Four ternary lanthanide complexes with unsaturated acid and 1,10-phenanthroline are prepared in methanol and characterized by elemental analysis, molar conductance, UV, IR, (()~1H) NMR and XPS. The results from this p...Four ternary lanthanide complexes with unsaturated acid and 1,10-phenanthroline are prepared in methanol and characterized by elemental analysis, molar conductance, UV, IR, (()~1H) NMR and XPS. The results from this paper show that the complexes Ln(phen)(SA)_3·2H_2O or Ln(phen)(CA)_3·H_2O (Ln=Ce(Ⅲ), Sm(Ⅲ) and Eu(Ⅲ), (phen=1,10-)phenanthroline, SA=Sorbate and CA=Cinnamate) has better anti-inflammatory effect than cerium nitrate and their gremores are steadier than cerium nitrate gremor. And there is a kind of medicament which can replace the cerium nitrate gremor completely in treating burn.展开更多
Current methods for nasal spray formulations have been elementary evaluating the dripping characteristics of a formulation and have not assessed the behavior of the nasal formulation in the presence of varying types o...Current methods for nasal spray formulations have been elementary evaluating the dripping characteristics of a formulation and have not assessed the behavior of the nasal formulation in the presence of varying types of mucus depending on the indication or diseased state. This research investigated the effects of nasal mucus on the dripping behavior of nasal formulations and focused on developing an improved in vitro analytical test method that is more physiologically relevant in characterizing nasal formulation dripping behavior. Method development was performed using simulated nasal mucus preparations for both healthy and diseased states as coatings for the dripping experiment representing a wide range of viscosity. Factors evaluated during development of this in vitro test method included amount of mucus, application of mucus, drying times, and compatibility of the mucus on a C18 Thin Layer Chromatography(TLC) substrate. The dripping behavior of nasal formulations containing a range of 1%Avicel to 3.5% Avicel was assessed by actuating the nasal spray on a perpendicular TLC plate coated with either healthy or diseased simulated nasal mucus. After actuation of the nasal spray, the dripping of the formulation on the coated TLC plate was measured after the plate was repositioned vertically. The method that was developed generated reproducible results on the dripping behavior of nasal formulations and provided critical information about the compatibility of the formulation with the nasal mucus for different diseased states, aiding in nasal spray formulation development and physical characterization of the nasal spray.展开更多
Oleic acid is a common pharmaceutical excipient that has been widely used in various dosage forms. Gas chromatography （GC） has often been used as the quantitation method for fatty acids normally requiring a derivati...Oleic acid is a common pharmaceutical excipient that has been widely used in various dosage forms. Gas chromatography （GC） has often been used as the quantitation method for fatty acids normally requiring a derivatization step. The aim of this study was to develop a simple, robust, and derivatization-free GC method that is suitable for routine analysis of all the major components in oleic acid USP-NF （United States Pharmacopeia-National Formulary） material. A gas chromatography-flame ionization detection （GC-FID） method was developed for direct quantitative analysis of oleic acid and related fatty acids in oleic acid USP-NF material. Fifteen fatty acids were separated using a DB-FFAP （nitroterephthalic acid modified polyethylene glycol） capillary GC column （30 m × 0.32 mm i.d.） with a total run time of 20 rain. The method was validated in terms of specificity, linearity, precision, accuracy, sensitivity, and robust- ness. The method can be routinely used for the purpose of oleic acid USP-NF material analysis.展开更多
The development and delivery of high quality therapeutic products necessitates the need for highthrough-put (HTP) process development tools. Traditionally, these works requires a combination of shake flask and small-s...The development and delivery of high quality therapeutic products necessitates the need for highthrough-put (HTP) process development tools. Traditionally, these works requires a combination of shake flask and small-scale stirred tank bioreactor (STR) which are labor and resource intensive and time-consuming. Here we demonstrate a strategy for rapid and robust cell culture process development by evaluating and implementing the use of a new HTP disposable micro bioreactor (MBR) called AMBRTM system (Advanced Microscale Bioreactor) that has the capabilities for automated sampling, feed addition, pH, dissolved oxygen (DO), gassing and agitation controls. In these studies the performance of two monoclonal antibody (MAb) producing cell lines (MAb1 and MAb2) was evaluated both in the AMBR system and 3-L STR. We demonstrated that cell culture performance (growth and viability, production titer and product quality) were similar in both vessel systems. Furthermore, process control and feed optimization were demonstrated in an additional cell line (MAb3) in the disposable MBR and its performance confirmed at STR scale. The results indicate that the AMBR system can be used to streamline the process development effort and facilitate a rapid and robust cell culture process development effort for MAb programs in a HTP manner.展开更多
A novel method for simultaneous determination of kolliphor HS15 and miglyol 812 in microemulsion formulation was developed using ultra-high performance liquid chromatography coupled with a nano quantitation analytical...A novel method for simultaneous determination of kolliphor HS15 and miglyol 812 in microemulsion formulation was developed using ultra-high performance liquid chromatography coupled with a nano quantitation analytical detector （UHPLC-NQAD）. All components in kolliphor HS15 and miglyo1812 were well separated on an Acquity BEH C18 column. Mobile phase A was 0.1% trifluoroacetic acid （TFA） in water and mobile phase B was acetonitrile. A gradient elution sequence was programed initially with 60% organic solvent, slowly increased to 100% within 8 min. The flow rate was 0.7 mL/min. Good linearity （r 〉 0.95） was obtained in the range of 27.6-1381.1 μg/mL for polyoxyl 15 hydroxystearate in kolliphor HS15, 0.8-202.0 μg/mL for caprylic acid triglyceride and 2.7-221.9μg/mL for capric acid triglyceride in miglyol 812. The relative standard deviations （RSD） ranged from 0.6% to 1.7% for intra-day precision and from 0.4% to 2.7% for inter-day precision. The overall recoveries （accuracy） were 99.7%-101.4% for polyoxyl 15 hydroxystearate in kolliphor HS15, 96.7%-99.6% for caprylic acid triglyceride, and 94.1%- 103.3% for capric acid triglyceride in miglyol 812. Quantification limits （QL） were determined as 27.6 μg/ mL for polyoxy115 hydroxystearate in kolliphor HS15, 0.8 μg/mL for caprylic acid triglyceride, and 2.7 μg/ mL for capric acid triglyceride in miglyol 812. No interferences were observed in the retention time ranges of kolliphor HSI5 and miglyol 812. The method was validated in terms of specificity, linearity, precision, accuracy, QL, and robustness. The proposed method has been applied to microemulsion for- mulation analyses with good recoveries （82.2%-103.4%）.展开更多
Monoclonal antibodies(mAbs)have become a major class of therapeutic agents providing effective alternatives to treating various human diseases.To date,15 mAbs have been approved by regulatory agencies in the world for...Monoclonal antibodies(mAbs)have become a major class of therapeutic agents providing effective alternatives to treating various human diseases.To date,15 mAbs have been approved by regulatory agencies in the world for clinical use in oncology indications.The selectivity and specificity,the unique pharmacokinetics,and the ability to engage and activate the host immune system differentiate these biologics from traditional small molecule anticancer drugs.mAb-based regimens have brought clinical benefits,including improvements in overall survival,to patients with a variety of cancers.Many challenges still remain,however,to fully realize the potential of these new medicines.With our further understanding of cancer biology,mechanism of antibody action,and advancement of antibody engineering technologies,many novel antibody formats or antibody-derived molecules are emerging as promising new generation therapeutics.Carefully designed and engineered,they retain the advantage of specificity and selectivity of original antibodies,but in the meantime acquire additional special features such as improved pharmacokinetics,increased selectivity,and enhanced anticancer efficacy.Promising clinical results are being generated with these newly improved antibody-based therapeutics.展开更多
Background: Amnestic mild cognitive impairment (aMCI) and mild-to-moderate Alzheimer’s disease (AD) are clinically distinct but impact cognitive and functional ability similarly. Comprehensive assessment of cognitive...Background: Amnestic mild cognitive impairment (aMCI) and mild-to-moderate Alzheimer’s disease (AD) are clinically distinct but impact cognitive and functional ability similarly. Comprehensive assessment of cognitive and functional deficits may prove useful in informing differential diagnosis in early stages of dementia and in informing endpoint selection in therapeutic AD trials. Objective: The objective of this study was to characterize patterns of cognitive and functional impairment in aMCI and mild-to-moderate AD subjects compared to cognitively intact healthy elderly (HE). Methods: Thirty-one healthy elderly, 20 aMCI and 19 AD participants were administered a cognitive test battery that included the ADAS-Cog and functional assessments. Z-scores were calculated for all endpoints based on the HE reference group. Results: Cognitive deficits were observed in AD and aMCI participants relative to the referent group. On average, aMCI participants performed 1 - 2 standard deviations below HE on cognitive tests, and AD participants performed 2 - 3 standard deviations below HE. Domain-specific functional deficits among AD participants (z- score -0.4 to -6.4) were consistently greater than those of aMCI participants (z-score 0 to -1.7). Conclusion: This study provides further support for comprehensive assessment and monitoring of cognitive and functional domain scores in the diagnosis and treatment of aMCI and mild AD. Domain-specific cognitive scores may be more useful than composite scores in characterizing impairment and decline. Measuring domains such as attention, processing speed and executive function may increase the sensitivity of detecting disease progression and therapeutic effects, particularly in mild-moderate AD where memory decline may be too slow to detect drug effects during a typical clinical trial.展开更多
Neisseria meningitidis is a gram negative diplococcal bacterium. Worldwide, N. meningitidis is the leading cause of bacterial meningitis and sepsis, with five serogroups (A, B, C, Y, and W-135) responsible for the maj...Neisseria meningitidis is a gram negative diplococcal bacterium. Worldwide, N. meningitidis is the leading cause of bacterial meningitis and sepsis, with five serogroups (A, B, C, Y, and W-135) responsible for the majority of the disease. Multivalent (A, C, Y, and W-135) polysaccharide and conjugate vaccines have been licensed in the United States and elsewhere and are widely available. We have developed a multi-plexed electrochemiluminescent assay to quantitate serum antibody responses to meningococcal polysaccharides A, C, Y, and W-135 to allow for rapid evaluation of li- censed and investigational vaccines. A 96-well plate containing a carbon electrode arrayed with polysaccharides A, C, Y, and W-135 on separate spots within each well has been developed for simultaneous detection of polysaccharidespecific antibodies in serum samples from vaccinated individuals. The assay conditions were optimized using the anti-meningococcal serogroup A/C reference serum pool, CDC 1992 (NIBSC 99/706), through evaluation of plate types, coating polysaccharide concentrations, and blocking and serum diluent buffers. Comparison of single and multiplex assays demonstrated the sensitivity, specificity, and speed of the multi-plex format for the quantification of serum antibody responses to N. meningitidis polysaccharides A, C, Y and W-135.展开更多
With the ever increasing complexity of active pharmaceutical ingredient (API) preparations, more potential genotoxic impurities (PGI’s) are being observed. It is thus necessary to determine if these PGI’s are presen...With the ever increasing complexity of active pharmaceutical ingredient (API) preparations, more potential genotoxic impurities (PGI’s) are being observed. It is thus necessary to determine if these PGI’s are present in the final API’s, and if they are present, to ensure the levels are acceptable for any clinical uses. For PGI’s that have authentic standards available, quantitation can be accomplished in a straightforward manner. However, for PGI’s that are expected to form through rearrangements or side reactions, authentic standards may not be readily available, significantly complicating the analysis. In this study we describe a surrogate standard approach for quantifying PGI’s that allows for relative response factor calculations of PGI species utilizing both gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS).展开更多
When the event of interest never occurs for a proportion of subjects during the study period, survival models with a cure fraction are more appropriate in analyzing this type of data. Considering the non-linear relati...When the event of interest never occurs for a proportion of subjects during the study period, survival models with a cure fraction are more appropriate in analyzing this type of data. Considering the non-linear relationship between response variable and covariates, we propose a class of generalized transformation models motivated by Zeng et al. [1] transformed proportional time cure model, in which fractional polynomials are used instead of the simple linear combination of the covariates. Statistical properties of the proposed models are investigated, including identifiability of the parameters, asymptotic consistency, and asymptotic normality of the estimated regression coefficients. A simulation study is carried out to examine the performance of the power selection procedure. The generalized transformation cure rate models are applied to the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study (NHANES1) for the purpose of examining the relationship between survival time of patients and several risk factors.展开更多
Objective. To examine the short and long term efficacy and tolerabilty of rizatriptan 5 mg in adolescents with migraine. Methods. Two studies were condu cted in patients aged 12 to 17 years. The first study was a rand...Objective. To examine the short and long term efficacy and tolerabilty of rizatriptan 5 mg in adolescents with migraine. Methods. Two studies were condu cted in patients aged 12 to 17 years. The first study was a randomized, double blind, placebo controlled, single attack study followed by a randomized, 1 ye ar, open label extension. The second study was a randomized, 1 year, open lab el study. In the single attack study, patients treated a moderate or severe mig raine headache and up to two recurrences with rizatriptan 5-mg tablets (n = 234 ) or placebo (n = 242). Patients were instructed to use the study medication onl y on nonschool days. Headache severity, associated symptoms, and functional disa bility were assessed by the patient at 0.5,1, 1.5, 2, 3, and 4 hours after the i nitial dose. In the 1 year studies, patients treated up to 6 migraine attacks p er month with rizatriptan 5-mg tablets (n = 273), rizatriptan 5-mg wafers (n = 281), or standard care therapy (n = 132). Headache severity was assessed by the patient at 2 hours after the initial dose. In all studies, the primary efficacy measure was pain relief at 2 hours post dose. Results. In the single attack study, the proportion of patients with pain relief at 2 hours was not significan tly different between rizatriptan 5 mg (68.2%) and placebo (68.8%). Fewer pat ients than expected (about 30%) treated their migraine attacks on the weekend. Among these patients, the proportion with pain relief at 2 hours was significant ly higher in the rizatriptan group than in the placebo group (74%vs. 58%, P = 0.022). In the multiple attack studies, pain relief at 2 hours was achieved in significantly more attacks treated with rizatriptan 5-mg tablet (77%) or with rizatriptan 5-mg wafer (77%) than with standard care (64%). Rizatriptan 5 mg was well tolerated in both the studies, with an adverse event profile not signif icantly different from that of placebo or standard care. Conclusions. Rizatrip tan 5 mg was not more effective than placebo in the treatment of a single migrai ne attack in adolescents, but appeared to be more effective than standard care f or treating multiple attacks occurring over 1 year in these patients. Rizatripta n 5 mg was well tolerated in adolescents during short term and long term use.展开更多
Merck &Co., Inc. evaluates outcomes of the use of rizatriptan during pregnancy through a Pregnancy Registry in the United States (US) and spontaneous reports for pregnancies reported from sources outside the US. R...Merck &Co., Inc. evaluates outcomes of the use of rizatriptan during pregnancy through a Pregnancy Registry in the United States (US) and spontaneous reports for pregnancies reported from sources outside the US. Review of the outcomes of 25 prospective pregnancy reports in the Pregnancy Registry and reports from other sources does not suggest that treatment with rizatriptan predisposes patients to spontaneous abortions or congenital anomalies. However, the number of reports is small. Healthcare providers in the United States are encouraged to report any prenatal exposure to rizatriptan by calling the Pregnancy Registry at +1 (800) 986 8999 or visiting the Registry’s website at http://www.merckpregnancyregistries.com .展开更多
Cardiovascular disease(CVD)has become one of the commonest causes of comorbidity and mortality among People living with human immunodeficiency virus(HIV)(PLWH)on antiretroviral therapy(ART).Nearly 50%of PLWH are likel...Cardiovascular disease(CVD)has become one of the commonest causes of comorbidity and mortality among People living with human immunodeficiency virus(HIV)(PLWH)on antiretroviral therapy(ART).Nearly 50%of PLWH are likely to have an increased risk of developing CVD,including coronary heart disease,cerebrovascular disease,peripheral artery disease and aortic atherosclerosis.Aside from the common risk factors,HIV infection itself and side effects of antiretroviral therapy contribute to the pathophysiology of this entity.Potential non-pharmacological therapies are currently being tested worldwide for this purpose,including eating patterns such as Intermittent fasting(IF).IF is a widespread practice gaining high level of interest in the scientific community due to its potential benefits such as improvement in serum lipids and lipoproteins,blood pressure(BP),platelet-derived growth factor AB,systemic inflammation,and carotid artery intima-media thickness among others cardiovascular benefits.This review will focus on exploring the potential role of intermittent fasting as a non-pharmacological and cost-effective strategy in decreasing the burden of cardiovascular diseases among HIV patients on ART due to its intrinsic properties improving the main cardiovascular risk factors and modulating inflammatory pathways related to endothelial dysfunction,lipid peroxidation and aging.Intermittent fasting regimens need to be tested in clinical trials as an important,cost-effective,and revolutionary coadjutant of ART in the fight against the increased prevalence of cardiovascular disease in PLWH.展开更多
Background Transforming growth factor β （TGFβ） is one of the most important growth factors in the development of fibrosis and scarring on cornea. Smad7, an inhibitory Smad, can inhibit TGFβ signal transduction. I...Background Transforming growth factor β （TGFβ） is one of the most important growth factors in the development of fibrosis and scarring on cornea. Smad7, an inhibitory Smad, can inhibit TGFβ signal transduction. In recent years, effects of lentiviral-mediated Smad7 on inhibition of fibrosis on some organs have been studied, while little is known about the effects on cornea. This study aimed to determine the effects of lentiviral-mediated SmadTgene expression on keratocyte proliferation and fibrosis induced by TGF β2 in vitro. Methods Keratocytes were cultured from corneal tissue isolated from Sprague-Dawley （SD） rats and transfected with Smad7 expressing lentiviral vector （Lv-Smad7） or non-functioning control vector （Lv-blank）. Following the exposure to TGFβ2, keratocytes were processed for immunoblotting to assess the phosphorylation of Smad2 as down-stream event of TGFβ/Smad signaling. Expression of fibrotic markers a-smooth muscle actin （a-SMA）, type III collagen （collagen III） were measured by Western blotting and quantitative real time polymerase chain reaction （PCR）. Overall cell proliferation was determined by 3-（4,5-dimethyl-thiazol-2-yl）-2,5-diphenyltetrazolium bromide （MTT） assay and the expression of cell cycle-related marker Ki67 at both mRNA and protein levels. Results The Smad7 gene transfer suppressed TGFβ/Smad signaling in keratocytes by down-regulating phosphorylation of Smad2. Markers of cell proliferation and fibrosis including Ki67, a-SMA, collagen III were inhibited by introduction of Smad 7 into TGFβ exposed keratocytes. Consequently, the rate of cell proliferation was attenuated. Conclusion Smad7gene transfer inhibited fibrogenic responses of keratocytes to TGFβ2.展开更多
文摘Four ternary lanthanide complexes with unsaturated acid and 1,10-phenanthroline are prepared in methanol and characterized by elemental analysis, molar conductance, UV, IR, (()~1H) NMR and XPS. The results from this paper show that the complexes Ln(phen)(SA)_3·2H_2O or Ln(phen)(CA)_3·H_2O (Ln=Ce(Ⅲ), Sm(Ⅲ) and Eu(Ⅲ), (phen=1,10-)phenanthroline, SA=Sorbate and CA=Cinnamate) has better anti-inflammatory effect than cerium nitrate and their gremores are steadier than cerium nitrate gremor. And there is a kind of medicament which can replace the cerium nitrate gremor completely in treating burn.
文摘Current methods for nasal spray formulations have been elementary evaluating the dripping characteristics of a formulation and have not assessed the behavior of the nasal formulation in the presence of varying types of mucus depending on the indication or diseased state. This research investigated the effects of nasal mucus on the dripping behavior of nasal formulations and focused on developing an improved in vitro analytical test method that is more physiologically relevant in characterizing nasal formulation dripping behavior. Method development was performed using simulated nasal mucus preparations for both healthy and diseased states as coatings for the dripping experiment representing a wide range of viscosity. Factors evaluated during development of this in vitro test method included amount of mucus, application of mucus, drying times, and compatibility of the mucus on a C18 Thin Layer Chromatography(TLC) substrate. The dripping behavior of nasal formulations containing a range of 1%Avicel to 3.5% Avicel was assessed by actuating the nasal spray on a perpendicular TLC plate coated with either healthy or diseased simulated nasal mucus. After actuation of the nasal spray, the dripping of the formulation on the coated TLC plate was measured after the plate was repositioned vertically. The method that was developed generated reproducible results on the dripping behavior of nasal formulations and provided critical information about the compatibility of the formulation with the nasal mucus for different diseased states, aiding in nasal spray formulation development and physical characterization of the nasal spray.
文摘Oleic acid is a common pharmaceutical excipient that has been widely used in various dosage forms. Gas chromatography （GC） has often been used as the quantitation method for fatty acids normally requiring a derivatization step. The aim of this study was to develop a simple, robust, and derivatization-free GC method that is suitable for routine analysis of all the major components in oleic acid USP-NF （United States Pharmacopeia-National Formulary） material. A gas chromatography-flame ionization detection （GC-FID） method was developed for direct quantitative analysis of oleic acid and related fatty acids in oleic acid USP-NF material. Fifteen fatty acids were separated using a DB-FFAP （nitroterephthalic acid modified polyethylene glycol） capillary GC column （30 m × 0.32 mm i.d.） with a total run time of 20 rain. The method was validated in terms of specificity, linearity, precision, accuracy, sensitivity, and robust- ness. The method can be routinely used for the purpose of oleic acid USP-NF material analysis.
文摘The development and delivery of high quality therapeutic products necessitates the need for highthrough-put (HTP) process development tools. Traditionally, these works requires a combination of shake flask and small-scale stirred tank bioreactor (STR) which are labor and resource intensive and time-consuming. Here we demonstrate a strategy for rapid and robust cell culture process development by evaluating and implementing the use of a new HTP disposable micro bioreactor (MBR) called AMBRTM system (Advanced Microscale Bioreactor) that has the capabilities for automated sampling, feed addition, pH, dissolved oxygen (DO), gassing and agitation controls. In these studies the performance of two monoclonal antibody (MAb) producing cell lines (MAb1 and MAb2) was evaluated both in the AMBR system and 3-L STR. We demonstrated that cell culture performance (growth and viability, production titer and product quality) were similar in both vessel systems. Furthermore, process control and feed optimization were demonstrated in an additional cell line (MAb3) in the disposable MBR and its performance confirmed at STR scale. The results indicate that the AMBR system can be used to streamline the process development effort and facilitate a rapid and robust cell culture process development effort for MAb programs in a HTP manner.
文摘A novel method for simultaneous determination of kolliphor HS15 and miglyol 812 in microemulsion formulation was developed using ultra-high performance liquid chromatography coupled with a nano quantitation analytical detector （UHPLC-NQAD）. All components in kolliphor HS15 and miglyo1812 were well separated on an Acquity BEH C18 column. Mobile phase A was 0.1% trifluoroacetic acid （TFA） in water and mobile phase B was acetonitrile. A gradient elution sequence was programed initially with 60% organic solvent, slowly increased to 100% within 8 min. The flow rate was 0.7 mL/min. Good linearity （r 〉 0.95） was obtained in the range of 27.6-1381.1 μg/mL for polyoxyl 15 hydroxystearate in kolliphor HS15, 0.8-202.0 μg/mL for caprylic acid triglyceride and 2.7-221.9μg/mL for capric acid triglyceride in miglyol 812. The relative standard deviations （RSD） ranged from 0.6% to 1.7% for intra-day precision and from 0.4% to 2.7% for inter-day precision. The overall recoveries （accuracy） were 99.7%-101.4% for polyoxyl 15 hydroxystearate in kolliphor HS15, 96.7%-99.6% for caprylic acid triglyceride, and 94.1%- 103.3% for capric acid triglyceride in miglyol 812. Quantification limits （QL） were determined as 27.6 μg/ mL for polyoxy115 hydroxystearate in kolliphor HS15, 0.8 μg/mL for caprylic acid triglyceride, and 2.7 μg/ mL for capric acid triglyceride in miglyol 812. No interferences were observed in the retention time ranges of kolliphor HSI5 and miglyol 812. The method was validated in terms of specificity, linearity, precision, accuracy, QL, and robustness. The proposed method has been applied to microemulsion for- mulation analyses with good recoveries （82.2%-103.4%）.
文摘Monoclonal antibodies(mAbs)have become a major class of therapeutic agents providing effective alternatives to treating various human diseases.To date,15 mAbs have been approved by regulatory agencies in the world for clinical use in oncology indications.The selectivity and specificity,the unique pharmacokinetics,and the ability to engage and activate the host immune system differentiate these biologics from traditional small molecule anticancer drugs.mAb-based regimens have brought clinical benefits,including improvements in overall survival,to patients with a variety of cancers.Many challenges still remain,however,to fully realize the potential of these new medicines.With our further understanding of cancer biology,mechanism of antibody action,and advancement of antibody engineering technologies,many novel antibody formats or antibody-derived molecules are emerging as promising new generation therapeutics.Carefully designed and engineered,they retain the advantage of specificity and selectivity of original antibodies,but in the meantime acquire additional special features such as improved pharmacokinetics,increased selectivity,and enhanced anticancer efficacy.Promising clinical results are being generated with these newly improved antibody-based therapeutics.
文摘Background: Amnestic mild cognitive impairment (aMCI) and mild-to-moderate Alzheimer’s disease (AD) are clinically distinct but impact cognitive and functional ability similarly. Comprehensive assessment of cognitive and functional deficits may prove useful in informing differential diagnosis in early stages of dementia and in informing endpoint selection in therapeutic AD trials. Objective: The objective of this study was to characterize patterns of cognitive and functional impairment in aMCI and mild-to-moderate AD subjects compared to cognitively intact healthy elderly (HE). Methods: Thirty-one healthy elderly, 20 aMCI and 19 AD participants were administered a cognitive test battery that included the ADAS-Cog and functional assessments. Z-scores were calculated for all endpoints based on the HE reference group. Results: Cognitive deficits were observed in AD and aMCI participants relative to the referent group. On average, aMCI participants performed 1 - 2 standard deviations below HE on cognitive tests, and AD participants performed 2 - 3 standard deviations below HE. Domain-specific functional deficits among AD participants (z- score -0.4 to -6.4) were consistently greater than those of aMCI participants (z-score 0 to -1.7). Conclusion: This study provides further support for comprehensive assessment and monitoring of cognitive and functional domain scores in the diagnosis and treatment of aMCI and mild AD. Domain-specific cognitive scores may be more useful than composite scores in characterizing impairment and decline. Measuring domains such as attention, processing speed and executive function may increase the sensitivity of detecting disease progression and therapeutic effects, particularly in mild-moderate AD where memory decline may be too slow to detect drug effects during a typical clinical trial.
文摘Neisseria meningitidis is a gram negative diplococcal bacterium. Worldwide, N. meningitidis is the leading cause of bacterial meningitis and sepsis, with five serogroups (A, B, C, Y, and W-135) responsible for the majority of the disease. Multivalent (A, C, Y, and W-135) polysaccharide and conjugate vaccines have been licensed in the United States and elsewhere and are widely available. We have developed a multi-plexed electrochemiluminescent assay to quantitate serum antibody responses to meningococcal polysaccharides A, C, Y, and W-135 to allow for rapid evaluation of li- censed and investigational vaccines. A 96-well plate containing a carbon electrode arrayed with polysaccharides A, C, Y, and W-135 on separate spots within each well has been developed for simultaneous detection of polysaccharidespecific antibodies in serum samples from vaccinated individuals. The assay conditions were optimized using the anti-meningococcal serogroup A/C reference serum pool, CDC 1992 (NIBSC 99/706), through evaluation of plate types, coating polysaccharide concentrations, and blocking and serum diluent buffers. Comparison of single and multiplex assays demonstrated the sensitivity, specificity, and speed of the multi-plex format for the quantification of serum antibody responses to N. meningitidis polysaccharides A, C, Y and W-135.
文摘With the ever increasing complexity of active pharmaceutical ingredient (API) preparations, more potential genotoxic impurities (PGI’s) are being observed. It is thus necessary to determine if these PGI’s are present in the final API’s, and if they are present, to ensure the levels are acceptable for any clinical uses. For PGI’s that have authentic standards available, quantitation can be accomplished in a straightforward manner. However, for PGI’s that are expected to form through rearrangements or side reactions, authentic standards may not be readily available, significantly complicating the analysis. In this study we describe a surrogate standard approach for quantifying PGI’s that allows for relative response factor calculations of PGI species utilizing both gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS).
文摘When the event of interest never occurs for a proportion of subjects during the study period, survival models with a cure fraction are more appropriate in analyzing this type of data. Considering the non-linear relationship between response variable and covariates, we propose a class of generalized transformation models motivated by Zeng et al. [1] transformed proportional time cure model, in which fractional polynomials are used instead of the simple linear combination of the covariates. Statistical properties of the proposed models are investigated, including identifiability of the parameters, asymptotic consistency, and asymptotic normality of the estimated regression coefficients. A simulation study is carried out to examine the performance of the power selection procedure. The generalized transformation cure rate models are applied to the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study (NHANES1) for the purpose of examining the relationship between survival time of patients and several risk factors.
文摘Objective. To examine the short and long term efficacy and tolerabilty of rizatriptan 5 mg in adolescents with migraine. Methods. Two studies were condu cted in patients aged 12 to 17 years. The first study was a randomized, double blind, placebo controlled, single attack study followed by a randomized, 1 ye ar, open label extension. The second study was a randomized, 1 year, open lab el study. In the single attack study, patients treated a moderate or severe mig raine headache and up to two recurrences with rizatriptan 5-mg tablets (n = 234 ) or placebo (n = 242). Patients were instructed to use the study medication onl y on nonschool days. Headache severity, associated symptoms, and functional disa bility were assessed by the patient at 0.5,1, 1.5, 2, 3, and 4 hours after the i nitial dose. In the 1 year studies, patients treated up to 6 migraine attacks p er month with rizatriptan 5-mg tablets (n = 273), rizatriptan 5-mg wafers (n = 281), or standard care therapy (n = 132). Headache severity was assessed by the patient at 2 hours after the initial dose. In all studies, the primary efficacy measure was pain relief at 2 hours post dose. Results. In the single attack study, the proportion of patients with pain relief at 2 hours was not significan tly different between rizatriptan 5 mg (68.2%) and placebo (68.8%). Fewer pat ients than expected (about 30%) treated their migraine attacks on the weekend. Among these patients, the proportion with pain relief at 2 hours was significant ly higher in the rizatriptan group than in the placebo group (74%vs. 58%, P = 0.022). In the multiple attack studies, pain relief at 2 hours was achieved in significantly more attacks treated with rizatriptan 5-mg tablet (77%) or with rizatriptan 5-mg wafer (77%) than with standard care (64%). Rizatriptan 5 mg was well tolerated in both the studies, with an adverse event profile not signif icantly different from that of placebo or standard care. Conclusions. Rizatrip tan 5 mg was not more effective than placebo in the treatment of a single migrai ne attack in adolescents, but appeared to be more effective than standard care f or treating multiple attacks occurring over 1 year in these patients. Rizatripta n 5 mg was well tolerated in adolescents during short term and long term use.
文摘Merck &Co., Inc. evaluates outcomes of the use of rizatriptan during pregnancy through a Pregnancy Registry in the United States (US) and spontaneous reports for pregnancies reported from sources outside the US. Review of the outcomes of 25 prospective pregnancy reports in the Pregnancy Registry and reports from other sources does not suggest that treatment with rizatriptan predisposes patients to spontaneous abortions or congenital anomalies. However, the number of reports is small. Healthcare providers in the United States are encouraged to report any prenatal exposure to rizatriptan by calling the Pregnancy Registry at +1 (800) 986 8999 or visiting the Registry’s website at http://www.merckpregnancyregistries.com .
文摘Cardiovascular disease(CVD)has become one of the commonest causes of comorbidity and mortality among People living with human immunodeficiency virus(HIV)(PLWH)on antiretroviral therapy(ART).Nearly 50%of PLWH are likely to have an increased risk of developing CVD,including coronary heart disease,cerebrovascular disease,peripheral artery disease and aortic atherosclerosis.Aside from the common risk factors,HIV infection itself and side effects of antiretroviral therapy contribute to the pathophysiology of this entity.Potential non-pharmacological therapies are currently being tested worldwide for this purpose,including eating patterns such as Intermittent fasting(IF).IF is a widespread practice gaining high level of interest in the scientific community due to its potential benefits such as improvement in serum lipids and lipoproteins,blood pressure(BP),platelet-derived growth factor AB,systemic inflammation,and carotid artery intima-media thickness among others cardiovascular benefits.This review will focus on exploring the potential role of intermittent fasting as a non-pharmacological and cost-effective strategy in decreasing the burden of cardiovascular diseases among HIV patients on ART due to its intrinsic properties improving the main cardiovascular risk factors and modulating inflammatory pathways related to endothelial dysfunction,lipid peroxidation and aging.Intermittent fasting regimens need to be tested in clinical trials as an important,cost-effective,and revolutionary coadjutant of ART in the fight against the increased prevalence of cardiovascular disease in PLWH.
文摘Background Transforming growth factor β （TGFβ） is one of the most important growth factors in the development of fibrosis and scarring on cornea. Smad7, an inhibitory Smad, can inhibit TGFβ signal transduction. In recent years, effects of lentiviral-mediated Smad7 on inhibition of fibrosis on some organs have been studied, while little is known about the effects on cornea. This study aimed to determine the effects of lentiviral-mediated SmadTgene expression on keratocyte proliferation and fibrosis induced by TGF β2 in vitro. Methods Keratocytes were cultured from corneal tissue isolated from Sprague-Dawley （SD） rats and transfected with Smad7 expressing lentiviral vector （Lv-Smad7） or non-functioning control vector （Lv-blank）. Following the exposure to TGFβ2, keratocytes were processed for immunoblotting to assess the phosphorylation of Smad2 as down-stream event of TGFβ/Smad signaling. Expression of fibrotic markers a-smooth muscle actin （a-SMA）, type III collagen （collagen III） were measured by Western blotting and quantitative real time polymerase chain reaction （PCR）. Overall cell proliferation was determined by 3-（4,5-dimethyl-thiazol-2-yl）-2,5-diphenyltetrazolium bromide （MTT） assay and the expression of cell cycle-related marker Ki67 at both mRNA and protein levels. Results The Smad7 gene transfer suppressed TGFβ/Smad signaling in keratocytes by down-regulating phosphorylation of Smad2. Markers of cell proliferation and fibrosis including Ki67, a-SMA, collagen III were inhibited by introduction of Smad 7 into TGFβ exposed keratocytes. Consequently, the rate of cell proliferation was attenuated. Conclusion Smad7gene transfer inhibited fibrogenic responses of keratocytes to TGFβ2.
