity profiling. All stressed samples w ere assayed and mass balance w as> 96%. Forced degradation results indicated that MAC tablets w ere sensitive to hydrolysis (acid and alkali) and thermal conditions. The developed method is suitable for both assay and impurity determination,w hich is applicable to the pharmaceutical industry.
