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Lin S, Ma H, Zhang S, Fan W, Shen C, Chen J, Jin M, Li K, He Q. The combination of paeonol, diosmetin-7- O- β- D-glucopyranoside, and 5-hydroxymethylfurfural from Trichosanthis pericarpium alleviates arachidonic acid-induced thrombosis in a zebrafish model. Front Pharmacol 2024; 15:1332468. [PMID: 38487165 PMCID: PMC10937350 DOI: 10.3389/fphar.2024.1332468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 01/17/2024] [Indexed: 03/17/2024] Open
Abstract
Trichosanthis fruit (TF) is a classic medicinal material obtained from Shandong, China. The peel of this fruit (Trichosanthis pericarpium, TP) is known to exert anti-thrombotic effects. However, the anti-thrombotic active components and mechanisms of TP have yet to be fully elucidated. Combined with zebrafish models and high-performance liquid chromatography (HPLC), this study evaluated the endogenous anti-thrombotic effects with the combination of three compounds from TP. First, we used HPLC to investigate the components in the water extract of TP. Next, we used the zebrafish model to investigate the anti-thrombotic activity of the three compound combinations by evaluating a range of indicators. Finally, the expression of related genes was detected by real-time quantitative polymerase chain reaction (qPCR). HPLC detected a total of eight components in TP water extract, with high levels of paeonol (Pae), diosmetin-7-O-β-D-glucopyranoside (diosmetin-7-O-glucoside), and 5-hydroxymethylfurfural (5-HMF). The most significant anti-thrombotic activity was detected when the Pae: diosmetin-7-O-glucoside:5-HMF ratio was 4:3:3. qPCR analysis revealed that the abnormal expression levels of f2, fga, fgb, vwf, ptgs1, and tbxas1 induced by arachidonic acid (AA) were improved. The combination of Pae, diosmetin-7-O-glucoside, and 5-HMF may alleviate AA-induced thrombosis by inhibiting the inflammatory reaction, coagulation cascade reaction, and arachidonic acid metabolism pathways.
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Affiliation(s)
- Shenghua Lin
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China
| | - Honglin Ma
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China
| | - Shanshan Zhang
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China
| | - Wei Fan
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China
| | - Chuanlin Shen
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China
| | - Jiayu Chen
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China
| | - Meng Jin
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China
| | - Kun Li
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Qiuxia He
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China
- Science and Technology Service Platform, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China
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Wan EYF, Yu EYT, Chan L, Mok AHY, Wang Y, Chan EWY, Wong ICK, Lam CLK. Comparative Risks of Nonsteroidal Anti-inflammatory Drugs on Cardiovascular Diseases: A Population-Based Cohort Study. J Clin Pharmacol 2023; 63:126-134. [PMID: 36063443 DOI: 10.1002/jcph.2142] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 08/16/2022] [Indexed: 12/15/2022]
Abstract
Through examining the incidence of cardiovascular diseases (CVDs) among nonsteroidal anti-inflammatory drug (NSAID) users and nonusers, this study aims to compare the risks contributed by different NSAIDs in a Chinese population. The retrospective cohort including 4 298 368 adults without CVD from electronic health records between 2008 and 2017 in Hong Kong was adopted. A total of 4.5% of individuals received NSAIDs including celecoxib, etoricoxib, diclofenac, ibuprofen, indomethacin, mefenamic acid, or naproxen for ≥4 consecutive weeks at baseline. Cox regression, including NSAID use as a time-dependent covariate and adjusted with patient's characteristics, was conducted to examine the association between NSAID exposure and incident CVD. After a median follow-up of 6.9 years (30 million person-years), a total of 258 601 cases of incident CVD was recorded. NSAID use was shown to be associated with a significantly higher risk of CVD (hazard ratio [HR], 1.32 [95%CI, 1.28-1.37]) compared to non-NSAID use. Similar results in coronary heart disease (HR, 1.37 [95%CI, 1.31-1.43]), stroke (HR, 1.27 [95%CI, 1.21-1.33]), and heart failure (HR, 1.25 [95%CI, 1.16-1.34]) were obtained. Overall, similar CVD risk was observed across users of NSAIDs except for etoricoxib, which showed a higher risk (HR, 2.01 [95%CI, 1.63-2.48]). Considering that a higher CVD risk was consistently displayed among NSAID users, NSAIDs should be used cautiously, and the usage of etoricoxib in the Chinese population should be reviewed.
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Affiliation(s)
- Eric Yuk Fai Wan
- Department of Family Medicine and Primary Care, The University of Hong Kong, Ap Lei Chau, Hong Kong, China.,Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Ap Lei Chau, Hong Kong, China.,Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Sha Tin, Hong Kong, China
| | - Esther Yee Tak Yu
- Department of Family Medicine and Primary Care, The University of Hong Kong, Ap Lei Chau, Hong Kong, China
| | - Linda Chan
- Department of Family Medicine and Primary Care, The University of Hong Kong, Ap Lei Chau, Hong Kong, China
| | - Anna Hoi Ying Mok
- Department of Family Medicine and Primary Care, The University of Hong Kong, Ap Lei Chau, Hong Kong, China
| | - Yuan Wang
- Department of Family Medicine and Primary Care, The University of Hong Kong, Ap Lei Chau, Hong Kong, China
| | - Esther Wai Yin Chan
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Ap Lei Chau, Hong Kong, China.,Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Sha Tin, Hong Kong, China.,Department of Pharmacy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.,The University of Hong Kong Shenzhen Institute of Research and Innovation, Shenzhen, China
| | - Ian Chi Kei Wong
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Ap Lei Chau, Hong Kong, China.,Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Sha Tin, Hong Kong, China.,Research Department of Practice and Policy, School of Pharmacy, University College London, London, UK.,Aston Pharmacy School, Aston University, Birmingham, UK.,Department of Pharmacy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Cindy Lo Kuen Lam
- Department of Family Medicine and Primary Care, The University of Hong Kong, Ap Lei Chau, Hong Kong, China.,Department of Family Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
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Scarlet Flax Linum grandiflorum (L.) In Vitro Cultures as a New Source of Antioxidant and Anti-Inflammatory Lignans. Molecules 2021; 26:molecules26154511. [PMID: 34361665 PMCID: PMC8348589 DOI: 10.3390/molecules26154511] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/17/2021] [Accepted: 07/23/2021] [Indexed: 11/17/2022] Open
Abstract
In vitro cultures of scarlet flax (Linum grandiflorum L.), an important ornamental flax, have been established as a new possible valuable resource of lignans and neolignans for antioxidant and anti-inflammatory applications. The callogenic potential at different concentrations of α-naphthalene acetic acid (NAA) and thidiazuron (TDZ), alone or in combinations, was evaluated using both L. grandiflorum hypocotyl and cotyledon explants. A higher callus induction frequency was observed on NAA than TDZ, especially for hypocotyl explants, with a maximum frequency (i.e., 95.2%) on 1.0 mg/L of NAA. The presence of NAA (1.0 mg/L) in conjunction with TDZ tended to increase the frequency of callogenesis relative to TDZ alone, but never reached the values observed with NAA alone, thereby indicating the lack of synergy between these two plant growth regulators (PGRs). Similarly, in terms of biomass, NAA was more effective than TDZ, with a maximum accumulation of biomass registered for medium supplemented with 1.0 mg/L of NAA using hypocotyls as initial explants (DW: 13.1 g). However, for biomass, a synergy between the two PGRs was observed, particularly for cotyledon-derived explants and for the lowest concentrations of TDZ. The influence of these two PGRs on callogenesis and biomass is discussed. The HPLC analysis confirmed the presence of lignans (secoisolariciresinol (SECO) and lariciresinol (LARI) and neolignan (dehydrodiconiferyl alcohol [DCA]) naturally accumulated in their glycoside forms. Furthermore, the antioxidant activities performed for both hypocotyl- and cotyledon-derived cultures were also found maximal (DPPH: 89.5%, FRAP 866: µM TEAC, ABTS: 456 µM TEAC) in hypocotyl-derived callus cultures as compared with callus obtained from cotyledon explants. Moreover, the anti-inflammatory activities revealed high inhibition (COX-1: 47.4% and COX-2: 51.1%) for extract of hypocotyl-derived callus cultures at 2.5 mg/L TDZ. The anti-inflammatory action against COX-1 and COX-2 was supported by the IC50 values. This report provides a viable approach for enhanced biomass accumulation and efficient production of (neo)lignans in L. grandiflorum callus cultures.
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Tseng HH, Huang WR, Cheng CY, Chiu HC, Liao TL, Nielsen BL, Liu HJ. Aspirin and 5-Aminoimidazole-4-carboxamide Riboside Attenuate Bovine Ephemeral Fever Virus Replication by Inhibiting BEFV-Induced Autophagy. Front Immunol 2020; 11:556838. [PMID: 33329515 PMCID: PMC7732683 DOI: 10.3389/fimmu.2020.556838] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 10/21/2020] [Indexed: 12/21/2022] Open
Abstract
Recent study in our laboratory has demonstrated that BEFV-induced autophagy via activation of the PI3K/Akt/NF-κB and Src/JNK pathways and suppression of the PI3K-AKt-mTORC1 pathway is beneficial for virus replication. In the current study, we found that both aspirin and 5-aminoimidazole-4-carboxamide-1-β-riboside (AICAR) siginificantly attenuated virus replication by inhibiting BEFV-induced autophagy via suppressing the BEFV-activated PI3K/Akt/NF-κB and Src/JNK pathways as well as inducing reversion of the BEFV-suppressed PI3K-Akt-mTORC1 pathway. AICAR reversed the BEFV-activated PI3K/Akt/NF-κB and Src/JNK pathways at the early to late stages of infection and induced reversion of the BEFV-suppressed PI3K-AKt-mTORC1 pathway at the late stage of infection. Our findings reveal that inhibition of BEFV-induced autophagy by AICAR is independent of AMPK. Furthermore, we found that AICAR transcriptionally downregulates the ATG related genes ULK1, Beclin 1, and LC3 and enhances Atg7 degradation by the proteasome pathway. Aspirin suppresses virus replication by inhibiting BEFV-induced autophagy. It directly suppressed the NF-κB pathway and reversed the BEFV-activated Src/JNK pathway at the early stage of infection and reversed the BEFV-suppressed PI3K/Akt/mTOR pathway at the late stage of infection. The current study provides mechanistic insights into the effects of aspirin and AICAR on BEFV replication through suppression of BEFV-induced autophagy.
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Affiliation(s)
- Hsu-Hung Tseng
- Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan.,Division of General Surgery, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan
| | - Wei-Ru Huang
- Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan.,The iEGG and Animal Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
| | - Ching-Yuan Cheng
- Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan
| | - Hung-Chuan Chiu
- Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan.,The iEGG and Animal Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
| | - Tsai-Ling Liao
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.,Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.,Ph.D Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Brent L Nielsen
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, United States
| | - Hung-Jen Liu
- Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan.,The iEGG and Animal Biotechnology Center, National Chung Hsing University, Taichung, Taiwan.,Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.,Ph.D Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan.,Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
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Chang MC, Kwak SG, Park JS, Park D. The effectiveness of nonsteroidal anti-inflammatory drugs and acetaminophen in reduce the risk of amyotrophic lateral sclerosis? A meta-analysis. Sci Rep 2020; 10:14759. [PMID: 32901053 PMCID: PMC7479139 DOI: 10.1038/s41598-020-71813-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 08/05/2020] [Indexed: 12/12/2022] Open
Abstract
To test the hypothesis that aspirin, non-aspirin nonsteroidal anti-infammatory drugs (NA-NSAIDs), or acetaminophen can reduce the risk of ALS, we conducted a systematic review and meta-analysis of related previous studies. A comprehensive search was conducted on the PubMed, Embase, Cochrane Library and SCOPUS databases. It included studies published up to 29 February 2020 that fulfilled our inclusion criteria. Aspirin, acetaminophen and NA-NSAIDs use information, between the ALS and control groups, was collected for the meta-analysis. Rates of aspirin, NA-NSAID, and acetaminophen use in ALS group, compared with control group were investigated. In the results, only three studies that relate the risk of ALS to aspirin, NA-NSAIDs and acetaminophen use satisfied the inclusion criteria for the meta-analysis. Regarding aspirin, the studies did not show any statistically significant difference in aspirin use between the ALS and control groups (Odds ratio, 1.04 [95% confidence interval, 0.90-1.21]). NA-NSAIDs and acetaminophen use, however, did show up statistically significant differences in between the ALS and control groups. (Odds ratio, 0.82 [95% confidence interval, 0.73-0.91]) and (Odds ratio, 0.80 [95% confidence interval, 0.69-0.93]). However, our study has some limitations. Firstly, we only included a small number of studies. Secondly, the included studies did not control for past medical history, which may have confounded their results, and in turn, could have caused bias in our study. Thirdly, in this meta-analysis, the ALS patients were not subdivided into sporadic or familial type. Lastly, the studies also did not consider the types of NSAIDs and dosages used of each drug. For more convincing evidence regarding the effectiveness of aspirin, NA-NSAIDs and acetaminophen to reduce the risk of ALS occurrence, more qualified prospective studies are required. In conclusion, the use of NA-NSAIDs and acetaminophen is associated with a decreased risk for the development of ALS. In contrast, aspirin did not have any effect on the reduction of the risk of ALS occurrence.
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Affiliation(s)
- Min Cheol Chang
- Department of Rehabilitation Medicine, College of Medicine, Yeungnam University, Daegu, Republic of Korea
| | - Sang Gyu Kwak
- Department of Medical Statistics, College of Medicine, Catholic University of Daegu, Daegu, Republic of Korea
| | - Jin-Sung Park
- Department of Neurology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea
| | - Donghwi Park
- Department of Physical Medicine and Rehabilitation, Ulsan University Hospital, University of Ulsan College of Medicine, 877, Bangeojinsunghwndo-ro, Dong-gu, Ulsan, 44033, Republic of Korea.
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Sheng J, Meng Q, Yang Z, Guan J, Zhao Y, Zhang J, Wang Y, Zhao L, Wang Y. Identification of cryptotanshinone from Tongmai to inhibit thrombosis in zebrafish via regulating oxidative stress and coagulation cascade. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 76:153263. [PMID: 32563016 DOI: 10.1016/j.phymed.2020.153263] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 05/22/2020] [Accepted: 06/03/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Thromboembolic events are leading causes of mortality and morbidity all over the world. Tongmai (TM) is a botanical drug with valid clinical efficacy and safety in the management of thrombosis and ischemic cardiovascular diseases, however, its active compounds and underlying mechanism are largely unclear. PURPOSE To investigate the endogenous effects, therapeutic mechanism and active compounds of TM in thrombus formation. STUDY DESIGN Combined with transgenic zebrafish models and high-content imaging system, this study evaluated the endogenous antithrombotic effects of TM and screened for the active compounds. METHODS The PHZ-induced thrombotic model in erythrocytes or platelets labeled transgenic zebrafish were established, to dynamically evaluate the antithrombotic effects of TM. The oxidative damage levels were analyzed by specific fluorescent probes, and the expression levels of key factors in coagulation cascades and platelet activation were examined by QPCR. TM were dissected into fractions by reverse phase chromatography and subsequently screened for their antithrombotic effects in the transgenic fish models. The compounds of the active TM fraction were then analyzed by UPLC-Q-TOF analysis and further verified for their antithrombotic effects and mechanisms. RESULTS In PHZ-induced zebrafish thrombotic model, TM incubation markedly increased cardiac blood flow, decreased peripheral erythrocytes aggregation, and recovered peripheral platelet circulation. Besides, the levels of oxidative stress and lipid peroxidation were increased in the PHZ-induced thrombotic fish, which were greatly decreased by TM treatment. Moreover, TM significantly reduced the expression of coagulation factor II (thrombin) and the downstream fibrinogen. In order to identify the active compounds of TM, four fractions were separated from the extract by reverse phase chromatography, which were subsequently screened for their antithrombotic effects in the fish model. As a result, fraction 4 showed the strongest effect in inhibiting thrombosis. Finally, through UPLC-Q-TOF analysis and endogenous screening, cryptotanshione was identified as the main active compound with antithrombotic effects. CONCLUSION Our study demonstrated the endogenous antithrombotic effects of TM, which is possibly mediated by inhibiting oxidative stress and coagulation cascade. Cryptotanshione was identified as a major compound with antithrombotic activity and is a promising candidate for novel antithrombotic therapy.
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Affiliation(s)
- Jian Sheng
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Qingfen Meng
- Henan Fusen Pharmaceutical Co., Ltd., Nanyang, 474450, China
| | - Zhenzhong Yang
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jianli Guan
- Henan Fusen Pharmaceutical Co., Ltd., Nanyang, 474450, China
| | - Yu Zhao
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jide Zhang
- Henan Fusen Pharmaceutical Co., Ltd., Nanyang, 474450, China
| | - Yingchao Wang
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Lu Zhao
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
| | - Yi Wang
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
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Patrono C, Rocca B. Measurement of Thromboxane Biosynthesis in Health and Disease. Front Pharmacol 2019; 10:1244. [PMID: 31736753 PMCID: PMC6832017 DOI: 10.3389/fphar.2019.01244] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 09/27/2019] [Indexed: 12/17/2022] Open
Abstract
Thromboxane (TX) A2 is a chemically unstable lipid mediator involved in several pathophysiologic processes, including primary hemostasis, atherothrombosis, inflammation, and cancer. In human platelets, TXA2 is the major arachidonic acid derivative via the cyclooxygenase (COX)-1 pathway. Assessment of platelet TXA2 biosynthesis can be performed ex vivo through measurement of serum TXB2, an index of platelet COX-1 activity, as well as in vivo through measurement of urinary enzymatic metabolites, a non-invasive index of platelet activation. This article reviews the main findings of four decades of clinical investigation based on these analytical approaches, focusing on the measurement of TXA2 metabolites to characterize the pathophysiologic role of transiently or persistently enhanced platelet activation and to describe the clinical pharmacology of COX-1 inhibition in health and disease.
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Affiliation(s)
- Carlo Patrono
- Department of Pharmacology, Catholic University School of Medicine, Rome, Italy
| | - Bianca Rocca
- Department of Pharmacology, Catholic University School of Medicine, Rome, Italy
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Nyachieo A, Siristatidis CS, Vaidakis D, Cochrane Gynaecology and Fertility Group. Nonsteroidal anti-inflammatory drugs for assisted reproductive technology. Cochrane Database Syst Rev 2019; 10:CD007618. [PMID: 31628860 PMCID: PMC6800564 DOI: 10.1002/14651858.cd007618.pub2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Despite substantial improvements in the success of treatments through assisted reproduction technologies (ART), live birth rates remain constantly low, and practitioners are seeking aetiologic treatments to improve the outcomes.Local inflammatory response is believed to contribute to implantation failure, where prostaglandins may increase uterine contractions and decrease uterine receptivity, decreasing the possibility of an IVF cycle leading to successful embryo transfer. In this context, nonsteroidal anti-inflammatory drugs (NSAIDs) have been employed to inhibit the negative prostaglandin effect. They are often offered in clinical practice to improve ART outcomes, but current robust evidence on their efficacy is lacking. OBJECTIVES To evaluate the effectiveness and safety of nonsteroidal anti-inflammatory drugs as co-treatments in infertile women undergoing assisted reproduction, in terms of improving live birth and miscarriage rates. SEARCH METHODS We designed the search using standard Cochrane methods and performed it on databases from their inception to 20 February 2019.We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL via the Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, and the trial registers for ongoing and registered trials, grey literature and treatment guidelines. We handsearched reference lists of relevant systematic reviews and RCTs, and PubMed and Google for any recent trials. There were no restrictions by language or country of origin. SELECTION CRITERIA All RCTs on the use of NSAIDs as co-treatment during an ART cycle compared with no use or the use of placebo or any other similar drug, along with the comparison of any NSAID to another. DATA COLLECTION AND ANALYSIS We used standard methodological procedures recommended by Cochrane. Our primary outcomes were live birth/ongoing pregnancy and miscarriage. We performed statistical analysis using Review Manager 5. We assessed evidence quality using GRADE methods. MAIN RESULTS We found 11 RCTs (1884 women) suitable for inclusion in the review. Most studies were at unclear or high risk of bias. The main limitations in the overall quality of the evidence were high risk of bias, unexplained heterogeneity and serious imprecision and indirectness.There were no data on our primary outcome - live birth per woman randomised - in any review comparisons.NSAIDs vs. placebo/no treatmentWe are uncertain of an effect on ongoing pregnancy when NSAIDs were compared to placebo/no treatment (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.71 to 1.59; 4 studies, 1159 participants; I² = 53%; very low quality evidence). Results suggest that if the chance of ongoing pregnancy following placebo or no treatment is assumed to be 15%, the chance following the use of NSAIDs is estimated to be between 12% and 24%. Subgroup analysis according to the type of NSAID yielded similar results.We are also uncertain of an effect on miscarriage rates when NSAIDs were compared to placebo/no treatment (RR 0.62, 95% CI 0.33 to 1.16; 4 studies, 525 participants; I² = 43%; very low quality evidence). Results suggest that if the chance of miscarriage following placebo or no treatment is assumed to be 21%, the chance following the use of NSAIDs is estimated to be between 7% and 27%. The results were similar when two studies were excluded due to high risk of bias.Concerning the secondary outcomes, we are uncertain of an effect on clinical pregnancy rates (RR 1.23, 95% CI 1.00 to 1.52; 6 studies, 1570 participants; I² = 49%; low-quality evidence); on ectopic pregnancy (RR 0.56, 95% CI 0.05 to 5.89; 1 study, 72 participants); on multiple pregnancy (RR 2.00, 95% CI 0.18 to 21.67; 1 study, 180 participants); and on side effects (RR 1.39, 95% CI 0.02 to 119.35; 3 studies, 418 participants; I² = 79%). The evidence suggests that if the chance of clinical pregnancy following placebo or no treatment is assumed to be 30%, the chance following the use of NSAIDs is estimated to be between 31% and 45%. If the chance of ectopic pregnancy following placebo or no treatment is assumed to be 5%, the chance following the use of NSAIDs is estimated to be between 0.3% and 31%. If the chance of multiple pregnancy following placebo or no treatment is assumed to be 1%, the chance following the use of NSAIDs is estimated to be between 0.2 % and 24%.There were no cases of congenital anomalies during antenatal ultrasound screening of the women in one study.NSAID vs. another NSAIDOnly one study compared piroxicam with indomethacin: we are uncertain of an effect on ongoing pregnancy (RR 1.12, 95% CI 0.63 to 2.00; 1 study, 170 participants; very low quality evidence); and on miscarriage (RR 1.00, 95% CI 0.44 to 2.28; 1 study, 170 participants; very low quality evidence). The evidence suggests that if the chance of ongoing pregnancy following indomethacin is assumed to be 20%, the chance following the use of piroxicam is estimated to be between 13% and 40%; while for miscarriage, the evidence suggests that if the chance following indomethacin is assumed to be 12%, the chance following the use of piroxicam is estimated to be between 5% and 27%.Similar results were reported for clinical pregnancy (RR 1.07, 95% CI 0.71 to 1.63; 1 study, 170 participants; very low quality evidence).There were no data for the other outcomes specified in this review.NSAID vs. aspirinNo study reported this comparison. AUTHORS' CONCLUSIONS Currently we are uncertain of an effect of the routine use of NSAIDs as co-treatments in infertile women undergoing assisted reproduction in order to improve ongoing pregnancy and miscarriage rates. This is based on available data from RCTs, where very low quality evidence showed that there is no single outcome measure demonstrating a benefit with their use. Further large, well-designed randomised placebo-controlled trials reporting on live births are required to clarify the exact role of NSAIDs.
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Affiliation(s)
- Atunga Nyachieo
- Institute of Primate ResearchReproductive health and BiologyPOBox 24481‐00502KarenNairobiKenya
- University of NairobiDepartment of BiochemistryNairobiKenya
| | - Charalampos S Siristatidis
- Medical School, National and Kapodistrian University of AthensAssisted Reproduction Unit, 3rd Department of Obstetrics and GynaecologyAttikon University HospitalRimini 1AthensChaidariGreece12462
| | - Dennis Vaidakis
- University of Athens3rd Department of Obstetrics and Gynecology'Attikon' Hospital, ChaidariAthensGreece
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Choi S, Snider AJ. Diet, lipids and colon cancer. CELLULAR NUTRIENT UTILIZATION AND CANCER 2019; 347:105-144. [DOI: 10.1016/bs.ircmb.2019.07.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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10
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Kweon OJ, Lim YK, Kim B, Lee MK, Kim HR. Effectiveness of Platelet Function Analyzer-100 for Laboratory Detection of Anti-Platelet Drug-Induced Platelet Dysfunction. Ann Lab Med 2018; 39:23-30. [PMID: 30215226 PMCID: PMC6143472 DOI: 10.3343/alm.2019.39.1.23] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 05/24/2018] [Accepted: 08/16/2018] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND High on-treatment platelet reactivity (HTPR) is the phenomenon wherein patients exhibit normal platelet activity in laboratory testing despite adequate adherence to anti-platelet treatment. We investigated the detection rates of Platelet Function Analyzer (PFA)-100 (Dade Behring AG, Düdingen, Switzerland) for drug-induced platelet dysfunction and analyzed potential contributors to HTPR with practical PFA-100 data over six years. METHODS We used data from 6,957 patients who underwent PFA-100 testing after receiving aspirin, clopidogrel, or non-steroidal anti-inflammatory drugs (NSAIDs). Of these, 6,163 patients were tested with only the collagen/epinephrine cartridge (Col/EPI) of PFA-100; 794 were tested with both Col/EPI and the collagen/ADP cartridge (Col/ADP). We calculated PFA-100 closure time (CT) for each drug and compared the clinical and laboratory characteristics of the patients with prolonged CTs and normal CTs (i.e., HTPR). RESULTS In Col/EPI, 73.2% (365/499), 72.6% (390/537), and 55.3% (3,442/6,228) patients showed prolonged CTs for aspirin, clopidogrel, and NSAIDs, respectively. In Col/ADP, prolonged CTs were observed in 37.4% (34/91), 43.2% (35/81), and 29.6% (200/676) of patients receiving aspirin, clopidogrel, and NSAIDs, respectively. Of the patients tested with both cartridges, 88.9% (48/54), 95.3% (41/43), and 89.0% (577/648) of the patients receiving aspirin, clopidogrel, and NSAIDs had prolonged CTs, and 10.0% (79/794) showed normal CTs regardless of drugs. For clopidogrel users (both cartridges), there were more patients with malignancies in the normal CT than prolonged CT group. CONCLUSIONS PFA-100 is not sufficiently effective for laboratory screening of drug-induced platelet dysfunction. Malignancy may contribute to clopidogrel-related HTPR in PFA-100.
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Affiliation(s)
- Oh Joo Kweon
- Department of Laboratory Medicine, Aerospace Medical Center, Republic of Korea Air Force, Cheongju, Korea.,Department of Laboratory Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Yong Kwan Lim
- Department of Laboratory Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Bohyun Kim
- Department of Laboratory Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Mi Kyung Lee
- Department of Laboratory Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Hye Ryoun Kim
- Department of Laboratory Medicine, Chung-Ang University College of Medicine, Seoul, Korea.
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11
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Tarnawski AS, Ahluwalia A. Increased susceptibility of aging gastric mucosa to injury and delayed healing: Clinical implications. World J Gastroenterol 2018; 24:4721-4727. [PMID: 30479459 PMCID: PMC6235800 DOI: 10.3748/wjg.v24.i42.4721] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 10/12/2018] [Accepted: 10/21/2018] [Indexed: 02/06/2023] Open
Abstract
In this editorial we comment on the article by Fukushi K et al published in the recent issue of the World Journal of Gastroenterology 2018; 24(34): 3908-3918. We focus specifically on the mechanisms of the anti-thrombotic action of aspirin, gastric mucosal injury and aging-related increased susceptibility of gastric mucosa to injury. Aspirin is widely used not only for the management of acute and chronic pain and arthritis, but also importantly for the primary and secondary prevention of cardiovascular events such as myocardial infarcts and strokes. Clinical trials have consistently shown that antiplatelet therapy with long term, low dose aspirin (LDA) - 75 to 325 mg daily, dramatically reduces the risk of non-fatal myocardial infarcts, stroke and mortality in patients with established arterial diseases. However, such treatment considerably increases the risk of gastrointestinal (GI) ulcerations and serious bleeding by > 2-4 fold, especially in aging individuals. This risk is further increased in patients using LDA together with other antiplatelet agents, other nonsteroidal anti-inflammatory agents (NSAIDs) and/or alcohol, or in patients with Helicobacter pylori (H. pylori) infection. Previous studies by our group and others have demonstrated prominent structural and functional abnormalities in gastric mucosa of aging individuals (which we refer to as aging gastric mucosa or "aging gastropathy") compared to the gastric mucosa of younger individuals. Aging gastric mucosa has impaired mucosal defense, increased susceptibility to injury by a variety of noxious agents such as aspirin, other NSAIDs and ethanol, and delayed and impaired healing of injury. The mechanism underlying these abnormalities of aging gastric mucosa include reduced mucosal blood flow causing hypoxia, upregulation of PTEN, activation of pro-apoptotic caspase-3 and caspase-9, and reduced survivin (anti-apoptosis protein), importin-α (nuclear transport protein), vascular endothelial growth factor, and nerve growth factor. The decision regarding initiation of a long-term LDA therapy should be made after a careful consideration of both cardiovascular and GI risk factors. The latter include a previous history of GI bleeding and/or ulcers, age ≥ 70, male gender, concurrent use of other NSAIDs, alcohol consumption and H. pylori infection. Furthermore, the incidence of GI ulcers and bleeding can be reduced in patients on long term LDA treatment by several measures. Clinicians treating such patients should test for and eradicate H. pylori, instruct patients to avoid alcohol and non-aspirin NSAIDs, including cyclooxygenase-2-selective NSAIDs, and prescribe proton pump inhibitors in patients on LDA therapy. In the future, clinicians may be able to prescribe one of several potential new drugs, which include aspirin associated with phosphatidylcholine (PL2200), which retains all property of aspirin but reduces by approximately 50% LDA-induced GI ulcerations.
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Affiliation(s)
- Andrzej S Tarnawski
- Department of Gastroenterology Research, University of California Irvine and the Veterans Administration Long Beach Healthcare System, Long Beach, CA 90822, United States
| | - Amrita Ahluwalia
- Department of Gastroenterology Research, University of California Irvine and the Veterans Administration Long Beach Healthcare System, Long Beach, CA 90822, United States
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12
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Thiel C, Smit I, Baier V, Cordes H, Fabry B, Blank LM, Kuepfer L. Using quantitative systems pharmacology to evaluate the drug efficacy of COX-2 and 5-LOX inhibitors in therapeutic situations. NPJ Syst Biol Appl 2018; 4:28. [PMID: 30083389 PMCID: PMC6072773 DOI: 10.1038/s41540-018-0062-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 05/07/2018] [Accepted: 05/18/2018] [Indexed: 02/07/2023] Open
Abstract
A quantitative analysis of dose-response relationships is essential in preclinical and clinical drug development in order to optimize drug efficacy and safety, respectively. However, there is a lack of quantitative understanding about the dynamics of pharmacological drug-target interactions in biological systems. In this study, a quantitative systems pharmacology (QSP) approach is applied to quantify the drug efficacy of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors by coupling physiologically based pharmacokinetic models, at the whole-body level, with affected biological networks, at the cellular scale. Both COX-2 and 5-LOX are key enzymes in the production of inflammatory mediators and are known targets in the design of anti-inflammatory drugs. Drug efficacy is here evaluated for single and appropriate co-treatment of diclofenac, celecoxib, zileuton, and licofelone by quantitatively studying the reduction of prostaglandins and leukotrienes. The impact of rifampicin pre-treatment on prostaglandin formation is also investigated by considering pharmacokinetic drug interactions with diclofenac and celecoxib, finally suggesting optimized dose levels to compensate for the reduced drug action. Furthermore, a strong correlation was found between pain relief observed in patients as well as celecoxib- and diclofenac-induced decrease in prostaglandins after 6 h. The findings presented reveal insights about drug-induced modulation of cellular networks in a whole-body context, thereby describing complex pharmacokinetic/pharmacodynamic behavior of COX-2 and 5-LOX inhibitors in therapeutic situations. The results demonstrate the clinical benefit of using QSP to predict drug efficacy and, hence, encourage its use in future drug discovery and development programs.
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Affiliation(s)
- Christoph Thiel
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany
| | - Ines Smit
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD UK
| | - Vanessa Baier
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany
| | - Henrik Cordes
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany
| | - Brigida Fabry
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany
| | - Lars Mathias Blank
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany
| | - Lars Kuepfer
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany
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13
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Singh P, Kumar R, Singh AK, Yadav P, Khanna RS, Vinayak M, Tewari AK. Synthesis and crystal structure of quinolinium salt: Assignment on nonsteroidal anti-inflammatory activity and DNA cleavage activity. J Mol Struct 2018. [DOI: 10.1016/j.molstruc.2018.02.115] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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Dayakar C, Kumar BS, Sneha G, Sagarika G, Meghana K, Ramakrishna S, Prakasham RS, China Raju B. Synthesis, pharmacological activities and molecular docking studies of pyrazolyltriazoles as anti-bacterial and anti-inflammatory agents. Bioorg Med Chem 2017; 25:5678-5691. [PMID: 28927905 DOI: 10.1016/j.bmc.2017.08.042] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 08/02/2017] [Accepted: 08/25/2017] [Indexed: 11/28/2022]
Abstract
A series of novel pyrazolyl alcohols (5a-h), pyrazolyl azides (6a-h), and pyrazolyltriazoles (8a-h, 10a-p and 12a-l) were prepared and evaluated for their bioactivity (anti-bacterial and anti-inflammatory) profile. The compound 5c displayed the potent anti-bacterial activity against Micrococcus luteus (MIC 3.9 and MBC 7.81µg/mL). In vitro anti-inflammatory activity data denoted that compound 8b is effective among the tested compounds against IL-6 (IC50 6.23μM). Docking analysis of compounds 5f, 8a-b, 8e-f and 8h displayed high binding energies for the compounds 8a-b and 8h towards TNF-α dimer (2AZ5 protein) and IL-6 (1ALU protein). In vivo anti-inflammatory activity of compounds 8b and 8h with respect to LPS induced mice model indicated that compound 8h showed significant reduction in TNF-α.
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Affiliation(s)
- Cherupally Dayakar
- Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
| | - Buddana Sudheer Kumar
- Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
| | - Galande Sneha
- Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
| | - Gudem Sagarika
- Pharmacology and Toxicology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
| | - Koneru Meghana
- Pharmacology and Toxicology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
| | - Sistla Ramakrishna
- Pharmacology and Toxicology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
| | - Reddy Shetty Prakasham
- Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
| | - Bhimapaka China Raju
- Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
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Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) include aspirin, other traditional NSAIDs, and coxibs. Evidence obtained during the past 10 years has focused attention on the cardiovascular hazard associated with coxibs and some traditional NSAIDs. The large randomized trials of prolonged coxib treatment added importantly to information provided by epidemiological studies that had previously associated regular use of NSAIDs with increased blood pressure and enhanced risk of congestive heart failure, and identified an increased risk of myocardial infarction as a class effect of cyclooxygenase-2 inhibitors. The aim of this article is to review the cardiovascular effects of aspirin, other traditional NSAIDs, and coxibs, to discuss the mechanisms underlying these effects, and to provide a clinical perspective on the cardiovascular hazard associated with their use.
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Affiliation(s)
- Carlo Patrono
- Department of Pharmacology, Catholic University School of Medicine, Largo Francesco Vito, 1, 00168, Rome, Italy.
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16
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Abstract
The use of B cell depletion as a mode of treatment for non-Hodgkin’s lymphoma was first utilized in 1997 when Rituximab, a chimeric human-mouse monoclonal antibody which has a high affinity to the CD20 antigen expressed on B cells, became available. Over 500 000 lymphoma patients have been treated worldwide with this drug and it has a good safety record. The notion that B cells might be critical to the development of rheumatoid arthritis led to the extension of the use of B cell depletion to this condition and a recent double blind controlled trial has shown very encouraging results. In addition, B cell depletion either using Rituximab alone, or in combination with cyclophosphamide and corticosteroids has also been reported to have been of great benefit in some patients with severe systemic lupus erythematosus albeit in open label studies. This review considers the mechanism of action of the drug, the clinical trials that have been reported, and tries to place its current use in patients with autoimmune rheumatic disease in context.
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Affiliation(s)
- S A Chambers
- Centre for Rheumatology, The Middlesex Hospital, University College, London, UK
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Papanagnou P, Baltopoulos P, Tsironi M. Marketed nonsteroidal anti-inflammatory agents, antihypertensives, and human immunodeficiency virus protease inhibitors: as-yet-unused weapons of the oncologists' arsenal. Ther Clin Risk Manag 2015; 11:807-19. [PMID: 26056460 PMCID: PMC4445694 DOI: 10.2147/tcrm.s82049] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Experimental data indicate that several pharmacological agents that have long been used for the management of various diseases unrelated to cancer exhibit profound in vitro and in vivo anticancer activity. This is of major clinical importance, since it would possibly aid in reassessing the therapeutic use of currently used agents for which clinicians already have experience. Further, this would obviate the time-consuming process required for the development and the approval of novel antineoplastic drugs. Herein, both pre-clinical and clinical data concerning the antineoplastic function of distinct commercially available pharmacological agents that are not currently used in the field of oncology, ie, nonsteroidal anti-inflammatory drugs, antihypertensive agents, and anti-human immunodeficiency virus agents inhibiting viral protease, are reviewed. The aim is to provide integrated information regarding not only the molecular basis of the antitumor function of these agents but also the applicability of the reevaluation of their therapeutic range in the clinical setting.
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Affiliation(s)
- Panagiota Papanagnou
- Department of Nursing, Faculty of Human Movement and Quality of Life Sciences, University of Peloponnese, Sparta, Greece
| | - Panagiotis Baltopoulos
- Department of Sports Medicine and Biology of Physical Activity, Faculty of Physical Education and Sport Science, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Tsironi
- Department of Nursing, Faculty of Human Movement and Quality of Life Sciences, University of Peloponnese, Sparta, Greece
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18
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Xin W, Huang C, Zhang X, Xin S, Zhou Y, Ma X, Zhang D, Li Y, Zhou S, Zhang D, Zhang T, Du G. Methyl salicylate lactoside inhibits inflammatory response of fibroblast-like synoviocytes and joint destruction in collagen-induced arthritis in mice. Br J Pharmacol 2015; 171:3526-38. [PMID: 24712652 DOI: 10.1111/bph.12715] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Accepted: 03/23/2014] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND AND PURPOSE Methyl salicylate 2-O-β-d-lactoside (MSL), whose chemical structure is similar to that of salicylic acid, is a natural product derivative isolated from a traditional Chinese herb. The aim of this study was to investigate the therapeutic effect of MSL in mice with collagen-induced arthritis (CIA) and explore its underlying mechanism. EXPERIMENTAL APPROACH The anti-arthritic effects of MSL were evaluated on human rheumatoid fibroblast-like synoviocytes (FLS) in vitro and CIA in mice in vivo by obtaining clinical scores, measuring hind paw thickness and inflammatory cytokine levels, radiographic evaluations and histopathological assessments. KEY RESULTS Treatment with MSL after the onset of arthritis significantly prevented the progression and development of rheumatoid arthritis (RA) in CIA mice without megascopic gastric mucosa damage. In addition, MSL inhibited the production of pro-inflammatory mediators, the phosphorylation and translocation of NF-κB, and cell proliferation induced by TNF-α in FLS. MSL non-selectively inhibited the activity of COX in vitro, but was a more potent inhibitor of COX-2 than COX-1. MSL also inhibited the phosphorylation of inhibitor of NF-κB kinase, IκBα and p65, thus blocking the nuclear translocation of NF-κB in TNF-α-stimulated FLS. CONCLUSION AND IMPLICATIONS MSL exerts therapeutic effects on CIA mice, suppressing the inflammatory response and joint destruction by non-selectively inhibiting the activity of COX and suppressing activation of the NF-κB signalling pathway, but without damaging the gastric mucosa. Therefore, MSL has great potential to be developed into a novel therapeutic agent for the treatment of RA.
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Affiliation(s)
- Wenyu Xin
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, China; Binzhou Medical University, Yantai, China
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19
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Clinical implications of prescribing nonsteroidal anti-inflammatory drugs in oral health care—a review. Oral Surg Oral Med Oral Pathol Oral Radiol 2015; 119:264-71. [DOI: 10.1016/j.oooo.2014.12.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Revised: 10/28/2014] [Accepted: 12/02/2014] [Indexed: 01/09/2023]
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Jermany J, Branson J, Schmouder R, Guillaume M, Rordorf C. Lumiracoxib Does Not Affect the Ex Vivo Antiplatelet Aggregation Activity of Low-Dose Aspirin in Healthy Subjects. J Clin Pharmacol 2013; 45:1172-8. [PMID: 16172182 DOI: 10.1177/0091270005280377] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
This randomized, double-blind, placebo-controlled study evaluated the pharmacodynamic effects of concomitant low-dose aspirin and lumiracoxib in healthy subjects. Participants received lumiracoxib 400 mg once daily (n = 14) or placebo (n = 14) for 11 days, with concomitant low-dose aspirin (75 mg once daily) from days 5 to 11. Ex vivo pharmacodynamic assessments included assays of platelet aggregation and urinary thromboxane and prostacyclin metabolite profile. Arachidonic acid-stimulated platelet aggregation was reduced from 76.3% on day 4 to 4.8% on day 11 in the placebo group and from 75.8% on day 4 to 5.1% on day 11 in the lumiracoxib group. Collagen-induced platelet aggregation was reduced from 77.5% on day 4 to 52.8% on day 11 in the placebo group and from 79.5% on day 4 to 55.9% on day 11 in the lumiracoxib group. Urinary thromboxane and prostacyclin were unaffected by lumiracoxib. In conclusion, concomitant lumiracoxib did not interfere with the cyclooxygenase-1-mediated antiplatelet effects of low-dose aspirin.
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Affiliation(s)
- J Jermany
- Exploratory Clinical Development, Novartis Pharma AG, WSJ-103-4 D, CH-4002 Basel, Switzerland
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Ibrahim S, McCartney A, Markosyan N, Smyth EM. Heterodimerization with the prostacyclin receptor triggers thromboxane receptor relocation to lipid rafts. Arterioscler Thromb Vasc Biol 2012; 33:60-6. [PMID: 23162015 DOI: 10.1161/atvbaha.112.300536] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
OBJECTIVE Prostacyclin and thromboxane mediate opposing cardiovascular actions through receptors termed IP and TP, respectively. When dimerized with IP, the TP shifts to IP-like function. IP localizes to cholesterol-enriched membrane rafts, but TP and IPTP heterodimer localization is not defined. We examined these receptors' membrane localization and the role of rafts in receptor function. METHODS AND RESULTS Microdomain distribution of IP, TP, and IPTP heterodimers was examined in COS-7 cells by measuring energy transfer from renilla luciferase-fused receptors to fluorescently labeled rafts. IP raft association was confirmed. TP was raft excluded, but redistributed to rafts upon dimerization with IP. Signaling of the IP and IPTP heterodimer, but not TP alone, was suppressed after raft disruption by cholesterol depletion. Cholesterol enrichment also selectively suppressed IP and IPTP function. Native IP and IPTP signaling in smooth muscle cells and macrophages were similarly sensitive to cholesterol manipulation, whereas macrophages from hypercholesterolemic mice displayed suppressed IP and IPTP function. CONCLUSIONS IP and TP function within distinct microdomains. Raft incorporation of TP in the IPTP heterodimer likely facilitates its signaling shift. We speculate that changes in IP and IPTP signaling after perturbation of membrane cholesterol may contribute to cardiovascular disease associated with hypercholesterolemia.
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Affiliation(s)
- Salam Ibrahim
- Institute for Translational Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Midgley RS, McConkey CC, Johnstone EC, Dunn JA, Smith JL, Grumett SA, Julier P, Iveson C, Yanagisawa Y, Warren B, Langman MJ, Kerr DJ. Phase III Randomized Trial Assessing Rofecoxib in the Adjuvant Setting of Colorectal Cancer: Final Results of the VICTOR Trial. J Clin Oncol 2010; 28:4575-80. [DOI: 10.1200/jco.2010.29.6244] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose Laboratory and case-control studies suggest a pivotal role for the cyclooxygenase-2 (COX-2) pathway in colorectal carcinogenesis. The purpose of this study was to test whether the COX-2 inhibitor rofecoxib could reduce recurrence and improve survival when administered in the adjuvant setting of colorectal cancer (CRC). Patients and Methods Patients who had undergone potentially curative surgery and completion of adjuvant therapy for stage II and III CRC were randomly assigned to receive rofecoxib (20 mg daily) or placebo. The primary end point was overall survival (OS). Where formalin-fixed paraffin-embedded tumor tissue samples were available, COX-2 expression was evaluated by immunohistochemistry and correlated with clinical outcome. Results Two thousand four hundred thirty-four patients were entered onto the study. The trial was terminated early because of the worldwide withdrawal of rofecoxib. At this point, 1,167 patients had received rofecoxib and 1,160 patients had received placebo for median treatment durations of 7.4 and 8.2 months, respectively. For the rofecoxib and placebo arms, median follow-up times were 4.84 and 4.85 years, with 241 and 246 deaths and 297 and 329 recurrences, respectively. No difference was demonstrated in OS (hazard ratio [HR] = 0.97; 95% CI, 0.81 to 1.16; P = .75) or recurrence (HR = 0.89; 95% CI, 0.76 to 1.04; P = .15) comparing the two groups. Tumor COX-2 expression by immunohistochemistry was assessed for 871 patients, but neither prognostic nor predictive effects were observed. Conclusion In this study of abbreviated therapy in the adjuvant setting of CRC, rofecoxib did not improve OS or protect from recurrence in unselected patients. In addition, COX-2 expression did not correlate with prognosis overall or predict effectiveness of COX-2 inhibitors.
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Affiliation(s)
- Rachel S. Midgley
- From the University of Oxford; Oxford Radcliffe Hospitals Trust, Oxford; University of Warwick, Coventry; and Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom
| | - Christopher C. McConkey
- From the University of Oxford; Oxford Radcliffe Hospitals Trust, Oxford; University of Warwick, Coventry; and Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom
| | - Elaine C. Johnstone
- From the University of Oxford; Oxford Radcliffe Hospitals Trust, Oxford; University of Warwick, Coventry; and Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom
| | - Janet A. Dunn
- From the University of Oxford; Oxford Radcliffe Hospitals Trust, Oxford; University of Warwick, Coventry; and Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom
| | - Justine L. Smith
- From the University of Oxford; Oxford Radcliffe Hospitals Trust, Oxford; University of Warwick, Coventry; and Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom
| | - Simon A. Grumett
- From the University of Oxford; Oxford Radcliffe Hospitals Trust, Oxford; University of Warwick, Coventry; and Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom
| | - Patrick Julier
- From the University of Oxford; Oxford Radcliffe Hospitals Trust, Oxford; University of Warwick, Coventry; and Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom
| | - Claire Iveson
- From the University of Oxford; Oxford Radcliffe Hospitals Trust, Oxford; University of Warwick, Coventry; and Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom
| | - Yoko Yanagisawa
- From the University of Oxford; Oxford Radcliffe Hospitals Trust, Oxford; University of Warwick, Coventry; and Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom
| | - Bryan Warren
- From the University of Oxford; Oxford Radcliffe Hospitals Trust, Oxford; University of Warwick, Coventry; and Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom
| | - Michael J. Langman
- From the University of Oxford; Oxford Radcliffe Hospitals Trust, Oxford; University of Warwick, Coventry; and Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom
| | - David J. Kerr
- From the University of Oxford; Oxford Radcliffe Hospitals Trust, Oxford; University of Warwick, Coventry; and Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom
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Ibrahim S, Tetruashvily M, Frey AJ, Wilson SJ, Stitham J, Hwa J, Smyth EM. Dominant negative actions of human prostacyclin receptor variant through dimerization: implications for cardiovascular disease. Arterioscler Thromb Vasc Biol 2010; 30:1802-9. [PMID: 20522800 PMCID: PMC2924460 DOI: 10.1161/atvbaha.110.208900] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Prostacyclin and thromboxane mediate opposing cardiovascular effects through their receptors, the prostacyclin receptor (IP) and thromboxane receptor (TP). Individuals heterozygous for an IP variant, IP(R212C), displayed exaggerated loss of platelet IP responsiveness and accelerated cardiovascular disease. We examined association of IP(R212C) into homo- and heterodimeric receptor complexes and the impact on prostacyclin and thromboxane biology. METHODS AND RESULTS Dimerization of the IP, IP(R212C), and TPalpha was examined by bioluminesence resonance energy transfer in transfected HEK293 cells. We observed an equal propensity for formation of IPIP homodimers and IPTPalpha heterodimers. Compared with the IP alone, IP(R212C) displayed reduced cAMP generation and increased endoplasmic reticulum localization but underwent normal homo- and heterodimerization. When the IP(R212C) and IP were coexpressed, a dominant negative action of the variant was evident with enhanced wild-type IP localization to the endoplasmic reticulum and reduced agonist-dependent signaling. Further, the TPalpha activation response, which was shifted from inositol phosphate to cAMP generation following IPTPalpha heterodimerization, was normalized when the TPalpha instead dimerized with IP(R212C). CONCLUSIONS IP(R212C) exerts a dominant action on the wild-type IP and TPalpha through dimerization. This likely contributes to accelerated cardiovascular disease in individuals carrying 1 copy of the variant allele.
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Affiliation(s)
- Salam Ibrahim
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania
| | - Mazell Tetruashvily
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania
| | - Alex J Frey
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania
| | - Stephen J Wilson
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania
| | | | - John Hwa
- Yale University School of Medicine
| | - Emer M Smyth
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania
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Kawabe JI, Ushikubi F, Hasebe N. Prostacyclin in Vascular Diseases - Recent Insights and Future Perspectives -. Circ J 2010; 74:836-43. [DOI: 10.1253/circj.cj-10-0195] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Jun-ichi Kawabe
- Departments of Cardiovascular Regeneration and Innovation, Asahikawa Medical College
| | | | - Naoyuki Hasebe
- Departments of Cardiovascular Regeneration and Innovation, Asahikawa Medical College
- Department of Internal Medicine, Cardiovascular, Respiratory and Neurology Division, Asahikawa Medical College
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Rostom A, Muir K, Dube C, Lanas A, Jolicoeur E, Tugwell P. Prevention of NSAID-related upper gastrointestinal toxicity: a meta-analysis of traditional NSAIDs with gastroprotection and COX-2 inhibitors. DRUG HEALTHCARE AND PATIENT SAFETY 2009; 1:47-71. [PMID: 21701610 PMCID: PMC3108684 DOI: 10.2147/dhps.s4334] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2009] [Indexed: 12/26/2022]
Abstract
Background: Traditional NSAIDs (tNSAIDs) and COX-2 inhibitors (COX-2s) are important agents for the treatment of a variety or arthritic conditions. The purpose of this study was to systematically review the effectiveness of misoprostol, H2-receptor antagonists (H2RAs), and proton pump inhibitors (PPIs) for the prevention of tNSAID related upper gastrointestinal (GI) toxicity, and to review the upper gastrointestinal (GI) safety of COX-2s. Methods: An extensive literature search was performed to identify randomized controlled trials (RCTs) of prophylactic agents used for the prevention of upper GI toxicity, and RCTs that assessed the GI safety of the newer COX-2s. Meta-analysis was performed in accordance with accepted techniques. Results: 39 gastroprotection and 69 COX-2 RCTs met inclusion criteria. Misoprostol, PPIs, and double doses of H2RAs are effective at reducing the risk of both endoscopic gastric and duodenal tNSAID-induced ulcers. Standard doses of H2RAs are not effective at reducing the risk of tNSAID-induced gastric ulcers, but reduce the risk of duodenal ulcers. Misoprostol is associated with greater adverse effects than the other agents, particularly at higher doses. COX-2s are associated with fewer endoscopic ulcers and clinically important ulcer complications, and have fewer treatment withdrawals due to GI symptoms than tNSAIDS. Acetylsalicylic acid appears to diminish the benefit of COX-2s over tNSAIDs. In high risk GI patients, tNSAID with a PPI or a COX-2 alone appear to offer similar GI safety, but a strategy of a COX-2 with a PPI appears to offer the greatest GI safety. Conclusion: Several strategies are available to reduce the risk of upper GI toxicity with tNSAIDs. The choice between these strategies needs to consider patients’ underlying GI and cardiovascular risk.
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Affiliation(s)
- Alaa Rostom
- University of Calgary, Calgary, Alberta, Canada
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Abstract
Over recent years it has become clear that patients with inflammatory rheumatic diseases are at increased risk of developing atherosclerosis. The exact causes for this are probably related in part to a general adverse effect of inflammation on atherogenesis, and in part to immune mechanisms specific to individual rheumatic diseases. This review discusses proposed mechanisms of accelerated atherosclerosis, including abnormal lipid and lipoprotein profiles, oxidative stress, enhanced apoptosis, thrombophilia, immune complexes, and increased mononuclear cell infiltration of atherosclerotic lesions, and local generation of cytokines.
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Affiliation(s)
- D O Haskard
- The Eric Bywaters Centre for Vascular Inflammation, Imperial College London, Hammersmith Hospital, United Kingdom.
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Rostom A, Moayyedi P, Hunt R. Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: benefits versus risks. Aliment Pharmacol Ther 2009; 29:481-96. [PMID: 19053986 DOI: 10.1111/j.1365-2036.2008.03905.x] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, but are not without risks. AIM To provide evidence-based management recommendations to help clinicians determine optimal long-term NSAID therapy and the need for gastroprotective strategies based on an assessment of both gastrointestinal (GI) and cardiovascular (CV) risks. METHODS A multidisciplinary group of 21 voting participants revised and voted on the statements and the strength of evidence (assessed according to GRADE) at a consensus meeting. RESULTS An algorithmic approach was developed to help manage patients who require long-term NSAID therapy. The use of low-dose acetylsalicylic acid in patients with high CV risk was assumed. For patients at low GI and CV risk, a traditional NSAID alone may be acceptable. For patients with low GI risk and high CV risk, full-dose naproxen may have a lower potential for CV risk than other NSAIDs. In patients with high GI and low CV risk, a COX-2 inhibitor plus a proton pump inhibitor (PPI) may offer the best GI safety profile. When both GI and CV risks are high and NSAID therapy is absolutely necessary, risk should be prioritized. If the primary concern is GI risk, a COX-2 inhibitor plus a PPI is recommended; if CV risk, naproxen 500 mg b.d. plus a PPI would be preferred. NSAIDs should be used at the lowest effective dose for the shortest possible duration. CONCLUSION More large, long-term trials that examine clinical outcomes of complicated and symptomatic upper and lower GI ulcers are needed.
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Affiliation(s)
- A Rostom
- Division of Gastroenterology, University of Calgary Medical Clinic, AB, Canada.
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Wilson SJ, Cavanagh CC, Lesher AM, Frey AJ, Russell SE, Smyth EM. Activation-dependent stabilization of the human thromboxane receptor: role of reactive oxygen species. J Lipid Res 2009; 50:1047-56. [PMID: 19151335 DOI: 10.1194/jlr.m800447-jlr200] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Thromboxane A(2) (TxA(2)), the principle product of platelet COX-1-dependent arachidonic acid metabolism, directs multiple pro-atherogenic processes via its receptor, TP. Oxidative challenge offsets TP degradation, a key component in limiting TxA(2)'s actions. Following TP activation, we observed cellular reactive oxygen species (ROS) generation coincident with increased TP expression. We examined the link between TP-evoked ROS and TP regulation. TP expression was augmented in TPalpha-transfected cells treated with a TxA(2) analog [1S-1alpha,2beta(5Z),3alpha(1E,3R*),4alpha]]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-heptenoic acid (IBOP). This was reduced with a cellular antioxidant, N-acetyl cysteine, or two distinct NADPH oxidase inhibitors, diphenyleneiodonium and apocynin. Homologous upregulation of the native TP was also reduced in apocynin-treated aortic smooth muscle cells (ASMCs) and was absent in ASMCs lacking an NADPH oxidase subunit (p47(-/-)). TP transcription was not increased in IBOP-treated cells, indicating a posttranscriptional mechanism. IBOP induced translocation of TPalpha to the Golgi and reduced degradation of the immature form of the receptor. These data are consistent with a ROS-dependent mechanism whereby TP activation enhanced TP stability early in posttranscriptional biogenesis. Given the significant role played by TP and ROS in perturbed cardiovascular function, the convergence of TP on ROS-generating pathways for regulation of TxA(2)-dependent events may be critical for cardiovascular disease.
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Affiliation(s)
- Stephen J Wilson
- Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA
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Abstract
BACKGROUND Because of the prominence of pain-related conditions and the growing complexities of clinical management we aimed to explore and attempt to dispel the several myths that surround these serious therapeutic issues. AIMS We aimed to provide a careful analysis of the evidence and draw factually based guidance for physicians who manage the broad range of patients with pain. METHODS Current myths were identified based on the authors' clinical, scientific, and academic experience. Each contributor addressed specific topics and made his own selection of primary references and systematic reviews by searching in MEDLINE, EMBASE, and CINAHL databases (1990-2008) as well as in the proceedings of the major digestive and rheumatology meetings. The writing and references provided by each contributor were collectively analyzed and discussed by all authors during several meetings until the final manuscript was prepared and approved. RESULTS Seven major 'historical' myths that may perpetuate habits and beliefs in clinical practice were identified. Each of them was thoroughly examined and dispelled, drawing conclusions that should help guide physicians to better manage patients with pain. CONCLUSIONS Pain relief must be considered a human right, and patients with osteoarthritis pain should be treated appropriately with analgesic or/and anti-inflammatory drugs. The risk of gastrointestinal (GI) complications with traditional non-steroidal anti-inflammatory drugs (t-NSAIDs) is present from the first dose (with both short-term and long-term use), and strategies to prevent GI complications should be considered regardless of the duration of therapy. Compared with t-NSAIDs, coxib use is associated with a small but significant reduction of dyspepsia. While protecting the stomach, proton pump inhibitors do not prevent NSAID-induced intestinal damage. To this end, coxib therapy could be the preferred option, although further randomized studies are needed. A substantial number of patients who need NSAIDs are also taking low-dose aspirin for cardiovascular prophylaxis. From a GI perspective, the combination of aspirin plus a coxib provides a preferred option compared with aspirin plus a t-NSAID, for patients at high GI risk. As the incidence of renovascular adverse effects with t-NSAIDs and coxibs is similar, blood pressure should be monitored and managed appropriately in patients taking these drugs, although they should be avoided in those with severe congestive heart failure. Due to increased cardiovascular risk, which is dependent on the dose, duration of therapy, and base-line cardiovascular risk, both t-NSAIDs and coxibs should be used with caution in patients with underlying prothrombotic states and/or concomitant cardiovascular risk factors.
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Affiliation(s)
- Richard H Hunt
- McMaster University Medical Centre, Hamilton, Ontario, Canada
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Terán Estrada L. [Not Available]. REUMATOLOGIA CLINICA 2008; 4:107-114. [PMID: 21794510 DOI: 10.1016/s1699-258x(08)71813-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2005] [Accepted: 01/30/2008] [Indexed: 05/31/2023]
Affiliation(s)
- Leobardo Terán Estrada
- Servicio de Medicina Interna. Hospital General de Zona Morelia. Morelia. Michoacán. Instituto Mexicano del Seguro Social. México
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Brune K, Katus HA, Moecks J, Spanuth E, Jaffe AS, Giannitsis E. N-terminal pro-B-type natriuretic peptide concentrations predict the risk of cardiovascular adverse events from antiinflammatory drugs: a pilot trial. Clin Chem 2008; 54:1149-57. [PMID: 18451314 DOI: 10.1373/clinchem.2007.097428] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND we investigated whether higher concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) predicts cardiovascular adverse events (CV-AEs) in patients with osteoarthritis treated with antiinflammatory drugs. METHODS NT-proBNP was measured in baseline samples from 433 patients enrolled in a prospective randomized study designed to test the therapeutic effect of a novel metalloproteinase inhibitor. We monitored CV-AEs and retrospectively investigated their relationship to the concomitant use of selective cyclooxygenase-2 inhibitors (coxibs), traditional nonsteroidal antiinflammatory drugs (tNSAIDs), and glucocorticoids. CV-AEs included myocardial infarction, stroke, new or worsening of preexisting arterial hypertension, congestive heart failure, and several less severe CV-AEs. RESULTS we observed 82 mild to serious CV-AEs during an observational period of 200 days. The risk of such events was 1.95-fold higher in patients who were taking tNSAIDs, glucocorticoids, or coxibs (i.e., any inhibitor) and who had NT-proBNP concentrations > or = 100 ng/L than in patients taking any inhibitor who had NT-proBNP values <100 ng/L (P < 0.05). Patients taking coxibs (alone or in addition to tNSAIDs or glucocorticoids) with baseline NT-proBNP values > or = 100 ng/L had a 7.41-fold higher risk for CV-AEs than those with baseline values <100 ng/L (P < 0.01). Patients who were taking 2 or more antiinflammatory drugs and had NT-proBNP values > or = 100 ng/L had a 3.74-fold higher risk for CV-AEs than those with NT-proBNP values <100 ng/L (P < 0.05). An NT-proBNP value <100 ng/L was associated with negative predictive values of >85% across all treatment groups. CONCLUSIONS NT-proBNP may be a useful marker for anticipating cardiovascular risk associated with the use of antiinflammatory drugs for osteoarthritis.
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Affiliation(s)
- Kay Brune
- Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
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Abstract
OBJECTIVES Some studies have recently suggested a potential pharmacodynamic interaction between aspirin and some non-selective non-steroidal anti-inflammatory drugs (NSAIDs). We have evaluated the reality of this pharmacodynamic interaction and analyse its clinical pertinence. METHODS Literature review (Medline search - December 2005). RESULTS Several ex vivo studies show that some non-selective NSAIDs can block the active site of Cox1 thus preventing aspirin from exerting its platelet anti-aggregating cardio-preventive action. Cox2 selective molecules do not act at this site. The few studies, mainly case reports, have analysed the potential loss of the cardiovascular preventive benefit of aspirin in patients receiving concomitantly non-selective anti-inflammatory drugs with controversial results. IN PRACTICE It seems necessary to know the existence of this pharmacodynamic interaction between aspirin at a low dose and some non-selective anti-inflammatory drugs notably ibuprofen and naproxen. In the absence of a clear clinical demonstration, it is advisable to avoid the non-selective NSAIDs in patients treated with a low dose of aspirin. It might be advisable to switch to an anti-aggregating treatment other than aspirin (clopidrogel, etc.) in these cases. At the present time, however, there are no data on which to base such a recommendation.
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Rahme E, Watson DJ, Kong SX, Toubouti Y, LeLorier J. Association between nonnaproxen NSAIDs, COX-2 inhibitors and hospitalization for acute myocardial infarction among the elderly: a retrospective cohort study. Pharmacoepidemiol Drug Saf 2007; 16:493-503. [PMID: 17086567 DOI: 10.1002/pds.1339] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
PURPOSE To evaluate the association between rofecoxib, celecoxib, diclofenac, and ibuprofen and the risk of hospitalization for acute myocardial infarction (AMI) in an elderly population. METHODS We conducted a retrospective cohort study, using data from the government of Quebec health insurance agency databases, among patients 65-80 years of age who filled a prescription for any of the study drugs during 1999-2002. Cox regression models with time-dependent exposure were used to compare the incidence rates of hospitalization for AMI adjusting for patients' baseline characteristics. Analyses stratified by dose and number of supplied days were also conducted. RESULTS At the index date, a total of 91 062 patients were taking rofecoxib, 127 928 celecoxib, 49 193 diclofenac, and 15 601 ibuprofen. The adjusted hazard ratio (HR) (95%CI) of hospitalization for AMI were: celecoxib versus rofecoxib: 0.90 (0.79, 1.01); ibuprofen versus rofecoxib: 0.95 (0.65, 1.37); diclofenac versus rofecoxib: 1.01 (0.84, 1.22). In secondary analyses based on intended duration of use, neither COX-2 selective inhibitor was associated with a higher risk than ibuprofen or diclofenac. The unadjusted risk of AMI for all NSAIDs increased with dose. In the direct two way adjusted comparison of each NSAID stratified by dose, the only statistically significant difference was with rofecoxib >25 mg/day versus celecoxib >200 mg/day. CONCLUSION In this study there was no difference between AMI occurrence in elderly patients taking rofecoxib or celecoxib at recommended doses for chronic indications versus those taking ibuprofen/diclofenac. However, the risk of AMI was higher among patients using higher doses of rofecoxib (>25 mg/day) compared to patients using higher doses of celecoxib (>200 mg/day).
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Affiliation(s)
- Elham Rahme
- Department of Medicine McGill University, and Research Institute, McGill University Health Center, Montreal, Canada.
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Rostom A, Muir K, Dubé C, Jolicoeur E, Boucher M, Joyce J, Tugwell P, Wells GW. Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane Collaboration systematic review. Clin Gastroenterol Hepatol 2007; 5:818-28, 828.e1-5; quiz 768. [PMID: 17556027 DOI: 10.1016/j.cgh.2007.03.011] [Citation(s) in RCA: 169] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Nonselective non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 inhibitors (COX-2s) are used to treat a variety of arthritic and inflammatory conditions. The aim of this study was to assess the upper gastrointestinal (GI) harms of the long-term use of COX-2s, compared with nonselective NSAIDs and placebo, in arthritis sufferers. METHODS A systematic review of randomized controlled trials (RCTs) was conducted. Searches were conducted in (1) Cochrane Central Register of Controlled Trials (CENTRAL), (2) the Cochrane Collaboration Library (2005), (3) MEDLINE (to December 2006), and (4) Excerpta Medica Database (EMBASE) (to June 2005). Reference lists from trials and abstracts of conference proceedings were searched by hand, and experts were contacted to identify further relevant trials. RCTs of celecoxib, rofecoxib, etoricoxib, valdecoxib, and lumiracoxib were included if they reported on endoscopic ulcers, clinically important ulcer complications, or adverse gastrointestinal (GI) symptoms with the use of these COX-2s, compared with placebo or with nonselective NSAIDs. Study selection and data extraction were performed in duplicate by independent reviewers. Data were analyzed by using Review Manager 4.2 in accordance with accepted meta-analysis techniques. RESULTS Compared with nonselective NSAIDs, COX-2s produced significantly fewer gastroduodenal ulcers (relative risk, 0.26; 95% confidence interval, 0.23-0.30) and clinically important ulcer complications (relative risk, 0.39; 95% confidence interval, 0.31-0.50), as well as fewer treatment withdrawals caused by GI symptoms. The co-administration of acetylsalicylic acid appears to reduce the GI safety of COX-2s in subgroup analyses. CONCLUSIONS COX-2s appear to offer greater upper GI safety and are better tolerated than nonselective NSAIDs. The co-administration of acetylsalicylic acid might reduce the safety advantage of COX-2s over that of nonselective NSAIDs.
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Affiliation(s)
- Alaa Rostom
- Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada.
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Gridelli C, Gallo C, Ceribelli A, Gebbia V, Gamucci T, Ciardiello F, Carozza F, Favaretto A, Daniele B, Galetta D, Barbera S, Rosetti F, Rossi A, Maione P, Cognetti F, Testa A, Di Maio M, Morabito A, Perrone F. Factorial phase III randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study. Lancet Oncol 2007; 8:500-512. [PMID: 17513173 DOI: 10.1016/s1470-2045(07)70146-8] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND The addition of cyclo-oxygenase-2 (COX-2) inhibitors and prolonged constant infusion (PCI) of gemcitabine to treatment for advanced non-small-cell lung cancer (NSCLC) might improve treatment efficacy. We aimed to assess whether the addition of rofecoxib or PCI gemcitabine could improve overall survival compared with first-line treatment with cisplatin plus gemcitabine given by standard infusion. METHODS Patients with stage IV or IIIb (with supraclavicular nodes or pleural effusion) NSCLC who were under 70 years of age and who had performance status 0 or 1 were eligible for this multicentre, prospective, open-label, randomised phase III trial with 2 x 2 factorial design. Patients were randomly assigned to one of four treatment groups: group A, gemcitabine 1200 mg/m(2) in a 30-min intravenous infusion on days 1 and 8 and intravenous cisplatin 80 mg/m(2) on day 1, every 21 days for six cycles; group B, the same treatments as group A plus oral rofecoxib 50 mg/day until disease progression; group C, intravenous PCI gemcitabine 1200 mg/m(2) in a 120-min infusion on days 1 and 8 and intravenous cisplatin 80 mg/m(2) on day 1, every 21 days for six cycles; group D, the same drugs as group C plus oral rofecoxib 50 mg/day until disease progression. The primary endpoint was overall survival; secondary endpoints were progression-free survival, response rate, quality of life, and toxicity. Analyses were intention-to-treat. This trial is registered on the clinical trials site of the US National Institutes of Health website http://clinicaltrials.gov/ct/show/NCT00385606. FINDINGS Between Jan 30, 2003, and May 3, 2005, 400 patients were enrolled. Median age was 60 years (range 29-71). PCI gemcitabine did not improve overall survival (median 47 weeks [95% CI 40-55] vs 44 [36-52], with standard gemcitabine infusion, hazard ratio (HR) of death 0.93 [0.74-1.17], p=0.41), progression-free survival, nor any other secondary endpoint. Vomiting and fatigue were significantly worse with PCI gemcitabine. The two rofecoxib groups were closed early (on Oct 1, 2004) due to withdrawal of the drug because of safety issues. With intention-to-treat statistical analyses limited to 240 patients (ie, those randomised before July 1, 2004) who had at least 3 months of treatment, rofecoxib did not prolong overall survival (median 44 weeks [CI 36-55] vs 44 [40-54] without rofecoxib, and HR of death 1.00 [0.75-1.34], p=0.85), or progression-free survival, but did improve response rate (41%vs 26%, p=0.02), global quality of life, physical, emotional and role functioning, fatigue, and sleeping. Rofecoxib significantly increased the incidence of diarrhoea and decreased constipation, fatigue, fever, weight loss, and pain, and analgesic consumption. Severe cardiac ischaemia was more frequent with rofecoxib than without; however, the difference was not statistically significant in the primary analysis (p=0.06) and became significant when patients who were randomised between July 1, 2004, and Sept 30, 2004, were included in the analysis (p=0.03). INTERPRETATION Neither PCI gemcitabine nor rofecoxib prolonged survival in the patients in this study. Rofecoxib improved response rate and several quality-of-life items, including pain-related items and global quality of life. Further studies with less cardiotoxic COX-2 inhibitors are needed in NSCLC.
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Affiliation(s)
- Cesare Gridelli
- Medical Oncology, S Giuseppe Moscati Hospital, Avellino, Italy.
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Mazanec D, Reddy A. Medical management of cervical spondylosis. Neurosurgery 2007. [PMID: 17204885 DOI: 10.1227/01.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Medical management is often the initial management of cervical spondylitic syndromes, including radiculopathy, myelopathy, and neck pain. This includes pharmacological and rehabilitation treatment. Prospective studies comparing the efficacy of surgical versus medical management are lacking. The indications and efficacy of pharmacological and rehabilitative treatments are reviewed. The use of anti-inflammatory drugs, muscle relaxants, analgesics, antidepressants, anticonvulsants, steroids, facet joint ablation, and physical therapy are reviewed. A rationale for the medical management of acute neck pain, chronic neck pain, radiculopathy, and myelopathy is presented.
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Affiliation(s)
- Daniel Mazanec
- Cleveland Clinic Spine Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
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Franke A, Reiner L, Resch KL. Long-term benefit of radon spa therapy in the rehabilitation of rheumatoid arthritis: a randomised, double-blinded trial. Rheumatol Int 2007; 27:703-13. [PMID: 17203297 DOI: 10.1007/s00296-006-0293-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2006] [Accepted: 12/02/2006] [Indexed: 10/23/2022]
Abstract
This study investigates the effects of radon (plus CO2) baths on RA in contrast to artificial CO2 baths in RA rehabilitation using a double-blinded trial enrolling 134 randomised patients of an in-patient rehabilitative programme (further 73 consecutive non-randomised patients are not reported here). The outcomes were limitations in occupational context/daily living (main outcome), pain, medication and further quantities. These were measured before the start, after the end of treatment and quarterly in the year thereafter. Repeated-measures analysis of covariance (RM-ANCOVA) of the intent-to-treat population was performed with group main effects (GME) and group x course interactions (G x C) reported. Hierarchically ordered hypotheses ensured the adherence of the nominal significance level. The superiority of the radon treatment was found regarding the main outcome (RM-ANCOVA until 12 months: p(GME) = 0.15, p(G x C) = 0.033). Consumption of steroids (p(GME) = 0.064, p(G x C) = 0.025) and NSAIDs (p(GME) = 0.035, p(G x C) = 0.008) were significantly reduced. The results suggest beneficial long-term effects of radon baths as adjunct to a multimodal rehabilitative treatment of RA.
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Affiliation(s)
- Annegret Franke
- FBK Spa Medicine Research Institute, Lindenstr.5, 08645 Bad Elster, Germany.
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Affiliation(s)
- Daniel Mazanec
- Cleveland Clinic Spine Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
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Fatokun AA, Stone TW, Smith RA. Cell death in rat cerebellar granule neurons induced by hydrogen peroxide in vitro: mechanisms and protection by adenosine receptor ligands. Brain Res 2006; 1132:193-202. [PMID: 17188658 DOI: 10.1016/j.brainres.2006.11.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2006] [Revised: 11/02/2006] [Accepted: 11/03/2006] [Indexed: 11/23/2022]
Abstract
Oxidative stress, resulting from excessive production of reactive oxygen species (ROS), is a pathological state that causes profound cellular damage and eventual death resulting from the overactivation of glutamate receptors, and the generation of nitric oxide, superoxide and hydrogen peroxide (H(2)O(2)). As such, H(2)O(2) represents an important model for studying the neuropathology of oxidative stress in a variety of CNS disorders. The effects of H(2)O(2) on the viability of post-natal cerebellar granule neurons (CGNs), the nature of the cell death involved and the potential protection by adenosine receptors against the damage were examined in the current study. Hydrogen peroxide (10-400 microM) reduced CGN viability in a concentration- and time-dependent manner. The addition of catalase (100 U/ml) prevented this effect, and the non-specific COX inhibitor aspirin (1 mM) also alleviated the damage. A combination of H(2)O(2) (5 microM) and Cu(2+) (0.5 mM) resulted in a significant damage that was not prevented by the hydroxyl radical scavenger mannitol (50 mM). The permeability transition pore blocker cyclosporin A, the caspase-3 inhibitor Z-DEVD-fmk (40 microM) and the PARP-1 inhibitor DPQ (10 microM) each significantly protected against peroxide damage. While the A(1) adenosine receptor agonist CPA and the A(2A) receptor antagonist ZM241385 (each at 100 nM) elicited protection, the A(1) adenosine receptor blocker DPCPX and the A(2A) receptor agonist CGS21680 (each at 100 nM) showed no effect. The data demonstrate that H(2)O(2) induced oxidative stress in CGNs, involving both apoptotic and necrotic death, and this can be ameliorated by A(1) receptor activation or A(2A) receptor blockade.
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Affiliation(s)
- Amos A Fatokun
- Division of Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, West Medical Building, University of Glasgow, Glasgow G12 8QQ, Scotland, UK
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Abstract
Virtually all human cell types can express both cyclooxygenase (COX)-1 and COX-2 under appropriate circumstances. Both isoforms can subserve physiologic and pathophysiologic roles when coupled with the appropriate stimuli and downstream prostaglandin (PG)H2-isomerases and prostanoid receptors. Although the ratio of maximal biosynthetic capacity of human platelets to the basal rate of production of thromboxane A2 is approximately 5000, this ratio is much lower in the case of PGI2, thus dictating quite different requirements for the extent and duration of COX inhibition in human platelets and vascular endothelial cells to detect functional and clinical effects. The development of low-dose aspirin as an antiplatelet agent has been instrumental in characterizing the role of platelet COX-1 in atherothrombosis. Similarly, though quite unexpectedly, the development of coxibs as anti-inflammatory agents has been instrumental in elucidating the role of endothelial COX-2 in vascular occlusion. Because of differential requirements for the inhibition of thromboxane A2 versus PGI2 biosynthesis in vivo, most traditional nonsteroidal anti-inflammatory drugs tend to mimic the effects of coxibs, rather than aspirin, on prostanoid-dependent cardiovascular homeostasis.
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Affiliation(s)
- Carlo Patrono
- Department of Pharmacology, University of Rome La Sapienza, Rome, Italy.
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Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006; 332:1302-8. [PMID: 16740558 PMCID: PMC1473048 DOI: 10.1136/bmj.332.7553.1302] [Citation(s) in RCA: 943] [Impact Index Per Article: 49.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To assess the effects of selective cyclo-oxygenase-2 (COX 2) inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of vascular events. DESIGN Meta-analysis of published and unpublished tabular data from randomised trials, with indirect estimation of the effects of traditional NSAIDs. DATA SOURCES Medline and Embase (January 1966 to April 2005); Food and Drug Administration records; and data on file from Novartis, Pfizer, and Merck. REVIEW METHODS Eligible studies were randomised trials that included a comparison of a selective COX 2 inhibitor versus placebo or a selective COX 2 inhibitor versus a traditional NSAID, of at least four weeks' duration, with information on serious vascular events (defined as myocardial infarction, stroke, or vascular death). Individual investigators and manufacturers provided information on the number of patients randomised, numbers of vascular events, and the person time of follow-up for each randomised group. RESULTS In placebo comparisons, allocation to a selective COX 2 inhibitor was associated with a 42% relative increase in the incidence of serious vascular events (1.2%/year v 0.9%/year; rate ratio 1.42, 95% confidence interval 1.13 to 1.78; P = 0.003), with no significant heterogeneity among the different selective COX 2 inhibitors. This was chiefly attributable to an increased risk of myocardial infarction (0.6%/year v 0.3%/year; 1.86, 1.33 to 2.59; P = 0.0003), with little apparent difference in other vascular outcomes. Among trials of at least one year's duration (mean 2.7 years), the rate ratio for vascular events was 1.45 (1.12 to 1.89; P = 0.005). Overall, the incidence of serious vascular events was similar between a selective COX 2 inhibitor and any traditional NSAID (1.0%/year v 0.9%/year; 1.16, 0.97 to 1.38; P = 0.1). However, statistical heterogeneity (P = 0.001) was found between trials of a selective COX 2 inhibitor versus naproxen (1.57, 1.21 to 2.03) and of a selective COX 2 inhibitor versus non-naproxen NSAIDs (0.88, 0.69 to 1.12). The summary rate ratio for vascular events, compared with placebo, was 0.92 (0.67 to 1.26) for naproxen, 1.51 (0.96 to 2.37) for ibuprofen, and 1.63 (1.12 to 2.37) for diclofenac. CONCLUSIONS Selective COX 2 inhibitors are associated with a moderate increase in the risk of vascular events, as are high dose regimens of ibuprofen and diclofenac, but high dose naproxen is not associated with such an excess.
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Affiliation(s)
- Patricia M Kearney
- Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford OX3 7LF
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Moncada S. Adventures in vascular biology: a tale of two mediators. Philos Trans R Soc Lond B Biol Sci 2006; 361:735-59. [PMID: 16627292 PMCID: PMC1609404 DOI: 10.1098/rstb.2005.1775] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2005] [Accepted: 10/03/2005] [Indexed: 12/18/2022] Open
Abstract
I would like to thank the Royal Society for inviting me to deliver the Croonian Lecture. In so doing, the Society is adding my name to a list of very distinguished scientists who, since 1738, have preceded me in this task. This is, indeed, a great honour. For most of my research career my main interest has been the understanding of the normal functioning of the blood vessel wall and the way this is affected in pathology. During this time, our knowledge of these subjects has grown to such an extent that many people now believe that the conquering of vascular disease is a real possibility in the foreseeable future. My lecture concerns the discovery of two substances, prostacyclin and nitric oxide. I would like to describe the moments of insight and some of the critical experiments that contributed significantly to the uncovering of their roles in vascular biology. The process was often adventurous, hence the title of this lecture. It is the excitement of the adventure that I would like to convey in the text that follows.
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Affiliation(s)
- S Moncada
- The Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
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Cipollone F, Fazia ML. Cyclooxygenase-2 inhibition: Vascular inflammation and cardiovascular risk. Curr Atheroscler Rep 2006; 8:245-51. [PMID: 16640962 DOI: 10.1007/s11883-006-0080-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The inducible isoform of cyclooxygenase-2 (COX-2) plays a role in pathophysiologic processes like inflammation and pain but is also constitutively expressed in tissues such as the kidney or vascular endothelium, where it exerts important physiologic functions. Although much evidence exists that implicates COX-2 in atherosclerosis, its role in this setting remains substantially uncertain. This observation is also confirmed by the results of clinical trials of selective COX-2 inhibitors. Treatment with these drugs, developed with the assumption that they would be as effective as nonselective COX inhibitors but without their gastrointestinal side effects, has been reported to be associated with an increased cardiovascular risk. In this article, we review the pattern of expression of COX-2 in the cellular players of atherothrombosis, its role as a determinant of plaque vulnerability, and the vascular effects on prostanoid inhibition by COX-2 inhibitors.
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Affiliation(s)
- Francesco Cipollone
- Centro Regionale per la Prevenzione dell'Aterosclerosi, Via Colle dell'Ara, 66013 Chieti, Italy.
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Abstract
A new class of drugs, the selective cyclooxygenase-2 (COX-2) inhibitors, or coxibs, have recently been marketed as an alternative to conventional nonsteroidal anti-inflammatory drugs (NSAIDs) on the basis of a lower risk of gastrointestinal side effects. The recent withdrawal of rofecoxib, along with safety concerns about other COX-2 selective inhibitors raises important questions about the cardiovascular toxicity of these drugs. Recently some concerns arose even for a possible cardiotoxicity of nonselective nonsteroidal anti-inflammatory drugs. From data available so far, it seems that coxibs still remain a rational choice for patients with low cardiovascular risk and high gastrointestinal risk. Long-term studies with a cardiovascular endpoint involving both selective and nonselective anti-inflammatory drugs are warranted.
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Affiliation(s)
- R Caporali
- University of Pavia, IRCCS Policlinico S Matteo, Pavia, Italy.
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Elliott RA, Hooper L, Payne K, Brown TJ, Roberts C, Symmons D. Preventing non-steroidal anti-inflammatory drug-induced gastrointestinal toxicity: are older strategies more cost-effective in the general population? Rheumatology (Oxford) 2005; 45:606-13. [PMID: 16368733 DOI: 10.1093/rheumatology/kei241] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVES To assess the relative cost-effectiveness of five gastroprotective strategies for patients in the general population not judged to be at high gastrointestinal (GI) risk requiring regular traditional (t) non-steroidal anti-inflammatory drugs (NSAIDs) for over 3 weeks: tNSAID/H(2) receptor antagonists (H(2)RAs); tNSAID/proton pump inhibitors (PPIs); tNSAID/misoprostol; COX-2 preferential NSAIDs or COX-2-specific NSAIDs (COXIBs). METHODS A systematic review of outcomes and UK cost data were combined in an incremental economic analysis. Incremental cost-effectiveness ratios were generated for quality-adjusted life years (QALYs) gained. RESULTS Cost-utility analysis showed a tNSAID with a H(2)RA is safer and less costly than tNSAIDs alone, and equally effective and less costly than COXIBs. tNSAID/misoprostol was also dominated by tNSAID/H(2)RA due to withdrawal caused by side-effects reducing overall health status. The incremental increase in QALYs gained by using COXIBs instead of tNSAID/H(2)RA would cost 670,000 pounds per QALY gained. The incremental increase in QALYs gained by using tNSAID/PPI instead of COXIBs would cost 26,000 pounds per QALY gained. If the decision-maker will pay up to 140,000 pounds per extra QALY, the optimal strategy is tNSAID/H(2)RA. If the decision-maker will pay over this the optimal strategy is tNSAID/PPI. CONCLUSION The economic analysis suggests that there may be a case for prescribing H(2)RAs in all patients requiring NSAIDs. Our recommendations are tentative due to the quality of the data available and the assumptions we have had to make in our model, and it is possible that other strategies may be preferred in patients with higher baseline GI risk.
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Affiliation(s)
- R A Elliott
- School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK.
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Williams GW. An update on nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors. Curr Pain Headache Rep 2005; 9:377-89. [PMID: 16282038 DOI: 10.1007/s11916-005-0017-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Selective inhibitors of the cyclooxygenase-2 enzyme were developed to treat pain and inflammation while reducing the risk of the serious gastrointestinal side effects seen with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). The results of several clinical trials have demonstrated an apparent increased risk of serious cardiovascular events in patients taking the COX-2-selective inhibitors. Although the risk was observed originally with trials conducted with rofecoxib, it was attributed generally to the entire class of COX-2-selective drugs based on a similar mechanism of action and a hypothesis that predicted the possibility of a prothrombotic effect of the drugs compared with nonselective NSAIDs. Subsequent studies have demonstrated that elevated cardiovascular risk is not limited to the use of COX-2-specific inhibitors. An increase in cardiovascular risk actually has been seen with anti-inflammatory drugs of the NSAID class, regardless of whether they are selective or nonselective inhibitors. The US Food and Drug Administration has recommended that all such drugs carry a black box warning for gastrointestinal and cardiovascular risks.
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Affiliation(s)
- Gary W Williams
- Scripps Clinic, Mail Drop 406-C, 10666 North Torrey Pines Road, La Jolla, CA 92037, USA.
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Gasparini G, Gattuso D, Morabito A, Longo R, Torino F, Sarmiento R, Vitale S, Gamucci T, Mariani L. Combined Therapy with Weekly Irinotecan, Infusional 5‐Fluorouracil and the Selective COX‐2 Inhibitor Rofecoxib Is a Safe and Effective Second‐Line Treatment in Metastatic Colorectal Cancer. Oncologist 2005; 10:710-7. [PMID: 16249351 DOI: 10.1634/theoncologist.10-9-710] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The purpose of this study was to determine the tolerability and activity of rofecoxib (Vioxx; Merck & Co., Inc., Whitehouse Station, NJ, http://www.merck.com) combined with weekly irinotecan (Camptosar; Pfizer Pharmaceuticals, New York, http://www.pfizer.com) and infusional 5-fluorouracil (5-FU) as second-line therapy in metastatic colorectal cancer (MCRC). Enrolled patients had previously treated metastatic disease, were aged > or =18 to < or =75 years, and had adequate performance status. A cycle of treatment consisted of i.v. irinotecan on days 1, 8, 15, and 22, rofecoxib at an oral dose of 50 mg/day, and infusional 5-FU at a fixed dose of 200 mg/m(2) per day for 5 weeks followed by 3 weeks of therapy with rofecoxib alone. In the dose-finding study, the starting dose of irinotecan was 87.5 mg/m(2) and further dose escalations were planned by increments of 12.5 mg/m(2) up to 125 mg/m(2). Forty-eight consecutive patients were enrolled in the study. Among the 15 cases enrolled in the dose-finding study, one patient experienced grade 3 reversible diarrhea as the dose-limiting toxicity, at the fourth dose level tested. Therefore, the dose of irinotecan for the phase II study was 125 mg/m(2), and 33 patients were enrolled and received a total of 75 cycles. Hematological side effects were moderate, with grade 4 neutropenia recorded in only two patients. The most common nonhematological toxicity was diarrhea, occurring in 25 patients (75.8%) and considered to be of grade 3 in 12 patients (36.4%). Sixteen patients achieved partial responses (48.5%; 95% confidence interval [CI], 30.8%-66.5%), and another 10 patients (30.3%) had stable disease. The median time to progression was 7 months (95% CI, 5-12) and the median overall survival (OS) was 18 months; the 1-year estimated OS rate was 69.4%. The unique schedule tested in this study is feasible, is well-tolerated, and has promising activity in patients with MCRC after progression on oxaliplatin (Eloxatin; Sanofi-Synthelabo Inc., New York, http://www.sanofi-synthelabo.us)-based chemotherapy.
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Fortun PJ, Hawkey CJ. Life after Vioxx: the clinical implications. Br J Hosp Med (Lond) 2005; 66:264-7. [PMID: 15920854 DOI: 10.12968/hmed.2005.66.5.18418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The withdrawal of Vioxx, as a result of concerns regarding cardiovascular risk, has left unanswered questions about the safety of COX-2 inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) in general. However, to what extent should the concerns about Vioxx be extended to other anti-inflammatory drugs?
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Affiliation(s)
- P J Fortun
- Wolfson Digestive Diseases Centre, Institute of Clinical Research, University of Nottingham, Nottingham NG7 2UH
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Capone ML, Sciulli MG, Tacconelli S, Grana M, Ricciotti E, Renda G, Di Gregorio P, Merciaro G, Patrignani P. Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects. J Am Coll Cardiol 2005; 45:1295-301. [PMID: 15837265 DOI: 10.1016/j.jacc.2005.01.045] [Citation(s) in RCA: 199] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2004] [Revised: 12/17/2004] [Accepted: 01/04/2005] [Indexed: 01/05/2023]
Abstract
OBJECTIVES We investigated the occurrence of pharmacodynamic interaction between low-dose aspirin and naproxen. BACKGROUND The uncertainty of cardioprotection by naproxen has encouraged its combination with aspirin in patients with arthritis and cardiovascular disease. METHODS The incubation of washed platelets with naproxen for 5 min before the addition of aspirin reduced the irreversible inhibition of thromboxane (TX)B(2) production by aspirin. The pharmacodynamic interaction between the two drugs was then investigated in four healthy volunteers who received aspirin (100 mg daily) for 6 days and then the combination of aspirin and naproxen for further 6 days: aspirin 2 h before naproxen (500 mg, twice-daily dosing). After 14 days of washout, naproxen was given 2 h before aspirin for further 6 days. RESULTS The inhibition of serum TXB(2) production (index of platelet cyclooxygenase [COX]-1 activity) and platelet aggregation ex vivo and urinary 11-dehydro-TXB(2) levels (index of TXB(2) biosynthesis in vivo) by aspirin alone (99 +/- 0.2%, 95 +/- 0.6%, and 81 +/- 4%, respectively) was not significantly altered by the co-administration of naproxen, given either 2 h after aspirin or in reverse order. In a second study, the concurrent administration of a single dose of aspirin and naproxen did not affect platelet TXB(2) production and aggregation at 1 h after dosing, when aspirin alone causes maximal inhibitory effect. Moreover, the rapid recovery of platelet COX-1 activity and function supports the occurrence of a pharmacodynamic interaction between naproxen and aspirin. CONCLUSIONS Naproxen interfered with the inhibitory effect of aspirin on platelet COX-1 activity and function. This pharmacodynamic interaction might undermine the sustained inhibition of platelet COX-1 that is necessary for aspirin's cardioprotective effects.
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Affiliation(s)
- Marta L Capone
- Department of Medicine and Center of Excellence on Aging, School of Medicine, G. d'Annunzio University, Chieti, Italy
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