Publications by authors named "ZhengQing Li"

17 Publications

  • Page 1 of 1

Synthesis and evolution of neuroprotective effects of oxymatrine derivatives as anti-Alzheimer's disease agents.

Chem Biol Drug Des 2021 Jul 31;98(1):175-181. Epub 2021 May 31.

Heilongjiang University of Chinese Medicine, Harbin, China.

While screening for natural product scaffolds as potential anti-Alzheimer's disease (AD), oxymatrine (OMT) was found to relieve symptoms of AD through diminishing death of neuronal cells caused by microglia-induced inflammation. In this study, 13 derivatives of OMT were synthesized and their neuroprotective effects were evaluated on Aβ -induced PC12 cells using MTT method. In addition, the best neuroprotective potencies were obtained with compounds 4, 6e, and 6f, which were selected for evaluation of decrease in IL-1β and TNF-α in Aβ -treated PC12 cells. Collectively, these data reveal that derivatives 6e and 6f possess the best ability of diminish IL-1β production and reverse cell damage in all compounds, which are possible to develop as therapeutic agents for AD.
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http://dx.doi.org/10.1111/cbdd.13862DOI Listing
July 2021

Preparation of the peroxisome proliferator-activated receptor α polyclonal antibody: Its application in fatty liver hemorrhagic syndrome.

Int J Biol Macromol 2021 Jul 7;182:179-186. Epub 2021 Apr 7.

Jiangxi Provincial Key Laboratory for Animal Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China. Electronic address:

Peroxisome proliferator-activated receptor α (PPARα) play a key role in the regulation of metabolic homeostasis, inflammation, cellular growth, and differentiation. To further explore the potential role of PPARα in the energy homeostasis of fatty liver hemorrhagic syndrome (FLHS), we reported the prokaryotic expression and purification of chicken PPARα subunit protein, and successfully prepared a polyclonal antibody against PPARα recombinant protein. The 987 bp PPARα subunit genes were cloned into the pEASY-T3 clone vector. Then the plasmid PCR products encoding 329 amino acids were ligated to pEASY-Blunt E2 vector and transformed into BL21 to induce expression. The recombinant PPARα subunit protein, containing His-tag, was purified by affinity column chromatography using Ni-NTA affinity column. Rabbit antiserum was generated by using the concentration of recombinant PPARα subunit protein as the antigen. The results of western blotting showed that the antiserum can specifically recognize chicken endogenous PPARα protein. Immunohistochemistry and immunofluorescence showed that the PPARα mainly existed in the nucleus of hepatocytes, renal epithelial cells and hypothalamic endocrine nerve cells. More importantly, western blotting and real-time quantitative PCR indicated that FLHS significantly decreased the expression of PPARα.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.04.018DOI Listing
July 2021

Comparing immersiveness and perceptibility of spherical and curved displays.

Appl Ergon 2021 Jan 19;90:103271. Epub 2020 Sep 19.

University of Toronto, 5 King's College Road, Toronto, Canada.

Curved displays are believed to create a feeling of immersiveness similar to virtual reality. However systematic studies are needed to demonstrate that this is, in fact, true and under what conditions. In an experimental study 24 participants compared five different displays (concave, convex, hemisphere, sphere and a flat display) in terms of their immersiveness and perceptibility, and they also rated their overall preferences. Both immersiveness and perceptibility affected overall preference ratings. Participants gave higher preference ratings to the convex and concave displays, which were rated high in immersiveness and perceptibility, but gave lower preference ratings to the hemisphere/spherical display which had high ratings on immersiveness but low ratings on perceptibility. The study results imply that curved displays do indeed create a feeling of immersiveness. Concave and convex displays were rated highly favorably and should receive more attention for applications where visual experience and a feeling of immersiveness is particularly important.
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http://dx.doi.org/10.1016/j.apergo.2020.103271DOI Listing
January 2021

Hepatoprotective activity assessment of amino acids derivatives of picroside I and II.

Chem Biol Drug Des 2021 Feb 23;97(2):341-348. Epub 2020 Sep 23.

Key Laboratory of Chinese Materia Medica, Heilongjiang University of Chinese Medicine, Ministry of Education, Harbin, China.

Picrorhiza kurroa has a long medicinal history as a traditional medicinal plant in China and India that is widely used in clinical treatments. It is a common treatment for liver diseases, fever, diarrhoea, indigestion, and some other diseases. Modern pharmacological studies proved that P. kurroa rhizomes have high levels of picroside I and II, which were identified as main constituents with anti-inflammatory and hepatoprotective activities. In our study, we used picroside I and II as the lead compounds to generate derivatives by reactions with Boc-valine or Boc-proline, which underwent dehydration and condensation with the hydroxyl groups in the lead compounds in the presence of coupling reagent N,N'-dicyclohexylcarbodiimide. We synthesized 11 derivatives and examined their hepatoprotective effects in vitro by assessing the proliferation rates of H O -exposed HepG2 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. We found that some derivatives promoted higher proliferation rates in HepG2 cells than the natural compounds before derivatization, suggesting that those derivatives possessed an improved hepatoprotective capacity. The novel derivatization strategy for picrosides had the additional benefit that the esterification of their hydroxyl groups created derivatives not only with increased stability but also with improved pharmacokinetic properties and potentially prolonged half-life.
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http://dx.doi.org/10.1111/cbdd.13786DOI Listing
February 2021

Synthesis and biological evaluation of picroside derivatives as hepatoprotective agents.

Nat Prod Res 2019 Oct 8;33(19):2845-2850. Epub 2018 Nov 8.

a Key Laboratory of Chinese Materia Medica, Heilongjiang University of Chinese Medicine, Ministry of Education , Harbin 150040 , People's Republic of China.

as a hepatoprotective herb, has been applied for thousands of years, and picroside was proved to be its active constituent. In this study, twelve derivatives of picroside were synthesized and the hepatoprotective activity of the derivatives was evaluated on SMMC-7721 cells. Six out of the derivatives had shown a better protective effect on HO-induced SMMC-7221 cells than picroside, and the activity of two derivatives ( and ) was stronger than that of the reference compound, silybin. Compound shown the strongest protective effect (EC = 6.064 ± 1.295 μM).
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http://dx.doi.org/10.1080/14786419.2018.1508143DOI Listing
October 2019

Synthesis and Promotion of the Osteoblast Proliferation Effect of Morroniside Derivatives.

Molecules 2018 06 11;23(6). Epub 2018 Jun 11.

Key Laboratory of Chinese Materia Medica, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin 150040, China.

Hance has been used in fractures for thousands of years, but research on its active components, such as morroniside, until now had not been carried out. In this study, morroniside was taken as the leading compound, and fourteen derivatives were synthesized. The promotion of osteoblast proliferation effect of the derivatives was evaluated on MC3T3-E1 cells. Five derivatives (, , , , and ) showed a good proliferation effect on MC3T3-E1 cells, and their promoted expression effects on OC (Osteocalcin) and ALP (Alkaline phosphatase) in MC3T3-E1 cells were measured. Compound was shown to have the strongest proliferation effect (EC = 14.78 ± 1.17 μg/mL) and to significantly promote the expression of OC and ALP.
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http://dx.doi.org/10.3390/molecules23061412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099551PMC
June 2018

c-kit Positive Cardiac Outgrowth Cells Demonstrate Better Ability for Cardiac Recovery Against Ischemic Myopathy.

J Stem Cell Res Ther 2017 Oct 13;7(10). Epub 2017 Oct 13.

Department of Cardiovascular Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan.

Objective: Resident cardiac stem cells are expected to be a therapeutic option for patients who suffer from severe heart failure. However, uncertainty remains over whether sorting cells for c-kit, a stem cell marker, improves therapeutic outcomes.

Materials And Methods: Cardiac outgrowth cells cultured from explants of rat heart atrium were sorted according to their positivity (+) or negativity (-) for c-kit. These cells were exposed to hypoxia for 3 d, and subsequently harvested for mRNA expression measurement. The cell medium was also collected to assess cytokine secretion. To test for a functional benefit in animals, myocardial infarction (MI) was induced in rats, and c-kit+ or c-kit- cells were injected. The left ventricular ejection fraction (LVEF) was measured for up to 4 weeks, after which the heart was harvested for biological and histological analyses.

Results And Conclusion: Expression of the angiogenesis-related genes, VEGF and ANGPTL2, was significantly higher in c-kit+ cells after 3 d of hypoxic culture, although we found no such difference prior to hypoxia. Secretion of VEGF and ANGPTL2 was greater in the c-kit+ group than in the c-kit- group, while hypoxia tended to increase cytokine expression in both groups. In addition, IGF-1 was significantly increased in the c-kit+ group, consistent with the relatively low expression of cleaved-caspase 3 revealed by western blot assay, and the relatively low count of apoptotic cells revealed by histochemical analysis. Administration of c-kit+cells into the MI heart improved the LVEF and increased neovascularization. These results indicate that c-kit+cells may be useful in cardiac stem cell therapy.
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http://dx.doi.org/10.4172/2157-7633.1000402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726283PMC
October 2017

Effect and mechanism of Sorbus pohuashanensis (Hante) Hedl. flavonoids protect against arsenic trioxide-induced cardiotoxicity.

Biomed Pharmacother 2017 Apr 13;88:1-10. Epub 2017 Jan 13.

College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen 518060, China.

The cardiotoxicity of arsenic trioxide (ATO) limits its clinical application in cancer treatment. Evidences suggest that sorbus has antioxidant activity and its consumption has been linked with improved cardioprotection. In this study, we investigated the cardio-protective effect and mechanisms of Sorbus pohuashanensis (Hante) Hedl. flavonoids (SPF) against ATO in BALB/c mice and H9c2 cells. Eleven major flavonoids were confirmed by ultra-performance liquid chromatography electrospray ionization quadrupole time of flight mass spectrometry (UPLC-ESI-Q-TOF-MS). SPF recovered the ATO-induced disordered electrocardiogram (ECG) and abnormal cardiac structure in the heart of mice. At the same time, SPF significantly reduced levels of creatine kinase (CK), creatine kinase-MB (CK-MB) lactate dehydrogenase (LDH), and glutamic oxaloacetic transaminase (GOT) against ATO-induced injury and inhibited ATO-induced apoptosis both in vivo and in vitro. In addition, SPF regulated ATO-induced oxidative stress damage by increasing the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in vivo and in vitro, and reducing reactive oxygen species (ROS). Analysis of the oxidative stress pathways showed that SPF prevented the ATO-induced downregulation of phosphorylated protein kinase B (p-Akt) in vivo and in vitro. Pre-treatment of H9c2 cells with SPF inhibited attenuation of nuclear factor (Nrf2) and heme oxygenase (HO-1). Hence, SPF could be used as a preventive and therapeutic plant ingredient against ATO-induced cardiotoxicity.
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http://dx.doi.org/10.1016/j.biopha.2016.12.130DOI Listing
April 2017

Differential HbA1c response in the placebo arm of DPP-4 inhibitor clinical trials conducted in China compared to other countries: a systematic review and meta-analysis.

BMC Pharmacol Toxicol 2016 09 7;17(1):40. Epub 2016 Sep 7.

Faculty of Health Sciences, University of Macau, Taipa, Macau.

Background: It has been observed that the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors as compared to the placebo groups in some clinical trials conducted in China is weaker than that in trials conducted outside China, leading to the suspicion that this may be caused by differential Glycosylated Hemoglobin (HbA1c) response in the placebo arm of DPP-4 inhibitor clinical trials conducted in China compared to other countries.

Methods: We searched published articles and other documents related to phase III placebo-control trials of DPP-4 inhibitors in Type 2 diabetes mellitus (T2DM). We included studies from different countries and compared those conducted in China to those conducted in other countries. Meta-regression analysis was used to analyze the HbA1c response in the placebo arms.

Results: A total of 66 studies met the inclusion criteria and 10 were conducted within China. There were a total of 8303 participants (mean age 56, male 57 %) in placebo groups. The pooled change in HbA1c for the placebo groups of 10 trials conducted in patients with T2DM in China was 0.26 % (95 % CI [-0.36 %, -0.16 %], p-value < 0.001), compared to 0.015 % (95 % CI [-0.05 %, 0.08 %], p-value is 0.637) for 56 trials conducted outside of China. The difference of placebo effect between trials conducted in and outside China is -0.273 % (95 % CI [-0.42 %, -0.13 %], p-value is less than 0.001) while after excluding trials conducted in Japan, the difference is -0.203 % (95 % CI [-0.35 %, -0.06 %], p-value is 0.005). They are both statistically significant.

Conclusions: The meta-analysis in the article demonstrates that there is statistically significant difference in the HbA1c response in the placebo arm of DPP-4 inhibitor clinical trials conducted in China compared to other countries. This differential HbA1c response in the placebo arm should be taken into consideration by both experimenters and medical decision makers when future DPP-4 studies are conducted in China.
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http://dx.doi.org/10.1186/s40360-016-0084-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013632PMC
September 2016

Administration of cells with thermosensitive hydrogel enhances the functional recovery in ischemic rat heart.

J Tissue Eng 2016 Jan-Dec;7:2041731416646676. Epub 2016 May 4.

Department of Cardiovascular Surgery, Faculty of Medicine, Juntendo University, Tokyo, Japan.

The lack of cell retention clearly represents a potentially serious limitation for therapeutic efficacy of stem cells. To enhance the efficacy, we developed a novel hydrogel that is thermosensitive and biodegradable and possesses desirable stiffness in a solid form. Immediately after induction of myocardial infarction of male rat, cardiac outgrowth cells embedded in hydrogel (HG) or saline (CO) were injected directly into the peri-infarct area. Left ventricular ejection fraction, cell retention rate, and a spectrum of biochemical markers were measured to evaluate the effect of the treatment. Left ventricular ejection fraction was significantly higher in the cell-injected groups (HG and CO) than in the control group at 1 week after treatment. This functional benefit was continued only in the HG group, accompanied with more retained cells. Furthermore, the expression of insulin-like growth factor-1 was significantly higher in the HG group with less progression of cell apoptosis.
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http://dx.doi.org/10.1177/2041731416646676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858721PMC
May 2016

Recommendations for safety planning, data collection, evaluation and reporting during drug, biologic and vaccine development: a report of the safety planning, evaluation, and reporting team.

Clin Trials 2009 Oct;6(5):430-40

Eli Lilly and Company, Indianapolis, IN, USA.

Background: The Safety Planning, Evaluation and Reporting Team (SPERT) was formed in 2006 by the Pharmaceutical Research and Manufacturers of America.

Purpose: SPERT's goal was to propose a pharmaceutical industry standard for safety planning, data collection, evaluation, and reporting, beginning with planning first-in-human studies and continuing through the planning of the post-product-approval period.

Methods: SPERT's recommendations are based on our review of relevant literature and on consensus reached in our discussions.

Results: An important recommendation is that sponsors create a Program Safety Analysis Plan early in development. We also give recommendations for the planning of repeated, cumulative meta-analyses of the safety data obtained from the studies conducted within the development program. These include clear definitions of adverse events of special interest and standardization of many aspects of data collection and study design. We describe a 3-tier system for signal detection and analysis of adverse events and highlight proposals for reducing "false positive" safety findings. We recommend that sponsors review the aggregated safety data on a regular and ongoing basis throughout the development program, rather than waiting until the time of submission.

Limitations: We recognize that there may be other valid approaches.

Conclusions: The proactive approach we advocate has the potential to benefit patients and health care providers by providing more comprehensive safety information at the time of new product marketing and beyond.
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http://dx.doi.org/10.1177/1740774509344101DOI Listing
October 2009

Vertebral fracture risk reduction with risedronate in post-menopausal women with osteoporosis: a meta-analysis of individual patient data.

Aging Clin Exp Res 2005 Apr;17(2):150-6

McMaster University, Hamilton, Ontario, Canada.

Background And Aims: The effect of risedronate, a potent pyridinyl bisphosphonate, on vertebral fractures in post-menopausal women was evaluated in randomized, placebo-controlled clinical trials. These trials included two large vertebral fracture studies that used time-to-event methods to evaluate the effects of treatment on fracture risk, thereby allowing both the occurrence and the timing of fractures to be considered.

Methods: We used individual patient data (IPD) and time-to-event methods to perform a meta-analysis of the anti-fracture efficacy of risedronate (2.5 or 5 mg daily) in osteoporotic women enrolled in five double-blind, placebo-controlled clinical trials. Women were included in the analysis if, at baseline, they had either at least one prevalent vertebral fracture or a femoral neck bone mineral density (BMD) T-score of less than -2.5, were at least 1 year post-menopausal, and had had vertebral fracture assessments (N = 3331).

Results: Risedronate 5 mg daily reduced the risk of radiographically defined vertebral fracture by 64% (95% CI, 46 to 76%, p < 0.001) in the first year of treatment and 45% (95% CI, 31 to 57%, p < 0.001) in 3 years. The numbers of patients who needed to be treated with risedronate 5 mg to prevent one new vertebral fracture over 1 and 3 years were 21 and 13, respectively. Comparable findings were observed in sub-populations defined on the basis of either prevalent vertebral fracture without regard to femoral neck BMD, or femoral neck BMD without regard to vertebral fracture status. Risedronate significantly reduced the incidence of clinical (symptomatic) vertebral fractures in the first 6 months of treatment (p < 0.001).

Conclusions: This meta-analysis, based upon five trials and using IPD and time-to-event statistical methods, provides a more precise estimate of the effect of risedronate in reducing vertebral fracture risk in postmenopausal osteoporotic women than a meta-analysis using summary statistics from the literature.
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http://dx.doi.org/10.1007/BF03324588DOI Listing
April 2005

Longitudinal progression of fracture prevalence through a population of postmenopausal women with osteoporosis.

Osteoporos Int 2005 Mar 28;16(3):306-12. Epub 2004 Sep 28.

Helen Hayes Hospital, Route 9 W, West Haverstraw, NY 10993, USA.

Aim: To determine the longitudinal progression of fractures through a population of osteoporotic women with no existing vertebral fractures.

Methods: The probability of having one or more vertebral fractures in the next year given a current status of 0-13 existing vertebral fractures was estimated using data from control patients of an osteoporosis clinical trial program. Fracture probabilities were used to form a transition matrix that models the change in fracture state from one year to the next. A Markov model was used to show the distribution of fracture prevalence over time for a population of women with osteoporosis but, initially, with no existing vertebral fractures.

Results: An osteoporotic woman without existing vertebral fractures has a 7.7% chance (95% CI, 5.8% to 9.9%) of having a vertebral fracture within 1 year. After 5 years, 33% (95% CI, 25% to 41%) will have developed vertebral fractures, of which 11% (95% CI, 8% to 16%) will have > or =2 fractures. After 10 years, 55% (95% CI, 44% to 65%) will have developed vertebral fractures, of which 29% (95% CI, 22% 37%) will have > or =2 fractures. Each 1% absolute reduction in the annual first-fracture risk corresponds to an approximate 4% reduction in the 5-year fracture incidence. Therefore, reducing the risk of first fracture from 8% to 2% reduces the 5-year fracture incidence from approximately 34% to approximately 10%.

Conclusions: Fracture prevalence rapidly increases over time in a population of osteoporotic women despite treatment with calcium and vitamin D supplements. Identifying and treating patients at risk of fracture, but who have not yet sustained a fracture, will substantially reduce the long-term burden of osteoporosis.
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http://dx.doi.org/10.1007/s00198-004-1691-5DOI Listing
March 2005

Relationship between changes in bone mineral density and fracture risk reduction with antiresorptive drugs: some issues with meta-analyses.

J Bone Miner Res 2004 Feb 16;19(2):330-7. Epub 2003 Dec 16.

INSERM Research Unit 403, Claude Bernard University of Lyon, Lyon, France.

Unlabelled: Published meta-analyses have investigated the relationship between changes in BMD and fracture risk reduction observed with antiresorptive agents, with inconsistent results. Many factors may affect the outcome of such analyses. Our work explores some of these factors and illustrates the need for caution in interpreting the results of meta-analyses.

Introduction: The role of the increase in bone mineral density (BMD) in fracture risk reduction observed in osteoporotic patients treated with antiresorptive drugs is unclear. We examined the effects of study selection, the use of summary statistics or individual patient data (IPD) as the basis for the analyses, and the choice of BMD values used on the outcome of meta-analyses.

Materials And Methods: To evaluate the effects of study selection, we performed Poisson regression analyses using the results from a number of published studies. To evaluate the effects of using individual patient data instead of summary statistics, we simulated the IPD for vertebral fracture to match the summary statistics for published trials and compared these results with those based on meta-regression using summary statistics. We also evaluated the effect of varying the BMD increase with treatment (3-8%) used in predicting the fracture risk reductions in these simulations.

Results: The Poisson regression, which found a statistically significant relationship between nonvertebral fracture risk and spinal BMD when 18 trials of varying designs, duration, and sample size were included in the analysis (p = 0.02), was no longer significant when the analysis was based on the 7 large studies that were placebo-controlled, at least 3 years in duration (at least 1000 patient-years). Meta-analyses of simulated IPD from 12 trials of six antiresorptive agents gave accurate results regardless of the proportion of vertebral risk reduction assumed to be related to BMD change, whereas meta-regression based on summary statistics always produced an estimate around 50%. When the actual data from two risedronate studies were analyzed, the meta-regression based on summary statistics demonstrated a stronger correlation between BMD change and fracture risk reduction than the results based on the IPD analysis. In predicting the fracture risk reduction, the use of the average BMD gain (3%) observed in all studies in the calculations produced an overall fracture risk reduction very similar to the one observed clinically. In contrast, the use of a large BMD gain (8%) produced a substantially higher estimated fracture risk reduction and resulted in a high proportion of fracture risk reduction being attributed to BMD change.

Conclusions: Many factors may influence the outcome of meta-analyses, and caution should be used in interpreting the results of such analyses when exploring the relationship between BMD changes and fracture risk reduction with antiresorptive therapy of osteoporosis.
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http://dx.doi.org/10.1359/JBMR.0301228DOI Listing
February 2004

Exploring the relationship between surrogates and clinical outcomes: analysis of individual patient data vs. meta-regression on group-level summary statistics.

J Biopharm Stat 2003 Nov;13(4):777-92

Department of Biometrics and Statistical Sciences, The Procter & Gamble Company, Mason, Ohio 45040, USA.

There has been an increasing interest in exploring the relationship between a surrogate and a clinical outcome. Two different statistical approaches have been taken by researchers to quantify the treatment effect on the clinical outcome explained by the surrogate endpoint: 1) analysis based on individual patient data (IPD), and 2) meta-regression based on summary statistics from published literature. An analysis based on IPD models the associations between the surrogate and clinical outcome for patients directly and is able to adjust for patient-level covariates. A meta-regression models the trial-level associations using group-level summary statistics and trial-level covariates. The results from these two approaches can be quite disparate and researchers may reach different conclusions on scientific questions that they wish to answer. We demonstrate that the typical summary statistics, such as group means and event counts, do not provide a set of sufficient statistics for estimating the underlying relationship between the surrogate and clinical outcome for patients. Consequently, the associations derived from meta-regression do not necessarily reflect the causal relationship for patients and should be interpreted with caution. A meta-analysis of antiresorptive agents for osteoporosis serves to illustrate the magnitude of differences between the two approaches.
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http://dx.doi.org/10.1081/BIP-120024209DOI Listing
November 2003

Use of matched historical controls to evaluate the anti-fracture efficacy of once-a-week risedronate.

Osteoporos Int 2003 Jun 29;14(5):437-41. Epub 2003 Apr 29.

University of Cincinnati, Cincinnati, Ohio 45219, USA.

Placebo controls are essential to assess anti-fracture efficacy of new osteoporosis therapies, but inclusion of a placebo arm in a subsequent clinical trial may be limited by practical or ethical considerations; in these cases, use of an historical control may be appropriate. A recent active-controlled study of risedronate 35 mg once a week demonstrated that this regimen produces increases in bone mineral density (BMD) that are comparable to those seen with the risedronate 5 mg daily dose, which has proven anti-fracture efficacy. To assess the anti-fracture efficacy of this new regimen, we have analyzed the fracture data collected in an active controlled study of risedronate dosing regimens (the Once-a-Week study) using matched historical control data from previous placebo-controlled trials. Women in the Once-a-Week study were matched for age, years since menopause, BMD, and prevalent vertebral fracture status, with placebo patients in the Vertebral Efficacy of Risedronate Therapy (VERT) trials forming an historical placebo group. We also constructed an historical active treatment group from the 5 mg daily arm of the VERT trials for comparison with the 5 mg daily and 35 mg once weekly treatment groups in the Once-a-Week study. Data were obtained from the risedronate 5 mg daily group (n=480) and 35 mg once-a-week group (n=485) in the Once-a-Week study and historical control groups representing daily placebo patients (n=114, matched from 993) and risedronate 5 mg daily patients (n=120; matched from 990) in the VERT studies. Patients received calcium supplementation (1000 mg daily); vitamin D was given if baseline serum 25-hydroxyvitamin D levels were low. Over 1 year, new vertebral fracture risk in the 35 mg once-a-week group was reduced by 77% relative to the historical placebo group (1.2% versus 5.0%; RR 0.23; 95% CI, 0.54 to 0.91, P=0.018), similar to the 1-year risk reduction observed in the VERT trials of risedronate 5 mg daily (61-65%). The incidence of new vertebral fractures in the three active treatment groups was similar: 1.7% in the historical risedronate 5 mg group, 1.5% in the risedronate 5 mg daily group from the Once-a-Week study, and 1.2% in the 35 mg once-a-week group. Risedronate 35 mg once a week appears as effective as the 5 mg daily dose in reducing the risk of new vertebral fractures in the first year of treatment. The use of appropriate historical control data provides an approach to the assessment of fracture effects in osteoporosis trials for which placebo-controlled data are not available.
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http://dx.doi.org/10.1007/s00198-003-1401-8DOI Listing
June 2003

14 day endoscopy study comparing risedronate and alendronate in postmenopausal women stratified by Helicobacter pylori status.

J Rheumatol 2002 Sep;29(9):1965-74

University of Alberta, Edmonton, Canada.

Objective: Bisphosphonates are effective treatment for osteoporosis but have been associated with gastrointestinal (GI) mucosal injury. This study compared the incidence of gastric ulcers after treatment with risedronate, a pyridinyl bisphosphonate, or alendronate, a primary amino bisphosphonate, in healthy postmenopausal women stratified by Helicobacter pylori status.

Methods: Subjects were randomized to receive risedronate 5 mg (n = 318) or alendronate 10 mg (n = 317) daily for 14 days. Endoscopy and evaluator-blind assessments of the esophageal, gastric, and duodenal mucosa were performed at baseline and on Days 8 and 15.

Results: Overall, gastric ulcers > or = 3 mm were observed in 18 (6.0%) of 300 evaluable subjects in the risedronate group and 36 (12.1%) of 297 in the alendronate group during treatment (p = 0.013). On Day 8, the incidences of gastric ulcers in the risedronate and alendronate groups were 3.6% and 6.6%, respectively (p = 0.133), and on Day 15, they were 3.3% and 8.7% (p = 0.008). The incidence of gastric ulcers was not affected by H. pylori status. Mean gastric endoscopy scores at Days 8 and 15 were significantly lower in the risedronate group than in the alendronate group (p < 0.001). Mean esophageal and duodenal endoscopy scores were similar in the 2 groups at Days 8 and 15. When the treatment groups were combined, gastric endoscopy scores were significantly higher among H. pylori negative than H. pylori positive subjects at Days 8 and 15 (p < 0.05). Upper GI adverse events were reported by 18 (5.7%) subjects in the risedronate group (19 events) and 28 (8.8%) subjects in the alendronate group (32 events). Symptoms did not predict the presence of mucosal damage.

Conclusion: Risedronate was associated with a significantly lower incidence of gastric ulcers than alendronate. H. pylori infection did not increase the incidence of bisphosphonate related gastric ulcers. The findings from this 14 day study in healthy volunteers support the hypothesis that bisphosphonates may differ from one another in their potential to produce upper GI mucosal damage.
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September 2002
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