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Kaur A, Rehman HM, Mishra VK, Kaur G, Kaur M, Okla MK, Shah M, Bansal M. Aspirin vs. ibuprofen: unveiling the distinct cyclooxygenase-1/2 behaviour and dual efficacy of their synthesized analogues via molecular modeling and in vitro biological assessment. RSC Med Chem 2025:d4md00751d. [PMID: 40027346 PMCID: PMC11865951 DOI: 10.1039/d4md00751d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 01/20/2025] [Indexed: 03/05/2025] Open
Abstract
Dual inhibition of cyclooxygenase isozymes along with the platelet aggregation activities via the arachidonic acid pathway may offer a better anti-inflammatory agent with enhanced cardiac safety. Although the literature is more focused on COX-2 selectivity, sufficient or improved COX-1/COX-2 selectivity has garnered significant attention recently since it can ensure cardiovascular safety. Herein, in this regard, novel derivatives of non-steroidal anti-inflammatory drugs containing amide, thiourea, thiosemicarbazide, and triazole functionalities were synthesized and characterized. Calculations on the in silico drug-likeness and toxicological properties demonstrated the suitability of the compounds for oral administration. Meanwhile, the molecular docking results suggested two different mechanistic pathways for the anti-inflammatory and anti-platelet effects via COX-2 and COX-1 inhibition. Compounds 3 and 12 were shown to be the most efficient based on their excellent docking scores and favorable interactions, particularly with the selective side-pocket residues of COX-2 and main catalytic residues of COX-1. Furthermore, molecular dynamics simulation confirmed that compounds 3 and 12 exhibited good interactions at the active sites, having stable binding throughout 100 ns. Overall, two major findings were made in the current study. (i) Compound 12 bearing the triazole moiety proved to be the most effective cyclooxygenase inhibitor with IC50 values of 95.11 and 98.73 μM against COX-1 and COX-2 isozymes, respectively. It also maintained its anti-platelet activity (IC50 = 277.67 μM), confirming the dual functioning of compound 12. (ii) Compound 3 purely behaved as an anti-platelet agent (IC50 = 261.0 μM) in contrast to aspirin with fare inhibitory effects against COX-2.
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Affiliation(s)
- Amandeep Kaur
- Synthetic and Medicinal Chemistry Laboratory, Department of Chemistry, Punjabi University Patiala-147002 India
| | - Hafiz Muzzammel Rehman
- School of Biochemistry and Biotechnology, University of the Punjab Lahore Punjab Pakistan
| | - Vipin Kumar Mishra
- Chemistry Division, School of Advanced Sciences and Languages, VIT Bhopal University Bhopal India
| | - Gurmeet Kaur
- Synthetic and Medicinal Chemistry Laboratory, Department of Chemistry, Punjabi University Patiala-147002 India
| | - Mandeep Kaur
- Synthetic and Medicinal Chemistry Laboratory, Department of Chemistry, Punjabi University Patiala-147002 India
| | - Mohammad K Okla
- Botany and Microbiology Department, College of Science, King Saud University P.O. Box 2455 Riyadh 11451 Saudi Arabia
| | - Masaud Shah
- Department of Physiology, Ajou University South Korea
| | - Manisha Bansal
- Synthetic and Medicinal Chemistry Laboratory, Department of Chemistry, Punjabi University Patiala-147002 India
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Kim DH, Park MW, Shin HI, Lee BC, Kim DK, Cho CH, Kim YJ. Effectiveness and safety of human placenta hydrolysate injection into subacromial space in patients with shoulder impingement syndrome: a single-blind, randomized trial. BMC Musculoskelet Disord 2025; 26:11. [PMID: 39754114 PMCID: PMC11697622 DOI: 10.1186/s12891-024-08266-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 12/27/2024] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND Human placental hydrolysate (hPH) contains anti-inflammatory substances. This study aimed to analyze whether injecting hPH into the subacromial space could reduce pain in patients with shoulder impingement syndrome. METHODS This single-blind, randomized controlled study enrolled 50 patients with shoulder impingement syndrome who were randomly assigned to either the hPH or placebo groups. All patients received three ultrasound-guided subacromial space injections of 4 mL hPH or normal saline every week. Outcome measurements included the Visual Analog Scale (VAS) score during daily activity, Shoulder Pain and Disability Index (SPADI), and EuroQoL 5-Dimension 5-Level (EQ-5D-5L) utility index. Patients were followed up for nine weeks after the last injection. RESULTS Significant differences were noted in the VAS (p < 0.001) during daily activity, SPADI total score (p < 0.001), and EQ-5D-5L utility index (p < 0.001) nine weeks after the last injection between the hPH group and placebo group. Significant time effects were observed for all outcome measurements (all p < 0.001) in the hPH group but not in the placebo group. No severe complications, such as local infections or laboratory abnormalities, were reported during this study. CONCLUSIONS Subacromial injections showed significant improvement in pain, functional level, and quality of life in patients with shoulder impingement syndrome. Therefore, hPH can be used as an alternative treatment for shoulder impingement syndrome. TRIAL REGISTRATION The trial was registered on www. CLINICALTRIALS gov (NCT05528705, Registration Date: 06/09/2022).
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Affiliation(s)
- Du Hwan Kim
- Department of Physical Medicine and Rehabilitation, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
| | - Myung Woo Park
- Department of Physical Medicine and Rehabilitation, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Hyun Iee Shin
- Department of Physical Medicine and Rehabilitation, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Byung Chan Lee
- Department of Physical Medicine and Rehabilitation, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Don-Kyu Kim
- Department of Physical Medicine and Rehabilitation, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Chul-Hyun Cho
- Department of Orthopedic Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Ye-Ji Kim
- Department of Orthopedic Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
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Burlacu R, Bourdin V, Blin P, Camaioni F, Clairaz B, Lantéri-Minet M, Laroche F, Raineri F, Perrot S, Stahl JP, Thurin NH, Mouly S. [Over-the-counter non-steroidal anti-inflammatory medications: Focus on the management of acute pain]. Therapie 2024:S0040-5957(24)00177-X. [PMID: 39532557 DOI: 10.1016/j.therap.2024.10.061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 08/27/2024] [Accepted: 10/11/2024] [Indexed: 11/16/2024]
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are the second most widely used class of analgesics in France, after paracetamol. Some NSAIDs are available over the counter (OTC), without a prescription, on the advice of a pharmacist. NSAIDs have recently been the subject of safety alerts from France's Agence nationale de sécurité du médicament et des produits de santé (ANSM), highlighting a risk of worsening certain bacterial infections. This signal has not been confirmed by the European Medicines Agency (EMA) although a "risk of complications due to masking of symptoms of infection" has not been ruled out. These divergent messages can be confusing for healthcare professionals. This literature review, based on an analysis of nearly 200 scientific publications, considers the place of NSAIDs in the OTC management of migraine, tension headaches, postoperative analgesia, acute musculoskeletal and joint pain, dysmenorrhea, viral respiratory infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their toxicity. The role of the pharmacist in dispensing NSAIDs without a prescription is also addressed. NSAIDs offer rapid and effective pain management in a context of increasingly challenging access to care. Their safety profile is reassuring and generally well established but could be strengthened by conducting an ad hoc study to rule on the safety signal issued by the ANSM definitively. Pharmacists have the knowledge and tools to ensure the safe dispensing and rational use of NSAIDs, with or without a prescription. The introduction of risk minimization measures, such as decision-support tools, could enable further progress in ensuring the safe dispensing of OTC NSAIDs.
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Affiliation(s)
- Ruxandra Burlacu
- Inserm UMR-S 1144, département de médecine interne, département médico-universitaire INVICTUS, hôpital Lariboisière, Nord - université Paris-Cité, Assistance publique-Hôpitaux de Paris (AP-HP), 2, rue Ambroise-Paré, 75010 Paris, France
| | - Venceslas Bourdin
- Inserm UMR-S 1144, département de médecine interne, département médico-universitaire INVICTUS, hôpital Lariboisière, Nord - université Paris-Cité, Assistance publique-Hôpitaux de Paris (AP-HP), 2, rue Ambroise-Paré, 75010 Paris, France
| | - Patrick Blin
- Inserm CIC-P 1401, Bordeaux PharmacoEpi, université de Bordeaux, 33000 Bordeaux, France
| | - Fabrice Camaioni
- Fédération des syndicats pharmaceutiques de France (FSPF), 75009 Paris, France
| | - Béatrice Clairaz
- Société francophone des sciences pharmaceutiques officinales (SFSPO), 91570 Bièvres, France
| | - Michel Lantéri-Minet
- Département d'évaluation et traitement de la douleur et Fédération hospitalo-universitaire InovPain, centre hospitalo-universitaire de Nice, université Côte d'Azur, 06000 Nice, France; Inserm U1107, migraine et douleur trigéminale, Auvergne université, 63100 Clermont-Ferrand, France
| | - Françoise Laroche
- Inserm U 987, centre de la douleur, Sorbonne université, AP-HP, 75012 Paris, France
| | - François Raineri
- Société française de médecine générale, 92130 Issy-les-Moulineaux, France
| | - Serge Perrot
- Inserm U987, Centre de la douleur, hôpital Cochin, université Paris-Cité, 75000 Paris, France
| | - Jean-Paul Stahl
- Infectiologie, université Grenoble-Alpes, 38000 Grenoble, France
| | - Nicolas H Thurin
- Inserm CIC-P 1401, Bordeaux PharmacoEpi, université de Bordeaux, 33000 Bordeaux, France
| | - Stéphane Mouly
- Inserm UMR-S 1144, département de médecine interne, département médico-universitaire INVICTUS, hôpital Lariboisière, Nord - université Paris-Cité, Assistance publique-Hôpitaux de Paris (AP-HP), 2, rue Ambroise-Paré, 75010 Paris, France.
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Wang G, Sun J, Zhang Y, Wang N, Liu T, Ji W, Lv L, Yu X, Cheng X, Li M, Hu T, Shi Z. Aspirin reduces the mortality risk of patients with community-acquired pneumonia: a retrospective propensity-matched analysis of the MIMIC-IV database. Front Pharmacol 2024; 15:1402386. [PMID: 39346559 PMCID: PMC11427301 DOI: 10.3389/fphar.2024.1402386] [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: 03/17/2024] [Accepted: 09/02/2024] [Indexed: 10/01/2024] Open
Abstract
Background Community-acquired pneumonia (CAP) is a common infectious disease characterized by inflammation of the lung parenchyma in individuals who have not recently been hospitalized. It remains a significant cause of morbidity and mortality worldwide. Aspirin is a widely used drug, often administered to CAP patients. However, the benefits of aspirin remain controversial. Objective We sought to determine whether aspirin treatment has a protective effect on the outcomes of CAP patients. Methods We selected patients with CAP from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Propensity score matching (PSM) balanced baseline differences. A multivariate Cox regression model assessed the relationship between aspirin treatment and 28-day mortality. Results A total of 3,595 patients were included, with 2,261 receiving aspirin and 1,334 not. After PSM, 1,219 pairs were matched. The 28-day mortality rate for aspirin users was 20.46%, lower than non-users. Multivariate Cox regression indicated aspirin use was associated with decreased 28-day mortality (HR 0.75, 95% CI 0.63-0.88, p < 0.001). No significant differences were found between 325 mg/day and 81 mg/day aspirin treatments in terms of 28-day mortality, hospital mortality, 90-day mortality, gastrointestinal hemorrhage, and thrombocytopenia. However, intensive care unit (ICU) stay was longer for the 325 mg/day group compared to the 81 mg/day group (4.22 vs. 3.57 days, p = 0.031). Conclusion Aspirin is associated with reduced 28-day mortality in CAP patients. However, 325 mg/day aspirin does not provide extra benefits over 81 mg/day and may lead to longer ICU stays.
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Affiliation(s)
- Guangdong Wang
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Jiaolin Sun
- Department of Respiratory and Critical Care Medicine, Shanxi Provincial People's Hospital, Xi'an, Shanxi, China
| | - Yaxin Zhang
- Department of Neurology, Fujian Medical University Affiliated Xiamen Hong 'ai Hospital, Xiamen Fujian, China
| | - Na Wang
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Tingting Liu
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Wenwen Ji
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Lin Lv
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Xiaohui Yu
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Xue Cheng
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Mengchong Li
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Tinghua Hu
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Zhihong Shi
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China
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5
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Bassetti M, Andreoni M, Santus P, Scaglione F. NSAIDs for early management of acute respiratory infections. Curr Opin Infect Dis 2024; 37:304-311. [PMID: 38779903 PMCID: PMC11213495 DOI: 10.1097/qco.0000000000001024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
PURPOSE OF REVIEW To review the rationale for and the potential clinical benefits of an early approach to viral acute respiratory infections with NSAIDs to switch off the inflammatory cascade before the inflammatory process becomes complicated. RECENT FINDINGS It has been shown that in COVID-19 as in other viral respiratory infections proinflammatory cytokines are produced, which are responsible of respiratory and systemic symptoms. There have been concerns that NSAIDs could increase susceptibility to SARS-CoV-2 infection or aggravate COVID-19. However, recent articles reviewing experimental research, observational clinical studies, randomized clinical trials, and meta-analyses conclude that there is no basis to limit the use of NSAIDs, which may instead represent effective self-care measures to control symptoms. SUMMARY The inflammatory response plays a pivotal role in the early phase of acute respiratory tract infections (ARTIs); a correct diagnosis of the cause and a prompt therapeutic approach with NSAIDs may have the potential to control the pathophysiological mechanisms that can complicate the condition, while reducing symptoms to the benefit of the patient. A timely treatment with NSAIDs may limit the inappropriate use of other categories of drugs, such as antibiotics, which are useless when viral cause is confirmed and whose inappropriate use is responsible for the development of resistance.
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Affiliation(s)
- Matteo Bassetti
- Division of Infectious Diseases, Department of Health Sciences (DISSAL), University of Genova
- IRCCS Ospedale Policlinico San Martino, Genova
| | - Massimo Andreoni
- Infectious Disease Clinic, Policlinico Tor Vergata University Hospital
- Department of System Medicine Tor Vergata, University of Rome, Rome, Italy
| | - Pierachille Santus
- Division of Respiratory Diseases, Ospedale Luigi Sacco, Polo Universitario, ASST Fatebenefratelli-Sacco
- Department of Biomedical and Clinical Sciences (DIBIC), Università Degli Studi di Milano
| | - Francesco Scaglione
- Department of Oncology and Hemato-Oncology, Postgraduate School of Clinical Pharmacology and Toxicology, Università degli Studi di Milano, Milan, Italy
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Mariniello DF, Allocca V, D’Agnano V, Villaro R, Lanata L, Bagnasco M, Aronne L, Bianco A, Perrotta F. Strategies Tackling Viral Replication and Inflammatory Pathways as Early Pharmacological Treatment for SARS-CoV-2 Infection: Any Potential Role for Ketoprofen Lysine Salt? MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27248919. [PMID: 36558048 PMCID: PMC9782495 DOI: 10.3390/molecules27248919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/10/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
COVID-19 is an infective disease resulting in widespread respiratory and non-respiratory symptoms prompted by SARS-CoV-2 infection. Interaction between SARS-CoV-2 and host cell receptors prompts activation of pro-inflammatory pathways which are involved in epithelial and endothelial damage mechanisms even after viral clearance. Since inflammation has been recognized as a critical step in COVID-19, anti-inflammatory therapies, including both steroids and non-steroids as well as cytokine inhibitors, have been proposed. Early treatment of COVID-19 has the potential to affect the clinical course of the disease regardless of underlying comorbid conditions. Non-steroidal anti-inflammatory drugs (NSAIDs), which are widely used for symptomatic relief of upper airway infections, became the mainstay of early phase treatment of COVID-19. In this review, we discuss the current evidence for using NSAIDs in early phases of SARS-CoV-2 infection with focus on ketoprofen lysine salt based on its pharmacodynamic and pharmacokinetic features.
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Affiliation(s)
- Domenica Francesca Mariniello
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy
- U.O.C. Clinica Pneumologica “L. Vanvitelli”, A.O. dei Colli, Ospedale Monaldi, 80131 Naples, Italy
| | - Valentino Allocca
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy
- U.O.C. Clinica Pneumologica “L. Vanvitelli”, A.O. dei Colli, Ospedale Monaldi, 80131 Naples, Italy
| | - Vito D’Agnano
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy
- U.O.C. Clinica Pneumologica “L. Vanvitelli”, A.O. dei Colli, Ospedale Monaldi, 80131 Naples, Italy
| | - Riccardo Villaro
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy
| | - Luigi Lanata
- Medical Deptartment, Dompé Farmaceutici SpA, 20122 Milan, Italy
| | | | - Luigi Aronne
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy
- U.O.C. Clinica Pneumologica “L. Vanvitelli”, A.O. dei Colli, Ospedale Monaldi, 80131 Naples, Italy
| | - Andrea Bianco
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy
- U.O.C. Clinica Pneumologica “L. Vanvitelli”, A.O. dei Colli, Ospedale Monaldi, 80131 Naples, Italy
| | - Fabio Perrotta
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy
- U.O.C. Clinica Pneumologica “L. Vanvitelli”, A.O. dei Colli, Ospedale Monaldi, 80131 Naples, Italy
- Correspondence:
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Dey R, Dey S, Samadder A, Saxena AK, Nandi S. Natural Inhibitors against Potential Targets of Cyclooxygenase, Lipoxygenase and Leukotrienes. Comb Chem High Throughput Screen 2022; 25:2341-2357. [PMID: 34533441 DOI: 10.2174/1386207325666210917111847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 07/14/2021] [Accepted: 07/18/2021] [Indexed: 01/27/2023]
Abstract
BACKGROUND Cyclooxygenase (COX) and Lipoxygenase (LOX) enzymes catalyze the production of pain mediators like Prostaglandins (PGs) and Leukotrienes (LTs), respectively from arachidonic acid. INTRODUCTION The COX and LOX enzyme modulators are responsible for the major PGs and LTs mediated complications like asthma, osteoarthritis, rheumatoid arthritis, cancer, Alzheimer's disease, neuropathy and Cardiovascular Syndromes (CVS). Many synthetic Nonsteroidal Anti- Inflammatory Drugs (NSAIDs) used in the treatment have serious side effects like nausea, vomiting, hyperacidity, gastrointestinal ulcers, CVS, etc. Methods: The natural inhibitors of pain mediators have great acceptance worldwide due to fewer side effects on long-term uses. The present review is an extensive study of the advantages of plantbased vs synthetic inhibitors. RESULTS These natural COX and LOX inhibitors control inflammatory response without causing side-effect-related complicacy. CONCLUSION Therefore, the natural COX and LOX inhibitors may be used as alternative medicines for the management of pain and inflammation due to their less toxicity and resistivity.
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Affiliation(s)
- Rishita Dey
- Cytogenetics and Molecular Biology Lab., Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Sudatta Dey
- Cytogenetics and Molecular Biology Lab., Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Asmita Samadder
- Cytogenetics and Molecular Biology Lab., Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Anil Kumar Saxena
- Global Institute of Pharmaceutical Education and Research (Affiliated to Uttarakhand Technical University), Kashipur-244713, India
| | - Sisir Nandi
- Global Institute of Pharmaceutical Education and Research (Affiliated to Uttarakhand Technical University), Kashipur-244713, India
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9
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Lajoie J, Kowatsch MM, Mwangi LW, Boily-Larouche G, Oyugi J, Chen Y, Kimani M, Ho EA, Kimani J, Fowke KR. Low-Dose Acetylsalicylic Acid Reduces T Cell Immune Activation: Potential Implications for HIV Prevention. Front Immunol 2021; 12:778455. [PMID: 34868050 PMCID: PMC8637415 DOI: 10.3389/fimmu.2021.778455] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 10/22/2021] [Indexed: 12/23/2022] Open
Abstract
Introduction Acetylsalicylic acid (ASA) is a well-known and safe anti-inflammatory. At low-dose, it is prescribed to prevent secondary cardiovascular events in those with pre-existing conditions and to prevent preeclampsia. Little is known about how low-dose ASA affects the immune response. In this study, we followed women to assess how ASA use modifies T cells immune phenotypes in the blood and at the genital tract. Methods HIV uninfected women from Kenya were enrolled in this study and followed for one month to assess baseline responses including systemic/mucosal baseline immune activation. Participants then received 81mg of ASA daily for 6 weeks to assess changes to T cell immune activation (systemic and mucosal) relative to baseline levels. Results The concentration of ASA measured in the blood was 58% higher than the level measured at the female genital tract. In the blood, the level of ASA was inversely correlated with the following: the proportion of Th17 expressing HLA-DR (p=0.04), the proportion of effector CD4+ T cells expressing CCR5 (p=0.03) and the proportion of CD8+Tc17 expressing CCR5 (p=0.04). At the genital tract, ASA use correlated with a decreased of activated CD4+T cells [CD4+CCR5+CD161+ (p=0.02) and CD4+CCR5+CD95+ (p=0.001)]. Conclusion This study shows that ASA use impacts the immune response in both the systemic and genital tract compartments. This could have major implications for the prevention of infectious diseases such as HIV, in which the virus targets activated T cells to establish an infection. This could inform guidelines on ASA use in women. Clinical Trial Registration ClinicalTrials.gov, identifier NCT02079077.
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Affiliation(s)
- Julie Lajoie
- Laboratory of Viral Immunology, Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada.,Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya
| | - Monika M Kowatsch
- Laboratory of Viral Immunology, Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada
| | - Lucy W Mwangi
- Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya
| | - Geneviève Boily-Larouche
- Laboratory of Viral Immunology, Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada
| | - Julius Oyugi
- Laboratory of Viral Immunology, Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada.,Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya.,University of Nairobi Institute for Tropical and Infectious Diseases, University of Nairobi, Nairobi, Kenya
| | - Yufei Chen
- College of Pharmacy, University of Manitoba, Winnipeg, MB, Canada
| | - Makobu Kimani
- Partners for Health and Development in Africa, Nairobi, Kenya
| | - Emmanuel A Ho
- College of Pharmacy, University of Manitoba, Winnipeg, MB, Canada.,Laboratory for Drug Delivery and Biomaterials, School of Pharmacy, University of Waterloo, Waterloo, ON, Canada
| | - Joshua Kimani
- Laboratory of Viral Immunology, Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada.,University of Nairobi Institute for Tropical and Infectious Diseases, University of Nairobi, Nairobi, Kenya.,Partners for Health and Development in Africa, Nairobi, Kenya
| | - Keith R Fowke
- Laboratory of Viral Immunology, Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada.,Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya.,Partners for Health and Development in Africa, Nairobi, Kenya.,Department of Community Health Science, University of Manitoba, Winnipeg, MB, Canada
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10
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Polzin A, Dannenberg L, Helten C, Pöhl M, Metzen D, Mourikis P, Dücker C, Marschall U, L'Hoest H, Hennig B, Zako S, Trojovsky K, Petzold T, Jung C, Levkau B, Zeus T, Schrör K, Hohlfeld T, Kelm M. Excess Mortality in Aspirin and Dipyrone (Metamizole) Co-Medicated in Patients With Cardiovascular Disease: A Nationwide Study. J Am Heart Assoc 2021; 10:e022299. [PMID: 34726072 PMCID: PMC8751960 DOI: 10.1161/jaha.121.022299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background Pain is a major issue in our aging society. Dipyrone (metamizole) is one of the most frequently used analgesics. Additionally, it has been shown to impair pharmacodynamic response to aspirin as measured by platelet function tests. However, it is not known how this laboratory effect translates to clinical outcome. Methods and Results We conducted a nationwide analysis of a health insurance database in Germany comprising 9.2 million patients. All patients with a cardiovascular event in 2014 and subsequent secondary prevention with aspirin were followed up for 36 months. Inverse probability of treatment weighting analysis was conducted to investigate the rate of mortality, myocardial infarction, and stroke/transient ischemic attack between patients on aspirin‐dipyrone co‐medication compared with aspirin‐alone medication. Permanent aspirin‐alone medication was given to 26,200 patients, and 5946 patients received aspirin–dipyrone co‐medication. In the inverse probability of treatment weighted sample, excess mortality in aspirin–dipyrone co‐medicated patients was observed (15.6% in aspirin‐only group versus 24.4% in the co‐medicated group, hazard ratio [HR], 1.66 [95% CI, 1.56–1.76], P<0.0001). Myocardial infarction and stroke/transient ischemic attack were increased as well (myocardial infarction: 1370 [5.2%] versus 355 [5.9%] in aspirin‐only and co‐medicated groups, respectively; HR, 1.18 [95% CI, 1.05–1.32]; P=0.0066, relative risk [RR], 1.14; number needed to harm, 140. Stroke/transient ischemic attack, 1901 [7.3%] versus 506 [8.5%] in aspirin‐only and co‐medicated groups, respectively; HR, 1.22 [95% CI, 1.11–1.35]; P<0.0001, RR, 1.17, number needed to harm, 82). Conclusions In this observational, nationwide analysis, aspirin and dipyrone co‐medication was associated with excess mortality. This was in part driven by ischemic events (myocardial infarction and stroke), which occurred more frequently in co‐medicated patients as well. Hence, dipyrone should be used with caution in aspirin‐treated patients for secondary prevention.
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Affiliation(s)
- Amin Polzin
- Division of Cardiology, Pulmonology, and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) Heinrich Heine University Medical Center Düsseldorf Düsseldorf Germany
| | - Lisa Dannenberg
- Division of Cardiology, Pulmonology, and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) Heinrich Heine University Medical Center Düsseldorf Düsseldorf Germany
| | - Carolin Helten
- Division of Cardiology, Pulmonology, and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) Heinrich Heine University Medical Center Düsseldorf Düsseldorf Germany
| | - Martin Pöhl
- Division of Cardiology, Pulmonology, and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) Heinrich Heine University Medical Center Düsseldorf Düsseldorf Germany
| | - Daniel Metzen
- Division of Cardiology, Pulmonology, and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) Heinrich Heine University Medical Center Düsseldorf Düsseldorf Germany
| | - Philipp Mourikis
- Division of Cardiology, Pulmonology, and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) Heinrich Heine University Medical Center Düsseldorf Düsseldorf Germany
| | - Christof Dücker
- Institute for Clinical Pharmacology University Medical Center GöttingenGeorg-August University Göttingen Germany
| | - Ursula Marschall
- Department of Medicine and Health Services Research BARMER Statutory Health Insurance Fund Wuppertal Germany
| | - Helmut L'Hoest
- Department of Medicine and Health Services Research BARMER Statutory Health Insurance Fund Wuppertal Germany
| | - Beata Hennig
- Department of Medicine and Health Services Research BARMER Statutory Health Insurance Fund Wuppertal Germany
| | - Saif Zako
- Division of Cardiology, Pulmonology, and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) Heinrich Heine University Medical Center Düsseldorf Düsseldorf Germany
| | - Kajetan Trojovsky
- Division of Cardiology, Pulmonology, and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) Heinrich Heine University Medical Center Düsseldorf Düsseldorf Germany
| | - Tobias Petzold
- Medizinische Klinik und Poliklinik I Klinikum der Universität MünchenLudwig-Maximilians- University Munich Munich Germany
| | - Christian Jung
- Division of Cardiology, Pulmonology, and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) Heinrich Heine University Medical Center Düsseldorf Düsseldorf Germany
| | - Bodo Levkau
- Institute of Molecular Medicine III University Hospital DüsseldorfHeinrich Heine University Düsseldorf Dusseldorf Germany
| | - Tobias Zeus
- Division of Cardiology, Pulmonology, and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) Heinrich Heine University Medical Center Düsseldorf Düsseldorf Germany
| | - Karsten Schrör
- Institute for Pharmacology and Clinical Pharmacology Heinrich Heine University Dusseldorf Germany
| | - Thomas Hohlfeld
- Institute for Pharmacology and Clinical Pharmacology Heinrich Heine University Dusseldorf Germany
| | - Malte Kelm
- Division of Cardiology, Pulmonology, and Vascular Medicine, Cardiovascular Research Institute Düsseldorf (CARID) Heinrich Heine University Medical Center Düsseldorf Düsseldorf Germany
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11
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Mathpal D, Masand M, Thomas A, Ahmad I, Saeed M, Zaman GS, Kamal M, Jawaid T, Sharma PK, Gupta MM, Kumar S, Srivastava SP, Balaramnavar VM. Pharmacophore modeling, docking and the integrated use of a ligand- and structure-based virtual screening approach for novel DNA gyrase inhibitors: synthetic and biological evaluation studies. RSC Adv 2021; 11:34462-34478. [PMID: 35494744 PMCID: PMC9042709 DOI: 10.1039/d1ra05630a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/28/2021] [Indexed: 12/03/2022] Open
Abstract
Fluoroquinolones, a class of compound, act via inhibiting DNA gyrase and topoisomerase IV enzymes. This is an important class of drugs with high success rates for the treatment of tuberculosis and other bacterial infections. An indirect drug design approach was used to develop a meaningful pharmacophore model using the HypoGen module of Discovery Studio 2.0 on a set of 27 structurally diverse compounds with a wide range of biological activity (5 log units). The best hypothesis had three hydrogen bond acceptors (HBA) and one hydrophobic (Hy) moiety, showing r = 0.95, and it predicts the test set of 44 compounds well, with r 2 = 0.823. The same features (acceptor and hydrophobic functionality) were validated at the binding site of the DNA gyrase active site using GOLD version 3.0.1 and Molegro Virtual Docker, which showed corresponding hydrogen bond interactions and also π-π stacking interactions that correlated well with the PIC50 values (r 2 = 0.6142). The thoroughly validated model was used to screen an extensive database of 0.25 million compounds to identify potential leads. The validated model was implemented for the identification, design, synthesis, and biological evaluation of leads. Ten new chemical entities were synthesized based on our scaffold hopping techniques from the identified virtual screening and tested against the tuberculosis bacterium to obtain preliminary MIC values. The results showed that 3 out of 10 synthesized compounds exhibited good MICs, from 1.25 to 50 μM. This proves the robustness and applicability of the developed model, which is a promising tool for identifying new topoisomerase II inhibitors for the treatment of tuberculosis.
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Affiliation(s)
- Deepti Mathpal
- Sanskriti University, School of Pharmacy and Research 28 KM. Stone, Mathura - Delhi Highway, Chhata Mathura Uttar Pradesh (UP) 281401 India
| | - Mukesh Masand
- Department of Pharmacy, Faculty of Medicine and Allied Sciences, Galgotias University Gautam Buddha Nagar Uttar Pradesh 226001 India
| | - Anisha Thomas
- Department of Chemistry, School of Advanced Sciences, VIT Vellore India
| | - Irfan Ahmad
- Department of Clinical Laboratory Science, College of Applied Medical Sciences, King Khalid University Abha Saudi Arabia
| | - Mohd Saeed
- Department of Biology College of Sciences, University of Hail Saudi Arabia
| | - Gaffar Sarwar Zaman
- Department of Clinical Laboratory Science, College of Applied Medical Sciences, King Khalid University Abha Saudi Arabia
| | - Mehnaz Kamal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University P.O. Box No. 173 Al Kharj 11942 Kingdom of Saudi Arabia
| | - Talha Jawaid
- Department of Pharmacology, College of Medicine, Al Imam Mohammad Ibn Saud Islamic University (IMSIU) Riyadh 13317 Kingdom of Saudi Arabia
| | - Pramod K Sharma
- Department of Pharmacy, Faculty of Medicine and Allied Sciences, Galgotias University Gautam Buddha Nagar Uttar Pradesh 226001 India
| | - Madan M Gupta
- School of Pharmacy, Faculty of the West Indies St Augustine Trinidad and Tobago West Indies
| | - Santosh Kumar
- Government Degree College Hansaur Barabanki Uttar Pradesh (UP) 225415 India
| | - Swayam Prakash Srivastava
- Sanskriti University, School of Pharmacy and Research 28 KM. Stone, Mathura - Delhi Highway, Chhata Mathura Uttar Pradesh (UP) 281401 India
- Department of Pediatrics, Yale University School of Medicine New Haven CT 06520 USA
- Vascular Biology and Therapeutic Program, Yale University School of Medicine New Haven CT 06511 USA
| | - Vishal M Balaramnavar
- Sanskriti University, School of Pharmacy and Research 28 KM. Stone, Mathura - Delhi Highway, Chhata Mathura Uttar Pradesh (UP) 281401 India
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12
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Hu J, Ni Z, Zhu H, Li H, Chen Y, Shang Y, Chen D, Liu H. A novel drug delivery system -- Drug crystallization encapsulated liquid crystal emulsion. Int J Pharm 2021; 607:121007. [PMID: 34391854 DOI: 10.1016/j.ijpharm.2021.121007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 08/04/2021] [Accepted: 08/10/2021] [Indexed: 10/20/2022]
Abstract
Liquid crystals (LCs) are widely used for drug delivery due to their controlled and sustained drug release properties. In this paper, drug crystallization encapsulated liquid crystal emulsion, a novel drug delivery system, was proposed. The lamellar liquid crystals formed by hydrogenated lecithin, which are similar to the skin stratum corneum lipid structure, are adopted as the drug carrier to encapsulate non-steroidal anti-inflammatory drugs (NSAIDs). As the model drug, ketoprofen exists in the hydrophobic core of emulsion as a drug crystal when squalane is used as the oil phase. The microstructure, sustained drug release behaviors, physicochemical property and biocompatibility of the system were examined by polarized light microscopy, rheological measurements, differential scanning calorimetry, X-ray diffraction, small-angle X-ray scattering, in vitro release study, and in vitro cellular cytotoxicity assay. The results have shown that the novel system lowers the drug crystal melting point and improves the thermal stability of liquid crystal structure. Besides, the excellent biocompatibility and sustained release property through the additional dissolution step of drug crystal show its application potentials in the topical cosmeceuticals. The results will also be helpful for in-depth understanding of the physical state of encapsulated drug in the liquid crystal carrier systems.
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Affiliation(s)
- Jiajie Hu
- Key Laboratory for Advanced Materials, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Zhuoyao Ni
- Key Laboratory for Advanced Materials, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Hui Zhu
- Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang District, Shanghai 201100, China
| | - Hanglin Li
- Key Laboratory for Advanced Materials, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China
| | | | - Yazhuo Shang
- Key Laboratory for Advanced Materials, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China.
| | - Daijie Chen
- Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang District, Shanghai 201100, China
| | - Honglai Liu
- Key Laboratory for Advanced Materials, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China
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13
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Balaramnavar VM, Srivastava R, Varshney S, Kumar S, Rawat AK, Chandasana H, Chhonker YS, Bhatta RS, Srivastava AK, Gaikwad AN, Lakshmi V, Saxena AK. Synthesis, biological evaluation, and molecular docking study of some new rohitukine analogs as protein tyrosine phosphatase 1B inhibitors. Bioorg Chem 2021; 110:104829. [PMID: 33773222 DOI: 10.1016/j.bioorg.2021.104829] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 03/09/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023]
Abstract
Rohitukine (RH) was extracted from the stem bark of Dysoxylum binectariferum Hook. It was derivatized to different arylsulphanmides by treating with the corresponding aryl sulphonyl chlorides. These derivatives were tested in-vitro on protein tyrosine phosphatase 1B (PTP1B) inhibition. Among these the active compounds K2, K3, K5, and K8 significantly inhibited the PTP1B by 51.3%, 65.6%, 71.9%, and 55.9% respectively at 10 µg/ml, the results were also supported by in-silico docking experiments. The most potent compound K5 was analyzed for antidiabetic and antidyslipidemic activity in vivo. It showed a marked reduction in blood glucose level (random and fasting) and serum insulin level in db/db mice. It improved glucose intolerance as ascertained by the oral glucose tolerance test (OGTT). These NCEs (New Chemical Entities) also lowered cholesterol and triglyceride profiles while improved high-density lipoprotein cholesterol in db/db mice. The K5 was further evaluated for antiadipogenic activity on MDI (Methylisobutylxanthine, dexamethasone, and insulin)-induced adipogenesis. where it significantly inhibited MDI-induced adipogenesis in 3 T3-L1 preadipocytes, at 10 µM and 20 µM concentration. These results were compared with the parent compound RH which inhibited 35% and 45% lipid accumulation while the RH analog K5 inhibited the lipid accumulation by 41% and 51% at 10 and 20 µM concentration, respectively. These results well corroborated with in-silico studies.
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Affiliation(s)
- V M Balaramnavar
- Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Jankipuram, Extention Sector 10, Sitapur Road, Lucknow 226031, UP, India; Global Institute of Pharmaceutical Education and Research, Jaspur Road, Kashipur, Uttarakhand, India
| | - R Srivastava
- Department of Biochemistry, CSIR-Central Drug Research Institute, Jankipuram Extention, Sector 10, Sitapur Road, Lucknow 226031, UP, India
| | - S Varshney
- Department of Pharmacology, CSIR-Central Drug Research Institute, Jankipuram Extention Sector 10, Sitapur Road, Lucknow 226031, UP, India
| | - S Kumar
- Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Jankipuram, Extention Sector 10, Sitapur Road, Lucknow 226031, UP, India
| | - A K Rawat
- Department of Biochemistry, CSIR-Central Drug Research Institute, Jankipuram Extention, Sector 10, Sitapur Road, Lucknow 226031, UP, India
| | - H Chandasana
- Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Y S Chhonker
- Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - R S Bhatta
- Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - A K Srivastava
- Department of Biochemistry, CSIR-Central Drug Research Institute, Jankipuram Extention, Sector 10, Sitapur Road, Lucknow 226031, UP, India
| | - A N Gaikwad
- Department of Pharmacology, CSIR-Central Drug Research Institute, Jankipuram Extention Sector 10, Sitapur Road, Lucknow 226031, UP, India
| | - V Lakshmi
- Department of Biochemistry, King George's Medical University, Lucknow 226003, UP, India
| | - A K Saxena
- Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Jankipuram, Extention Sector 10, Sitapur Road, Lucknow 226031, UP, India.
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14
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Krauss E, Cronin M, Dengler N, Segal A. Interaction Between Low-Dose Aspirin and Nonsteroidal Anti-Inflammatory Drugs Can Compromise Aspirin's Efficacy in Preventing Venous Thrombosis Following Total Joint Arthroplasty. Clin Appl Thromb Hemost 2021; 26:1076029620920373. [PMID: 32453611 PMCID: PMC7370567 DOI: 10.1177/1076029620920373] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Total joint arthroplasty is a rapid recovery procedure with patients optimized quickly in preparation for discharge. Two significant postoperative goals are effective pain management and prevention of postoperative venous thromboembolism (VTE). Low-risk patients receive aspirin 81 mg twice daily for VTE prophylaxis; this dosing regimen has been reduced over the past few years from 325 mg to 162 mg to 81 mg twice daily. Unless contraindications exist, all patients receive multimodal pain management that includes the use of celecoxib or meloxicam. Upon reduction of the aspirin dose to 81 mg twice daily, we rapidly identified 2 patients who developed a pulmonary embolus when celecoxib or meloxicam was administered concurrently with aspirin. The interaction between nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin varies among the different NSAIDs. It is also highly dependent on numerous factors, including time of administration, dose of aspirin, and both pharmacodynamics and dose of the NSAID. Real-world outcomes of concomitant administration of NSAIDs with low-dose aspirin led to increased incidence of VTE, possibly due to competitive inhibition of aspirin at platelet receptor sites. This interaction was mitigated by altering the administration times of both agents.
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Affiliation(s)
- Eugene Krauss
- Syosset Hospital, Northwell Health, New York Orthopaedic and Spine Center, Great Neck, NY, USA.,Zucker School of Medicine at Hofstra/Northwell, Hofstra University School of Medicine, New York Orthopaedic and Spine Center, Great Neck, NY, USA.,Syosset Hospital, Northwell Health, Syosset, NY, USA
| | | | - Nancy Dengler
- Syosset Hospital, Northwell Health, Syosset, NY, USA
| | - Ayal Segal
- Syosset Hospital, Northwell Health, New York Orthopaedic and Spine Center, Great Neck, NY, USA.,Syosset Hospital, Northwell Health, Syosset, NY, USA
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15
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Abstract
The risk of coronary events with non-steroidal anti-inflammatory drugs has been the subject of much debate since the original trial of rofecoxib raised the issue. Since then, over almost 20 years, such risks have been shown in clinical trials of long-term high-dose users, and in observational studies comparing users with non-users. The roles of cyclooxygenase (COX)-2/COX-1 selectivity and COX-2 inhibitory potency have been proposed to explain this increased risk of myocardial infarction (MI). Among NSAIDs, diclofenac appeared to be associated with a relatively higher risk of MI, similar to that of rofecoxib, compatible with the drug's high COX-2 inhibitory potency. Recent studies have resulted in further information being available. A study in the Danish healthcare system using active comparators found a slightly increased risk of MI in healthy persons. However, risk decreased with increasing baseline cardiovascular risk, to the point that in patients at high cardiovascular risk, there was no additional risk associated with diclofenac compared with paracetamol or other NSAIDs. The other major study, from the SOS project, studied several million persons in four countries in Europe, comparing the use of many NSAIDs with non-use. That study found a slightly increased risk with diclofenac compared with non-use, but this was not different from other NSAIDs. Comparing risks with selectivity or potency found no effect of either. These studies refute the main hypotheses to explain the coronary risk of NSAIDs. Finding risk in healthy low-risk patients only questions the reality of a link between the use of the drugs and the occurrence of MI in these conditions. Biases or confounding may be the major reason for small increases in cardiovascular risks in healthy users of NSAIDs in real life.
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Affiliation(s)
- Nicholas Moore
- University of Bordeaux, Bordeaux, France. .,Bordeaux PharmacoEpi INSERM CIC1401, 126 rue Leo Saignat, 33076, Bordeaux, France.
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16
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Structural modification of aspirin to design a new potential cyclooxygenase (COX-2) inhibitors. In Silico Pharmacol 2020; 8:1. [PMID: 32181121 DOI: 10.1007/s40203-020-0053-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 02/27/2020] [Indexed: 12/22/2022] Open
Abstract
Aspirin (Asp) is one of the most important and ancient member of nonsteroidal anti-inflammatory drugs (NSAID), commonly used in medication of fever, pain and inflammation. It can inhibit the synthesis of prostaglandin by blocking the cyclooxygenase (COX). Attempts have been taken to analyze aspirin together with some of its modified derivatives applying quantum mechanical calculations in order to compare their physicochemical and biochemical properties. Density functional theory (DFT) with B3LYP/6-31G (d, p) basis set has been employed to elucidate their thermal, molecular orbital, equilibrium geometrical properties in gas phase. Molecular docking and nonbonding interactions have been performed against human cyclooxygenase-2 protein 5F1A to investigate the binding affinity and mode(s) of newly designed aspirin derivatives. ADMET prediction has been utilized to compare the absorption, metabolism, and carcinogenic properties of new derivatives with parent drug (Asp). Thermal and geometrical results support the thermochemical stability and equilibrium geometry of all the structures. From the molecular docking simulation, most of the derivatives exhibited better binding affinity than parent drug (Asp) with the receptor protein (5F1A). ADMET prediction disclosed the improved pharmacokinetic properties with lower acute oral toxicity of some derivatives. Based on quantum chemical, molecular docking and ADMET analysis, this investigation can be useful to understand the physicochemical and biochemical/biological activities of Asp and its modified derivatives to search a new antipyretic analgesic drug.
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17
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Krauss ES, Cronin M, Dengler N, Simonson BG, Enker P, Segal A. Lessons Learned: Using the Caprini Risk Assessment Model to Provide Safe and Efficacious Thromboprophylaxis Following Hip and Knee Arthroplasty. Clin Appl Thromb Hemost 2020; 26:1076029620961450. [PMID: 33141613 PMCID: PMC7675849 DOI: 10.1177/1076029620961450] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/10/2020] [Accepted: 09/04/2020] [Indexed: 12/27/2022] Open
Abstract
Two of the more common potential complications after arthroplasty are venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolus (PE), and excess bleeding. Appropriate chemoprophylaxis choices are essential to prevent some of these adverse events and from exacerbating others. Risk stratification to prescribe safe and effective medications in the prevention of postoperative VTE has shown benefit in this regard. The Department of Orthopaedic Surgery at Syosset Hospital/Northwell Health, which performs over 1200 arthroplasties annually, has validated and is using the 2013 version of the Caprini Risk Assessment Model (RAM) to stratify each patient for risk of postoperative VTE. This tool results in a culling of information, past and present, personal and familial, that provides a truly thorough evaluation of the patient's risk for postoperative VTE. The Caprini score then guides the medication choices for thromboprophylaxis. The Caprini score is only valuable if the data is properly collected, and we have learned numerous lessons after applying it for 18 months. Risk stratification requires practice and experience to achieve expertise in perioperative patient evaluation. Having access to pertinent patient information, while gaining proficiency in completing the Caprini RAM, is vital to its efficacy. Ongoing, real time analyses of patient outcomes, with subsequent change in process, is key to improving patient care.
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MESH Headings
- Aged
- Arthroplasty, Replacement/adverse effects
- Arthroplasty, Replacement/methods
- Arthroplasty, Replacement, Hip/adverse effects
- Arthroplasty, Replacement, Hip/methods
- Arthroplasty, Replacement, Knee/adverse effects
- Arthroplasty, Replacement, Knee/methods
- Female
- Hemorrhage/etiology
- Hemorrhage/prevention & control
- Humans
- Male
- Middle Aged
- Postoperative Complications/etiology
- Postoperative Complications/prevention & control
- Premedication
- Risk Assessment/methods
- Venous Thromboembolism/etiology
- Venous Thromboembolism/prevention & control
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Affiliation(s)
- Eugene S. Krauss
- Syosset Hospital, Northwell Health, Syosset, NY, USA
- Krauss Musculoskeletal Institute, Peconic Bay Medical
Center, Affiliate of Northwell Health, Riverhead, NY, USA
- New York Orthopaedic and Spine Center, Zucker School of
Medicine at Hofstra/Northwell, Hempstead, NY, USA
- New York Orthopaedic and Spine Center, Northwell Health,
Great Neck, NY, USA
| | | | - Nancy Dengler
- Syosset Hospital, Northwell Health, Syosset, NY, USA
| | - Barry G. Simonson
- Syosset Hospital, Northwell Health, Syosset, NY, USA
- Orthopaedic Institute of Great Neck, Northwell Health, Great
Neck, NY, USA
| | - Paul Enker
- Syosset Hospital, Northwell Health, Syosset, NY, USA
- Orthopaedic Institute of Great Neck, Northwell Health, Great
Neck, NY, USA
| | - Ayal Segal
- Syosset Hospital, Northwell Health, Syosset, NY, USA
- New York Orthopaedic and Spine Center, Northwell Health,
Great Neck, NY, USA
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18
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Driver B, Marks DC, van der Wal DE. Not all (N)SAID and done: Effects of nonsteroidal anti-inflammatory drugs and paracetamol intake on platelets. Res Pract Thromb Haemost 2020; 4:36-45. [PMID: 31989083 PMCID: PMC6971311 DOI: 10.1002/rth2.12283] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 09/07/2019] [Accepted: 10/19/2019] [Indexed: 12/12/2022] Open
Abstract
Platelets are key mediators of hemostasis and thrombosis and can be inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). As a result, platelet donors are temporarily deferred from donating if they have recently taken NSAIDs such as aspirin or ibuprofen. Despite these measures, a proportion of platelet donations show exposure to these drugs; however, little is known about the effect of NSAIDs and their metabolites on platelet quality in vivo and during storage. In this review, the effect of NSAIDs on platelet function is summarized, with a focus on the widely consumed over-the-counter (OTC) medications aspirin, ibuprofen, and the non-NSAID paracetamol. Aspirin and ibuprofen have well-defined antiplatelet effects. In comparison, studies regarding the effect of paracetamol on platelets report variable findings. The timing and order of NSAID intake is important, as concurrent NSAID use can inhibit or potentiate platelet activation depending on the drug taken. NSAID deferral periods and maximum platelet shelf-life is set by each country and are revised regularly. Reduced donor deferral periods and longer platelet storage times may affect the quality of platelet products, and it is therefore important to identify the possible impact of NSAID intake on platelet quality before and after storage.
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Affiliation(s)
- Ben Driver
- Research and DevelopmentAustralian Red Cross Blood ServiceSydneyNSWAustralia
| | - Denese C. Marks
- Research and DevelopmentAustralian Red Cross Blood ServiceSydneyNSWAustralia
- Sydney Medical SchoolThe University of SydneySydneyNSWAustralia
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19
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Trostchansky A, Moore-Carrasco R, Fuentes E. Oxidative pathways of arachidonic acid as targets for regulation of platelet activation. Prostaglandins Other Lipid Mediat 2019; 145:106382. [PMID: 31634570 DOI: 10.1016/j.prostaglandins.2019.106382] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 08/12/2019] [Accepted: 09/03/2019] [Indexed: 12/17/2022]
Abstract
Platelet activation plays an important role in acute and chronic cardiovascular disease states. Multiple pathways contribute to platelet activation including those dependent upon arachidonic acid. Arachidonic acid is released from the platelet membrane by phospholipase A2 action and is then metabolized in the cytosol by specific arachidonic acid oxidation enzymes including prostaglandin H synthase, 12-lipoxygenase, and cytochrome P450 to produce pro- and anti-inflammatory eicosanoids. This review aims to analyze the role of arachidonic acid oxidation on platelet activation, the enzymes that use it as a substrate associated as novel therapeutics target for antiplatelet drugs.
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Affiliation(s)
- Andres Trostchansky
- Departamento de Bioquimica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
| | - Rodrigo Moore-Carrasco
- Departamento de Bioquímica Clínica e Inmunohematología, Facultad de Ciencias de la Salud, Programa de Investigación Asociativa en Cáncer Gástrico (PIA-CG), Universidad de Talca, Chile
| | - Eduardo Fuentes
- Thrombosis Research Center, Medical Technology School, Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Interdisciplinary Center on Aging, Universidad de Talca, Talca, Chile.
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20
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Varrassi G, Alon E, Bagnasco M, Lanata L, Mayoral-Rojals V, Paladini A, Pergolizzi JV, Perrot S, Scarpignato C, Tölle T. Towards an Effective and Safe Treatment of Inflammatory Pain: A Delphi-Guided Expert Consensus. Adv Ther 2019; 36:2618-2637. [PMID: 31485978 PMCID: PMC6822819 DOI: 10.1007/s12325-019-01053-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Indexed: 12/17/2022]
Abstract
OBJECTIVE The clinical management of inflammatory pain requires an optimal balance between effective analgesia and associated safety risks. To date, mechanisms associated with inflammatory pain are not completely understood because of their complex nature and the involvement of both peripheral and central mechanisms. This Expert Consensus document is intended to update clinicians about evolving areas of clinical practice and/or available treatment options for the management of patients with inflammatory pain. METHOD An international group of experts in pain management covering the pharmacology, neurology and rheumatology fields carried out an independent qualitative systematic literature search using MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. RESULTS Existing guidelines for pain management provide recommendations that do not satisfactorily address the complex nature of pain. To achieve optimal outcomes, drug choices should be individualized to guarantee the best match between the characteristics of the patient and the properties of the medication. NSAIDs represent an important prescribing choice in the management of inflammatory pain, and the recent results on paracetamol question its appropriate use in clinical practice, raising the need for re-evaluation of the recommendations in the clinical practice guidelines. CONCLUSIONS Increasing clinicians' knowledge of the available pharmacologic options to treat different pain mechanisms offers the potential for safe, individualized treatment decisions. We hope that it will help implement the needed changes in the management of inflammatory pain by providing the best strategies and new insights to achieve the ultimate goal of managing the disease and obtaining optimal benefits for patients. FUNDING Dompé Farmaceutici SPA and Paolo Procacci Foundation.
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Affiliation(s)
- Giustino Varrassi
- Paolo Procacci Foundation, Rome, Italy.
- President of World Institute of Pain (WIP), Winston-Salem, NC, USA.
| | - Eli Alon
- University of Zurich, Zurich, Switzerland
| | - Michela Bagnasco
- Medical Affairs Department, Dompé Farmaceutici SpA, Milan, Italy
| | - Luigi Lanata
- Medical Affairs Department, Dompé Farmaceutici SpA, Milan, Italy
| | | | | | | | - Serge Perrot
- Descartes University and Cochin-Hotel Dieu Hospital, Paris, France
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21
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Pfrepper C, Deters S, Metze M, Siegemund R, Gockel I, Petros S. Metamizole inhibits arachidonic acid-induced platelet aggregation after surgery and impairs the effect of aspirin in hospitalized patients. Eur J Clin Pharmacol 2019; 75:777-784. [PMID: 30778625 DOI: 10.1007/s00228-019-02646-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 02/04/2019] [Indexed: 12/29/2022]
Abstract
PURPOSE The inhibitory effect of metamizole on platelet aggregation is known for several years, but most studies were conducted in healthy volunteers with contradictory results. Recent studies have shown an inhibitory effect of metamizole on acetylsalicylic acid (ASA)-induced platelet aggregation. We aimed to investigate the effect of metamizole on platelet aggregation after an elective surgery and the effect of metamizole on ASA-induced platelet aggregation in hospitalized patients. METHODS We performed platelet aggregation analysis after induction with ADP, arachidonic acid (AA), epinephrine, and collagen in 37 patients prior to an elective visceral or thoracic surgery and on postoperative day (POD) 1 and POD 3 1-2 h and 5-6 h after metamizole. In another cohort of 10 hospitalized patients receiving the combination of metamizole and ASA for more than 7 days, AA-induced platelet aggregation was analyzed in the morning prior to the intake of both drugs. RESULTS Metamizole induced a strong inhibitory effect on AA-induced platelet aggregation at all time points being detectable up to 41 h in some patients. Besides a less pronounced effect on collagen-induced platelet aggregation on POD 3 1-2 h after metamizole, all other inductors showed no effect. In 4 out of 10 hospitalized patients, no ASA-induced inhibition of platelet aggregation was detectable without correlation to sequence of administration. CONCLUSIONS The reason why some patients have a long-lasting inhibitory effect of metamizole on COX-induced platelet aggregation that might interfere with ASA should be investigated in a larger cohort of patients.
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Affiliation(s)
- C Pfrepper
- Division of Hemostaseology, University Hospital Leipzig, Liebigstr, 20, 04103, Leipzig, Germany.
| | - S Deters
- Division of Hemostaseology, University Hospital Leipzig, Liebigstr, 20, 04103, Leipzig, Germany
| | - M Metze
- Department of Cardiology, University Hospital Leipzig, Leipzig, Germany
| | - R Siegemund
- Division of Hemostaseology, University Hospital Leipzig, Liebigstr, 20, 04103, Leipzig, Germany
| | - I Gockel
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | - S Petros
- Division of Hemostaseology, University Hospital Leipzig, Liebigstr, 20, 04103, Leipzig, Germany
- University Hospital Leipzig, Medical ICU, Leipzig, Germany
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22
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Gurbel P, Tantry U, Weisman S. A narrative review of the cardiovascular risks associated with concomitant aspirin and NSAID use. J Thromb Thrombolysis 2018; 47:16-30. [DOI: 10.1007/s11239-018-1764-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Dubey PS, Sharma VK, Srinivasan H, Mitra S, Sakai VG, Mukhopadhyay R. Effects of NSAIDs on the Dynamics and Phase Behavior of DODAB Bilayers. J Phys Chem B 2018; 122:9962-9972. [PMID: 30351108 DOI: 10.1021/acs.jpcb.8b07093] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Despite well-known side effects, nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed drugs worldwide for their anti-inflammatory and antipyretic properties. Here, we report the effects of two NSAIDs, aspirin and indomethacin, on the thermotropic phase behavior and the dynamics of a dioctadecyldimethylammonium bromide (DODAB) lipid bilayer as studied using neutron scattering techniques. Elastic fixed window scans showed that the addition of aspirin and indomethacin affects the phase behavior of a DODAB bilayer in both heating and cooling cycles. Upon heating, there is a change in the coagel- to fluid-phase transition temperature from 327 K for pure DODAB bilayer to 321 and 323 K in the presence of aspirin and indomethacin, respectively. More strikingly, upon cooling, the addition of NSAIDs suppresses the formation of the intermediate gel phase observed in pure DODAB. The suppression of the gel phase on addition of the NSAIDs evidences the synchronous ordering of a lipid headgroup and chain. Analysis of quasi-elastic neutron scattering data showed that only localized internal motion exists in the coagel phase, whereas both internal and lateral motions exist in the fluid phase. The internal motion is described by a fractional uniaxial rotational diffusion model in the coagel phase and by a localized translation diffusion model in the fluid phase. In the coagel phase, the rotational diffusion coefficient of DODAB is found to be almost twice for the addition of the drugs, whereas the mobility fraction did not change for indomethacin but becomes twice for aspirin. In the fluid phase, the lateral motion, described well by a continuous diffusion model, is found to be slower by about ∼30% for indomethacin but almost no change for aspirin. For the internal motion, addition of aspirin leads to enhancement of the internal motion, whereas indomethacin did not show significant effect. This study shows that the effect of different NSAIDs on the dynamics of the lipid membrane is not the same; hence, one must consider these NSAIDs individually while studying their action mechanism on the cell membrane.
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Affiliation(s)
- P S Dubey
- Solid State Physics Division , Bhabha Atomic Research Centre , Mumbai 400085 , India
| | - V K Sharma
- Solid State Physics Division , Bhabha Atomic Research Centre , Mumbai 400085 , India
| | - H Srinivasan
- Solid State Physics Division , Bhabha Atomic Research Centre , Mumbai 400085 , India
| | - S Mitra
- Solid State Physics Division , Bhabha Atomic Research Centre , Mumbai 400085 , India.,Homi Bhabha National Institute , Anushaktinagar , Mumbai 400094 , India
| | - V García Sakai
- ISIS Pulsed Neutron and Muon Facility, Science and Technology Facilities Council , Rutherford Appleton Laboratory , Didcot OX11 0QX , U.K
| | - R Mukhopadhyay
- Solid State Physics Division , Bhabha Atomic Research Centre , Mumbai 400085 , India.,Homi Bhabha National Institute , Anushaktinagar , Mumbai 400094 , India
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24
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Dipyrone (metamizole) markedly interferes with platelet inhibition by aspirin in patients with acute and chronic pain: A case-control study. Eur J Anaesthesiol 2018; 34:288-296. [PMID: 28030443 DOI: 10.1097/eja.0000000000000581] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Nonopioid analgesic drugs may interfere with platelet inhibition by aspirin. Recent in vitro and clinical studies in patients with cardiovascular disease have suggested that this pharmacodynamic interaction may also occur with dipyrone, a nonopioid analgesic popular in Europe, Asia and South America. OBJECTIVE Dipyrone is used extensively in acute and chronic pain. This study was undertaken to provide clinical data, so far missing, on its interactions in this group of patients. DESIGN A case-control study. SETTING Primary care in one European university hospital centre. PATIENTS In total, 27 patients with stable cardiovascular, cerebrovascular or peripheral arterial disease and acute or chronic pain were identified and given dipyrone for at least 5 days in combination with low-dose aspirin. In total, 10 comparable patients on low-dose aspirin alone served as controls. MAIN OUTCOME MEASURES Platelet-rich plasma was prepared to determine arachidonic acid-induced aggregation (aggregometry) and thromboxane formation (immunoassay). Platelet sensitivity to aspirin was examined in vitro. The presence of dipyrone (metabolites) in plasma was confirmed by HPLC. Additional in vitro measurements examined the aspirin/dipyrone interaction in healthy donors. RESULTS Inhibition of aggregation was observed in only six of 27 patients receiving aspirin with dipyrone, with absence of complete inhibition by antiplatelet therapy showing in 78% of patients. In contrast, aggregation was completely inhibited in nine of 10 control patients (P < 0.001). Platelet thromboxane synthesis was higher in patients receiving dipyrone + aspirin compared with controls (387 ± 89 vs. 7 ± 1 ng ml, P < 0.001). Aspirin added in vitro failed to inhibit aggregation and thromboxane synthesis in platelet-rich plasma from dipyrone-treated patients. In vitro measurements with blood from healthy individuals confirmed that dipyrone dramatically reduces inhibition of platelet thromboxane synthesis by aspirin. CONCLUSIONS Dipyrone given for 5 days or longer blunts platelet inhibition by low-dose aspirin in the majority of recipients. TRIAL REGISTRATION German Clinical Trials Register: DRKS ID DRKS00000204. Universal Trial Number (UTN): U1111-1113-3946.
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Bally M, Nadeau L, Brophy JM. Studying additive interaction in a healthcare database: Case study of NSAIDs, cardiovascular profiles, and acute myocardial infarction. PLoS One 2018; 13:e0201884. [PMID: 30096158 PMCID: PMC6086415 DOI: 10.1371/journal.pone.0201884] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Accepted: 07/24/2018] [Indexed: 11/29/2022] Open
Abstract
Purpose There are clinical trial data on risk of acute myocardial infarction (MI) with nonsteroidal anti-inflammatory drugs (NSAIDs) in patients at increased cardiovascular (CV) risk requiring chronic daily treatment. This study investigated whether risks of acute MI with real-world prescription NSAIDs, such as low-dose or intermittent use, vary according to an individual’s CV profile. Methods Nested case-control analyses were carried out on an administrative health cohort from Quebec, Canada by randomly selecting 10 controls per case matched on age ± 1 year, sex, and month and year of cohort entry. We measured the additive joint effects on acute MI of current NSAID use and presence of hypertension, coronary heart disease (CHD), history of previous MI, or concomitant use of cardioprotective aspirin. The endpoint was the relative excess risk due to interaction (RERI). To verify the robustness of interaction findings, we performed sensitivity analyses with varying specifications of NSAID exposure-related variables. Results The cohort consisted of 233 816 elderly individuals, including 21 256 acute MI cases. For hypertension, CHD, and previous MI, we identified additive interactions on MI risk with some but not all NSAIDs, which also depended on the definition of NSAID exposure. Hypertension was sub-additive with naproxen but not with the other NSAIDs. Celecoxib and CHD were sub-additive in the primary analysis only (modelling NSAID dose on index date or up to 7 days before–best-fitting base model) whereas celecoxib and rofecoxib were super-additive with a history of previous MI in the secondary analysis only (modelling NSAID use on index date). For cardioprotective aspirin we found no evidence for an additive interaction with any of the NSAIDs. Conclusions Alternative specifications of NSAID exposure concurred in finding that concomitant use of cardioprotective aspirin does not attenuate the risks of acute MI with NSAIDs. However we were unable to demonstrate consistent interactions between an individual’s cardiovascular comorbidities and NSAID-associated acute MI. Our study highlights challenges of studying additive interactions in a healthcare database and underscores the need for sensitivity analyses.
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Affiliation(s)
- Michèle Bally
- Department of Pharmacy and Research Center, University of Montreal Hospital, Montreal, Canada
- * E-mail:
| | - Lyne Nadeau
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Canada
| | - James M. Brophy
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Canada
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada
- Department of Medicine, McGill University Health Centre, Montreal, Canada
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Tsolaki E, Eleftheriou P, Kartsev V, Geronikaki A, Saxena AK. Application of Docking Analysis in the Prediction and Biological Evaluation of the Lipoxygenase Inhibitory Action of Thiazolyl Derivatives of Mycophenolic Acid. Molecules 2018; 23:E1621. [PMID: 29970872 PMCID: PMC6099768 DOI: 10.3390/molecules23071621] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 06/21/2018] [Accepted: 06/27/2018] [Indexed: 12/25/2022] Open
Abstract
5-LOX inhibition is among the desired characteristics of anti-inflammatory drugs, while 15-LOX has also been considered as a drug target. Similarity in inhibition behavior between soybean LOX-1 and human 5-LOX has been observed and soybean LOX (sLOX) type 1b has been used for the evaluation of LOX inhibition in drug screening for years. After prediction of LOX inhibition by PASS and docking as well as toxicity by PROTOX and ToxPredict sixteen (E)-N-(thiazol-2-yl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enamide derivatives with lengths varying from about 15⁻20 Å were evaluated in vitro for LOX inhibitory action using the soybean lipoxygenase sLOX 1b. Docking analysis was performed using soybean LOX L-1 (1YGE), soybean LOX-3 (1JNQ), human 5-LOX (3O8Y and 3V99) and mammalian 15-LOX (1LOX) structures. Different dimensions of target center and docking boxes and a cavity prediction algorithm were used. The compounds exhibited inhibitory action between 2.5 μΜ and 165 μΜ. Substituents with an electronegative atom at two-bond proximity to position 4 of the thiazole led to enhanced activity. Docking results indicated that the LOX structures 1JNQ, 3V99 and 1LOX can effectively be used for estimation of LOX inhibition and amino acid interactions of these compounds.
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Affiliation(s)
- Evangelia Tsolaki
- Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
| | - Phaedra Eleftheriou
- Department of Medical Laboratories, School of Health and Care Professions, Alexander Technological Educational Institute of Thessaloniki, 54700 Thessaloniki, Greece.
| | | | - Athina Geronikaki
- Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
| | - Anil K Saxena
- Division of Medicinal & Process Chemistry, Central Drug Research Institute, 226031 Lucknow, India.
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Hartinger J, Novotny R, Bilkova J, Kvasnicka T, Mitas P, Sima M, Hlubocky J, Kvasnicka J, Slanar O, Lindner J. Role of Dipyrone in the High On-Treatment Platelet Reactivity amongst Acetylsalicylic Acid-Treated Patients Undergoing Peripheral Artery Revascularisation. Med Princ Pract 2018; 27:356-361. [PMID: 29754149 PMCID: PMC6167732 DOI: 10.1159/000489970] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Accepted: 05/13/2018] [Indexed: 01/29/2023] Open
Abstract
OBJECTIVE To evaluate the effects of dipyrone on sensitivity to aspirin (acetylsalicylic acid [ASA]) in patients who underwent peripheral artery vascular reconstruction. SUBJECTS AND METHODS Impedance aggregometry and light transmission aggregometry were used to determine the effects of dipyrone on ASA treatment in 21 patients. Blood samples were drawn in a 7-day period after the surgery. The cut-off value for high on-treatment platelet reactivity (HTPR) was set at < 65% of aggregation inhibition for impedance aggregometry. For light transmission aggregometry the cut-off value for arachidonic acid-induced aggregation was set at > 20% of aggregating platelets, and the cut-off value for epinephrine-induced aggregation was > 44% of aggregating platelets. The cut-off value for each method was derived from a large number of patients treated with a daily dose of 100 mg of ASA. RESULTS We found HTPR in 14 (67%) of the 21 patients. None had primary resistance to ASA, i.e., after the addition of ASA in vitro all samples showed antiplatelet efficacy. Regression analysis showed a possible correlation between lower efficacy of ASA treatment and higher daily doses of dipyrone (p = 0.005 for impedance aggregometry, p = 0.04 for light transmission aggregometry), higher platelet count (p = 0.005 for impedance aggregometry), and shorter time from surgery (p = 0.03 for impedance aggregometry). CONCLUSION HTPR occurs in 67% of ASA-treated patients after lower limb vascular surgery. The occurrence of HTPR correlates with the daily dose of dipyrone. Therefore, dipyrone should not be used as a postoperative analgesic in ASA-treated patients after peripheral artery revascularisation due to its influence on the effectiveness of ASA.
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Affiliation(s)
- Jan Hartinger
- Department of Clinical Pharmacology and Pharmacy, Institute of Pharmacology, General University Hospital and 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | - Robert Novotny
- Transplant Surgery Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- *Robert Novotny, Transplant Surgery Department, Institute for Clinical and Experimental Medicine, Videnska 1958/9, CZ-140 21 Prague 4 (Czech Republic), E-Mail
| | - Jana Bilkova
- Thrombotic Centre, General University Hospital, Prague, Czech Republic
| | - Tomas Kvasnicka
- Thrombotic Centre, General University Hospital, Prague, Czech Republic
| | - Petr Mitas
- 2nd Department of Cardiovascular Surgery, General University Hospital and 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | - Martin Sima
- Department of Clinical Pharmacology and Pharmacy, Institute of Pharmacology, General University Hospital and 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | - Jaroslav Hlubocky
- 2nd Department of Cardiovascular Surgery, General University Hospital and 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | - Jan Kvasnicka
- Thrombotic Centre, General University Hospital, Prague, Czech Republic
| | - Ondrej Slanar
- Department of Clinical Pharmacology and Pharmacy, Institute of Pharmacology, General University Hospital and 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | - Jaroslav Lindner
- 2nd Department of Cardiovascular Surgery, General University Hospital and 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
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Lin TC, Solomon DH, Tedeschi SK, Yoshida K, Kao Yang YH. Comparative Risk of Cardiovascular Outcomes Between Topical and Oral Nonselective NSAIDs in Taiwanese Patients With Rheumatoid Arthritis. J Am Heart Assoc 2017; 6:e006874. [PMID: 29079568 PMCID: PMC5721772 DOI: 10.1161/jaha.117.006874] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 09/26/2017] [Indexed: 01/29/2023]
Abstract
BACKGROUND Topical NSAIDs have less systemic absorption than oral NSAIDs. We examined the risk of cardiovascular events associated with nonselective topical NSAIDs versus oral NSAIDs among patients with rheumatoid arthritis in Taiwan. METHODS AND RESULTS We conducted a retrospective cohort study that included patients with incident rheumatoid arthritis who were newly starting therapy with nonselective topical NSAIDs or oral NSAIDs. We used the Taiwan National Health Insurance Research Database (NHIRD). The first date patients received either type of NSAID was defined as the index date. NSAID exposures continued until there was a treatment gap of >30 days. The main outcome was composite cardiovascular events, including myocardial infarction, unstable angina, heart failure, stroke, or revascularization. Follow-up was censored at treatment discontinuation, switch or addition of other NSAID category, cardiovascular outcome, death, or the end of the study. Propensity score weighted Cox regression models were used to compare the risk of cardiovascular events between topical NSAIDs and oral NSAIDs. There were 10 758 and 78 056 treatment episodes for topical and oral NSAIDs identified. After weighting by propensity score, the cohorts were well balanced over all covariates. The crude cardiovascular event rate was 1.87 per 100 person-years for topical NSAIDs and 2.14 per 100 person-years for oral NSAIDs. Results of propensity score weighted Cox regression found the topical NSAID group had 36% lower risk for cardiovascular events compared with the oral NSAID group (hazard ratio, 0.64; 95% confidence interval, 0.43-0.95). CONCLUSIONS We found topical NSAID users experienced a reduced risk of cardiovascular events compared with oral NSAID users. If future studies with a larger sample size and longer follow-up confirm these results, NSAID prescribing might change accordingly.
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Affiliation(s)
- Tzu-Chieh Lin
- Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Daniel H Solomon
- Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA
- Harvard Medical School, Boston, MA
- Division of Pharmacoepideimiology and Pharmacoeconomics, Brigham and Women's Hospital, Boston, MA
| | - Sara K Tedeschi
- Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Kazuki Yoshida
- Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA
- Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Yea-Huei Kao Yang
- Health Outcome Research Center, National Cheng Kung University, Tainan, Taiwan
- School of Pharmacy, College of Medicine, Tainan, Taiwan
- Institute of Clinical Pharmacy and Pharmaceutical Science, National Cheng Kung University, Tainan, Taiwan
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Wilczyński M, Wybraniec MT, Sanak M, Góral J, Mizia-Stec K. Metamizole and Platelet Inhibition by Aspirin Following On-Pump Coronary Artery Bypass Grafting. J Cardiothorac Vasc Anesth 2017; 32:178-186. [PMID: 29107589 DOI: 10.1053/j.jvca.2017.06.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Indexed: 12/30/2022]
Abstract
OBJECTIVE The purpose of the study was to evaluate the impact of intravenous metamizole on platelet inhibition by aspirin in patients with coronary artery disease early after on-pump coronary artery bypass grafting (CABG). DESIGN Prospective, single-blind, randomized trial. SETTING Tertiary referal hospital. PARTICIPANTS The study comprised 43 patients with multivessel coronary artery disease undergoing CABG. INTERVENTIONS Patients were randomized to postoperative intravenous metamizole ± opioids (study group; n = 23) or opioids alone (control group; n = 20). Aspirin was withheld at least 7 days before the surgery and reinitiated (300 mg) immediately after the procedure prior to metamizole use, and continued daily thereafter (150 mg). Platelet function was evaluated using multielectrode impedance aggregometry (acid-induced platelet activation [ASPI] and collagen-induced platelet activation [COL] test), P-selectin expression and urinary 11-dehydro-thromboxane B2 (11-DTXB2) level at baseline, postoperative day (POD) 0, POD 1, POD 2, and POD 6. Residual platelet reactivity (RPR) was defined as ASPI test >400 AU*min. MEASUREMENTS AND MAIN RESULTS In all study participants, postoperative ASPI test value moderately decreased (1058.2 v 966.6 AU*min, p = 0.047), urinary 11-DTXB2 level increased (923.4 v 4367.3 pg/mg, p < 0.001), and P-selectin expression and COL test value remained stable postprocedure. The decreases of ASPI (p = 0.146) and COL test (p = 0.642), and P-selectin expression (p = 0.318) did not differ between both groups. Patients in the control group had higher postoperative increase of urinary 11-DTXB2 level (p = 0.001). The prevalence of RPR was high and comparable between study and control groups (day 1, 95.6% v 100%, p = 0.535; day 6, 100% v 90%, p = 0.21). Multivariate analysis revealed that metamizole use did not predict the fluctuations of ASPI and COL test values and P-selectin expression, yet it independently predicted postoperative change of 11-DTXB2 level (b = -0.518, p = 0.001). CONCLUSIONS Intravenous metamizole preceded by a loading dose of aspirin did not modify platelet response to aspirin in the postoperative period after CABG.
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Affiliation(s)
| | - Maciej T Wybraniec
- First Department of Cardiology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland; Public Hospital No 7 in Katowice, Upper Silesia Medical Center.
| | - Marek Sanak
- II Department of Internal Medicine, Division of Molecular Biology and Clinical Genetics, Jagiellonian University Medical College, Kraków, Poland
| | - Joanna Góral
- Department of Laboratory Medicine, Public Hospital No 7 in Katowice, Upper Silesia Medical Center, Katowice, Poland
| | - Katarzyna Mizia-Stec
- First Department of Cardiology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland; Public Hospital No 7 in Katowice, Upper Silesia Medical Center
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Molica F, Stierlin FB, Fontana P, Kwak BR. Pannexin- and Connexin-Mediated Intercellular Communication in Platelet Function. Int J Mol Sci 2017; 18:E850. [PMID: 28420171 PMCID: PMC5412434 DOI: 10.3390/ijms18040850] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 04/06/2017] [Accepted: 04/12/2017] [Indexed: 12/11/2022] Open
Abstract
The three major blood cell types, i.e., platelets, erythrocytes and leukocytes, are all produced in the bone marrow. While red blood cells are the most numerous and white cells are the largest, platelets are small fragments and account for a minor part of blood volume. However, platelets display a crucial function by preventing bleeding. Upon vessel wall injury, platelets adhere to exposed extracellular matrix, become activated, and form a platelet plug preventing hemorrhagic events. However, when platelet activation is exacerbated, as in rupture of an atherosclerotic plaque, the same mechanism may lead to acute thrombosis causing major ischemic events such as myocardial infarction or stroke. In the past few years, major progress has been made in understanding of platelet function modulation. In this respect, membrane channels formed by connexins and/or pannexins are of particular interest. While it is still not completely understood whether connexins function as hemichannels or gap junction channels to inhibit platelet aggregation, there is clear-cut evidence for a specific implication of pannexin1 channels in collagen-induced aggregation. The focus of this review is to summarize current knowledge of the role of connexins and pannexins in platelet aggregation and to discuss possible pharmacological approaches along with their limitations and future perspectives for new potential therapies.
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Affiliation(s)
- Filippo Molica
- Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland.
- Department of Medical Specializations, Cardiology, University of Geneva, 1211 Geneva, Switzerland.
| | - Florian B Stierlin
- Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland.
- Department of Medical Specializations, Cardiology, University of Geneva, 1211 Geneva, Switzerland.
- Geneva Platelet Group, University of Geneva, 1211 Geneva, Switzerland.
| | - Pierre Fontana
- Geneva Platelet Group, University of Geneva, 1211 Geneva, Switzerland.
- Division of Angiology and Haemostasis, Geneva University Hospitals, 1211 Geneva, Switzerland.
| | - Brenda R Kwak
- Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland.
- Department of Medical Specializations, Cardiology, University of Geneva, 1211 Geneva, Switzerland.
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Achilles A, Mohring A, Dannenberg L, Piayda K, Levkau B, Hohlfeld T, Zeus T, Kelm M, Polzin A. Analgesic medication with dipyrone in patients with coronary artery disease: Relation to MACCE. Int J Cardiol 2017; 236:76-81. [PMID: 28262342 DOI: 10.1016/j.ijcard.2017.02.122] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2016] [Revised: 02/19/2017] [Accepted: 02/24/2017] [Indexed: 01/07/2023]
Abstract
BACKGROUND The non-opioid analgesic dipyrone can trigger life-threatening blood formation disorders. However, it is frequently used, as many patients with coronary artery disease (CAD) rely on non-opioid analgesics to relieve pain. In this study, we investigated the incidence of death, myocardial infarction (MI) or stroke in CAD patients with aspirin and dipyrone comedication as compared to aspirin-alone. METHODS We conducted an observational pilot study in 72 CAD patients with aspirin ± dipyrone comedication in the department of cardiology of the University Hospital Düsseldorf. The primary end point was a composite of death, myocardial infarction (MI) or stroke. The secondary end points were the components of the primary end point. The median follow-up period was 3.2years. RESULTS The primary end point occurred 67% of patients in the aspirin+dipyrone group as compared to 31% in the aspirin-alone group (odds ratio [OR] 4.5, 95% confidence interval [CI] 1.7 to 12.3; P=0.0028;). All-cause mortality was significantly higher in the aspirin+dipyrone group (44%) than the aspirin-alone group (22%; OR 2.8, 95% CI 1.01 to 7.8; P=0.049). Ischemic events (MI and stroke) were more frequent in the aspirin+dipyrone group as compared to the aspirin alone group as well (OR 4, 95% CI 1.1 to 14; P=0.03). CONCLUSION In this hypothesis generating pilot analysis, dipyrone medication in aspirin treated coronary artery disease patients is associated with an increased cumulative incidence of death, MI or stroke as well as all-cause mortality and ischemic events. These data have to be confirmed in larger registries and trials. CLINICAL TRIAL REGISTRATION http://clinicaltrials.gov/ct2/show/NCT01402804; Identifier: NCT01402804; Date of registration: July 25, 2011.
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Affiliation(s)
- Alina Achilles
- Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany
| | - Annemarie Mohring
- Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany
| | - Lisa Dannenberg
- Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany
| | - Kerstin Piayda
- Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany
| | - Bodo Levkau
- Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Thomas Hohlfeld
- Institute for Pharmacology and Clinical Pharmacology, Heinrich Heine University, Dusseldorf, Germany
| | - Tobias Zeus
- Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany
| | - Malte Kelm
- Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany
| | - Amin Polzin
- Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany.
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32
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Aspirin, stroke and drug-drug interactions. Vascul Pharmacol 2016; 87:14-22. [DOI: 10.1016/j.vph.2016.10.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 10/06/2016] [Accepted: 10/14/2016] [Indexed: 12/29/2022]
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Abstract
Mainly due to the general demographic changes and decreasing mortality in rheumatic diseases based on therapeutic progress, the proportion of older patients treated by rheumatologists is growing. Drug treatment in the elderly, however, harbors certain risks including age-specific pharmacokinetic features and high rates of multimorbidity and polypharmacy resulting in a risk of drug interactions and adherence problems. Nevertheless, older patients suffering from rheumatic diseases ought to be treated with the same intensity and same targets as the younger counterparts. Bearing all these facts in mind it is a balancing act for rheumatologists to find an optimal treatment for the individual elderly patient. Fear of risks should not lead to hesitant use of drugs leaving these patients alone with treatment deficits, as some studies have suggested.
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Affiliation(s)
- K Krüger
- Rheumatologisches Praxiszentrum, St. Bonifatius Str. 5, 81541, München, Deutschland.
| | - A Strangfeld
- Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin, Deutschland
| | - C Kneitz
- Klinik für Innere Medizin II, Rheumatologie/Immunologie, Rheumazentrum, Klinikum Südstadt Rostock, Rostock, Deutschland
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Mesaros C, Blair IA. Mass spectrometry-based approaches to targeted quantitative proteomics in cardiovascular disease. Clin Proteomics 2016; 13:20. [PMID: 27713681 PMCID: PMC5050566 DOI: 10.1186/s12014-016-9121-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 07/19/2016] [Indexed: 01/11/2023] Open
Abstract
Mass spectrometry-based proteomics methodology has become an important tool in elucidating some of the underlying mechanisms involved in cardiovascular disease. The present review provides details on selected important protein targets where highly selective and specific mass spectrometry-based approaches have led to important new findings and provided new mechanistic information. The role of six proteins involved in the etiology of cardiovascular disease (acetylated platelet cyclooxygenase-1, serum apolipoprotein A1, apolipoprotein C-III, serum C-reactive protein, serum high mobility group box-1 protein, insulin-like growth factor I) and their quantification has been discussed. There are an increasing number of examples where highly selective mass spectrometry-based quantification has provided new important data that could not be obtained with less labor intensive and cheaper immunoassay-based procedures. It is anticipated that these findings will lead to significant advances in a number of important issues related to the role of specific proteins in cardiovascular disease. The availability of a new generation of high-resolution high-sensitivity mass spectrometers will greatly facilitate these studies so that in the future it will be possible to analyze serum proteins of relevance to cardiovascular disease with levels of specificity and/or sensitivity that cannot be attained by immunoassay-based procedures.
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Affiliation(s)
- Clementina Mesaros
- Penn SRP Center and Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104 USA ; BluePen Biomarkers, 3401 Grays Ferry Avenue, Philadelphia, PA 19146-2799 USA
| | - Ian A Blair
- Penn SRP Center and Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104 USA ; BluePen Biomarkers, 3401 Grays Ferry Avenue, Philadelphia, PA 19146-2799 USA
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35
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Deveza LA, Hunter DJ. Pain Relief for an Osteoarthritic Knee in the Elderly: A Practical Guide. Drugs Aging 2016; 33:11-20. [PMID: 26659733 DOI: 10.1007/s40266-015-0331-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In view of the increasing prevalence of knee osteoarthritis (OA) in the population worldwide, optimal management is critical to decrease the burden of this condition and minimize disability and personal suffering. Current care is based on a sequence of non-pharmacological, pharmacological, and surgical modalities, targeted to improving pain and function in the elderly population. The aim of this article is to provide a practical view of the efficacy of therapeutic options available along with clinically relevant considerations on the management of knee OA in this demographic group.
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Affiliation(s)
- Leticia A Deveza
- Rheumatology Department, Royal North Shore Hospital and Institute of Bone and Joint Research, Kolling Institute, University of Sydney, Reserve Road, St. Leonards, Sydney, NSW, 2065, Australia
| | - David J Hunter
- Rheumatology Department, Royal North Shore Hospital and Institute of Bone and Joint Research, Kolling Institute, University of Sydney, Reserve Road, St. Leonards, Sydney, NSW, 2065, Australia.
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Dannenberg L, Erschoff V, Bönner F, Gliem M, Jander S, Levkau B, Kelm M, Hohlfeld T, Zeus T, Polzin A. Dipyrone comedication in aspirin treated stroke patients impairs outcome. Vascul Pharmacol 2016; 87:66-69. [PMID: 27301652 DOI: 10.1016/j.vph.2016.06.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Revised: 06/03/2016] [Accepted: 06/10/2016] [Indexed: 11/16/2022]
Abstract
BACKGROUND >50% of stroke patients rely on analgesic medication to control pain. Aspirin is the mainstay of medical treatment of stroke patients; however analgesic medication with dipyrone impairs aspirin antiplatelet effects ex-vivo. The clinical impact of this impairment is unknown. Therefore, we aimed to determine aspirin antiplatelet effects and neurological outcome in stroke patients with aspirin and dipyrone comedication. METHODS We conducted a prospective cohort study in 41 patients with stroke. Primary outcome was pharmacodynamic response to aspirin in dipyrone treated stroke patients. Secondary outcome was neurological recovery after stroke. Pharmacodynamic response to aspirin was measured using arachidonic acid induced aggregation in light-transmission aggregometry. Neurological outcome was determined three months after stroke onset by telephone interview. RESULTS Patient's characteristics were similar in the aspirin-alone group and the aspirin+dipyrone group. Impaired pharmacodynamic response to aspirin occurred in 62% (14/21) of patients with aspirin and dipyrone co-medication. Only 10% (2/20) of aspirin treated patients without analgesic comedication displayed residual platelet reactivity (P=0.001; odds ratio [OR], 18 [95% CI, 3.2-100]). Excellent neurological recovery (measured by three months follow-up modified Rankin Scale<2) was observed in 80% (16/20) of patients in the aspirin-alone group and 48% (10/21) of patients in the aspirin+dipyrone group (P=0.037; OR, 4.4 [95% CI, 1.1-17.7]). CONCLUSIONS Dipyrone comedication in patients with stroke impairs pharmacodynamic response to aspirin. This is associated with worse clinical outcome. Therefore dipyrone should be used with caution in aspirin treated stroke patients. CLINICAL TRIAL REGISTRATION https://clinicaltrials.gov/show/NCT02148939; Identifier: NCT02148939.
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Affiliation(s)
- Lisa Dannenberg
- Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany
| | - Vladimir Erschoff
- Institute for Pharmacology and Clinical Pharmacology, Heinrich Heine University, Dusseldorf, Germany
| | - Florian Bönner
- Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany
| | - Michael Gliem
- Department of Neurology, Heinrich Heine University, Dusseldorf, Germany
| | - Sebastian Jander
- Department of Neurology, Heinrich Heine University, Dusseldorf, Germany
| | - Bodo Levkau
- Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Malte Kelm
- Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany
| | - Thomas Hohlfeld
- Institute for Pharmacology and Clinical Pharmacology, Heinrich Heine University, Dusseldorf, Germany
| | - Tobias Zeus
- Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany
| | - Amin Polzin
- Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany.
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Saito MS, Lourenço AL, Dias LRS, Freitas ACC, Vitorino MI, Albuquerque MG, Rodrigues CR, Cabral LM, Dias EP, Castro HC, Satlher PC. Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization. J Enzyme Inhib Med Chem 2016; 31:1591-601. [DOI: 10.3109/14756366.2016.1158712] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Max Seidy Saito
- Laboratório de Antibióticos, Bioquímica, Ensino e Modelagem Molecular (LABiEMol) – Instituto de Biologia, Universidade Federal Fluminense, Niterói, Brazil,
- Programa de Pós-Graduação em Patologia (PPG-UFF) – Hospital Universitário Antônio Pedro, Universidade Federal Fluminense, Niterói, Brazil,
| | - André Luiz Lourenço
- Laboratório de Antibióticos, Bioquímica, Ensino e Modelagem Molecular (LABiEMol) – Instituto de Biologia, Universidade Federal Fluminense, Niterói, Brazil,
- Programa de Pós-Graduação em Patologia (PPG-UFF) – Hospital Universitário Antônio Pedro, Universidade Federal Fluminense, Niterói, Brazil,
| | - Luiza Rosaria Sousa Dias
- Laboratório de Química Medicinal (LQMed) – Faculdade de Farmácia, Universidade Federal Fluminense, Niterói, Brazil,
| | | | - Maíra Ingrid Vitorino
- Laboratório de Antibióticos, Bioquímica, Ensino e Modelagem Molecular (LABiEMol) – Instituto de Biologia, Universidade Federal Fluminense, Niterói, Brazil,
| | | | | | - Lúcio Mendes Cabral
- Laboratório de Tecnologia Industrial Farmacêutica (LabTIF) – Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Eliane Pedra Dias
- Programa de Pós-Graduação em Patologia (PPG-UFF) – Hospital Universitário Antônio Pedro, Universidade Federal Fluminense, Niterói, Brazil,
| | - Helena Carla Castro
- Laboratório de Antibióticos, Bioquímica, Ensino e Modelagem Molecular (LABiEMol) – Instituto de Biologia, Universidade Federal Fluminense, Niterói, Brazil,
- Programa de Pós-Graduação em Patologia (PPG-UFF) – Hospital Universitário Antônio Pedro, Universidade Federal Fluminense, Niterói, Brazil,
| | - Plínio Cunha Satlher
- Laboratório de Antibióticos, Bioquímica, Ensino e Modelagem Molecular (LABiEMol) – Instituto de Biologia, Universidade Federal Fluminense, Niterói, Brazil,
- Laboratório de Tecnologia Industrial Farmacêutica (LabTIF) – Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Aminoshariae A, Kulild JC, Donaldson M. Short-term use of nonsteroidal anti-inflammatory drugs and adverse effects: An updated systematic review. J Am Dent Assoc 2016; 147:98-110. [PMID: 26562732 DOI: 10.1016/j.adaj.2015.07.020] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/21/2015] [Accepted: 07/31/2015] [Indexed: 01/08/2023]
Abstract
BACKGROUND In this article, the authors examine the available scientific evidence regarding adverse effects of short-term use of nonsteroidal anti-inflammatory drugs (NSAIDs). Short-term use was defined as 10 days or fewer. METHODS The authors reviewed randomized controlled clinical trials and cohort and case-controlled clinical studies published between 2001 and June 2015 in which the investigators reported on the safety of nonselective cyclooxygenase inhibitors and of cyclooxygenase-2 selective inhibitor NSAIDs. RESULTS The systematic review process according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines allowed the authors to identify 40 studies that met the inclusion criteria. CONCLUSIONS On the basis of the available scientific evidence, NSAIDs may be considered relatively safe drugs when prescribed at the most effective dose and for the shortest duration of time, which was defined to be 10 days or fewer. PRACTICAL IMPLICATIONS Although the US Food and Drug Administration recommends the use of NSAIDs beyond 10 days to be accompanied by a consultation with a health care provider, the use of NSAIDs may be considered relatively safe when prescribed at the most effective dose and for the shortest duration of time, which was defined as 10 days or fewer. Exceptions would be for patients at risk of developing NSAID-exacerbated respiratory disease, patients with prior myocardial infarction who are receiving antithrombotic therapy, patients with asthma, and patients with a history of renal disease.
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Abstract
PURPOSE OF REVIEW The indications for aspirin (ASA) for both primary and secondary prevention of thrombotic events continue to evolve. We review some of these indications and the recent literature regarding the perioperative administration of ASA. RECENT FINDINGS ASA for primary prevention of cardiac ischemia, stroke, cancer, and death remains controversial. When used for primary prevention, ASA may be safely discontinued perioperatively. Patients with coronary or carotid artery stents should continue to receive ASA perioperatively. For patients with ischemic heart disease currently receiving ASA for secondary prevention of cardiac ischemia and stroke undergoing general surgery, orthopedic surgery, ophthalmological surgery, cardiovascular surgery, major vascular surgery, or a urological procedure, continuation of ASA is probably well tolerated, but further study is required. There is no indication to initiate ASA perioperatively in patients with stable ischemic heart disease as the risks outweigh the benefits. Until further data become available, decisions regarding the perioperative continuation of ASA should be made on a case-by-case risk-benefit analysis. SUMMARY The continuation or discontinuation of ASA perioperatively remains a complicated issue. Further, well designed trials are needed for additional clarification.
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40
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Mandalapu D, Singh DK, Gupta S, Balaramnavar VM, Shafiq M, Banerjee D, Sharma VL. Discovery of monocarbonyl curcumin hybrids as a novel class of human DNA ligase I inhibitors: in silico design, synthesis and biology. RSC Adv 2016. [DOI: 10.1039/c5ra25853g] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
A pharmacophore model identified a novel class of hLigI inhibitors to treat cancer. 36 compounds were synthesized and the identified inhibitor, compound 23 shown antiligase activity at IC50 24.9 μM by abolishing the interaction between hLigI and DNA.
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Affiliation(s)
- Dhanaraju Mandalapu
- Medicinal & Process Chemistry Division
- CSIR-Central Drug Research Institute (CSIR-CDRI)
- Lucknow
- India
| | - Deependra Kumar Singh
- Molecular & Structural Biology Division
- CSIR-Central Drug Research Institute (CSIR-CDRI)
- Lucknow
- India
| | - Sonal Gupta
- Medicinal & Process Chemistry Division
- CSIR-Central Drug Research Institute (CSIR-CDRI)
- Lucknow
- India
- Academy of Scientific and Innovative Research (AcSIR)
| | - Vishal M. Balaramnavar
- Molecular & Structural Biology Division
- CSIR-Central Drug Research Institute (CSIR-CDRI)
- Lucknow
- India
| | - Mohammad Shafiq
- Molecular & Structural Biology Division
- CSIR-Central Drug Research Institute (CSIR-CDRI)
- Lucknow
- India
| | - Dibyendu Banerjee
- Molecular & Structural Biology Division
- CSIR-Central Drug Research Institute (CSIR-CDRI)
- Lucknow
- India
- Academy of Scientific and Innovative Research (AcSIR)
| | - Vishnu Lal Sharma
- Medicinal & Process Chemistry Division
- CSIR-Central Drug Research Institute (CSIR-CDRI)
- Lucknow
- India
- Academy of Scientific and Innovative Research (AcSIR)
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41
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Rowcliffe M, Nezami B, Westphal ES, Rainka M, Janda M, Bates V, Gengo F. Topical diclofenac does not affect the antiplatelet properties of aspirin as compared to the intermediate effects of oral diclofenac: A prospective, randomized, complete crossover study. J Clin Pharmacol 2015; 56:422-8. [PMID: 26265197 DOI: 10.1002/jcph.615] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Accepted: 08/06/2015] [Indexed: 11/07/2022]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) adversely interact with aspirin, diminishing its antiplatelet effect and potentially placing patients at an increased risk for recurrent thrombotic events. This crossover study aimed to determine whether the topical NSAID diclofenac epolamine 1.3% patch or oral diclofenac 50 mg interfered with the antiplatelet effects of aspirin 325 mg. Twelve healthy men and women aged 18-50 were included. Participants were randomized into 5 treatment arms: aspirin, diclofenac potassium 50 mg, diclofenac patch, diclofenac potassium plus ASA 325 mg, and diclofenac patch plus aspirin. Platelet responsiveness was determined using whole-blood impedance aggregation (WBA) to collagen 1 μg/mL and arachidonic acid (AA) 0.5 mM and was sampled every 2 hours. No significant difference in platelet function was observed following the diclofenac patch and aspirin vs aspirin alone. Oral diclofenac produced a mixed effect with significant reduction in platelet inhibition at hour 2 and hour 8 following aspirin administration. Topical diclofenac does not significantly interfere with the antiplatelet effects of aspirin and may be a safer alternative to the oral formulation.
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Affiliation(s)
- M Rowcliffe
- Dent Neurologic Institute, Amherst, NY, USA.,State University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA
| | | | | | - M Rainka
- Dent Neurologic Institute, Amherst, NY, USA
| | - M Janda
- State University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA
| | - V Bates
- Dent Neurologic Institute, Amherst, NY, USA
| | - F Gengo
- Dent Neurologic Institute, Amherst, NY, USA.,State University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA
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Sashidhara KV, Avula SR, Doharey PK, Singh LR, Balaramnavar VM, Gupta J, Misra-Bhattacharya S, Rathaur S, Saxena AK, Saxena JK. Designing, synthesis of selective and high-affinity chalcone-benzothiazole hybrids as Brugia malayi thymidylate kinase inhibitors: In vitro validation and docking studies. Eur J Med Chem 2015; 103:418-28. [DOI: 10.1016/j.ejmech.2015.09.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 09/01/2015] [Accepted: 09/02/2015] [Indexed: 11/29/2022]
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Polzin A, Hohlfeld T, Kelm M, Zeus T. Impairment of aspirin antiplatelet effects by non-opioid analgesic medication. World J Cardiol 2015; 7:383-391. [PMID: 26225198 PMCID: PMC4513489 DOI: 10.4330/wjc.v7.i7.383] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 05/28/2015] [Accepted: 06/16/2015] [Indexed: 02/06/2023] Open
Abstract
Aspirin is the mainstay in prophylaxis of cardiovascular diseases. Impaired aspirin antiplatelet effects are associated with enhanced incidence of cardiovascular events. Comedication with non-opioid analgesic drugs has been described to interfere with aspirin, resulting in impaired aspirin antiplatelet effects. Additionally, non-opioid analgesic medication has been shown to enhance the risk of cardiovascular events and death. Pain is very frequent and many patients rely on analgesic drugs to control pain. Therefore effective analgesic options without increased risk of cardiovascular events are desirable. This review focuses on commonly used non-opioid analgesics, interactions with aspirin medication and impact on cardiovascular risk.
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Moore N, Pollack C, Butkerait P. Adverse drug reactions and drug-drug interactions with over-the-counter NSAIDs. Ther Clin Risk Manag 2015. [PMID: 26203254 PMCID: PMC4508078 DOI: 10.2147/tcrm.s79135] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have a long history of safe and effective use as both prescription and over-the-counter (OTC) analgesics/antipyretics. The mechanism of action of all NSAIDs is through reversible inhibition of cyclooxygenase enzymes. Adverse drug reactions (ADRs) including gastrointestinal bleeding as well as cardiovascular and renal effects have been reported with NSAID use. In many cases, ADRs may occur because of drug-drug interactions (DDIs) between the NSAID and a concomitant medication. For example, DDIs have been reported when NSAIDs are coadministered with aspirin, alcohol, some antihypertensives, antidepressants, and other commonly used medications. Because of the pharmacologic nature of these interactions, there is a continuum of risk in that the potential for an ADR is dependent on total drug exposure. Therefore, consideration of dose and duration of NSAID use, as well as the type or class of comedication administered, is important when assessing potential risk for ADRs. Safety findings from clinical studies evaluating prescription-strength NSAIDs may not be directly applicable to OTC dosing. Health care providers can be instrumental in educating patients that using OTC NSAIDs at the lowest effective dose for the shortest required duration is vital to balancing efficacy and safety. This review discusses some of the most clinically relevant DDIs reported with NSAIDs based on major sites of ADRs and classes of medication, with a focus on OTC ibuprofen, for which the most data are available.
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Affiliation(s)
- Nicholas Moore
- Department of Pharmacology, Université de Bordeaux, Bordeaux, France
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Machado-Alba JE, García S, Calvo-Torres LF, Bañol-Giraldo AM. Patrones de prescripción del ácido acetilsalicílico. REVISTA COLOMBIANA DE CARDIOLOGÍA 2015. [DOI: 10.1016/j.rccar.2015.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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46
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Lourenço AL, Saito MS, Dorneles LEG, Viana GM, Sathler PC, Aguiar LCDS, de Pádula M, Domingos TFS, Fraga AGM, Rodrigues CR, de Sousa VP, Castro HC, Cabral LM. Synthesis and antiplatelet activity of antithrombotic thiourea compounds: biological and structure-activity relationship studies. Molecules 2015; 20:7174-200. [PMID: 25903367 PMCID: PMC6272548 DOI: 10.3390/molecules20047174] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 04/08/2015] [Accepted: 04/13/2015] [Indexed: 12/31/2022] Open
Abstract
The incidence of hematological disorders has increased steadily in Western countries despite the advances in drug development. The high expression of the multi-resistance protein 4 in patients with transitory aspirin resistance, points to the importance of finding new molecules, including those that are not affected by these proteins. In this work, we describe the synthesis and biological evaluation of a series of N,N'-disubstituted thioureas derivatives using in vitro and in silico approaches. New designed compounds inhibit the arachidonic acid pathway in human platelets. The most active thioureas (compounds 3d, 3i, 3m and 3p) displayed IC50 values ranging from 29 to 84 µM with direct influence over in vitro PGE2 and TXA2 formation. In silico evaluation of these compounds suggests that direct blockage of the tyrosyl-radical at the COX-1 active site is achieved by strong hydrophobic contacts as well as electrostatic interactions. A low toxicity profile of this series was observed through hemolytic, genotoxic and mutagenic assays. The most active thioureas were able to reduce both PGE2 and TXB2 production in human platelets, suggesting a direct inhibition of COX-1. These results reinforce their promising profile as lead antiplatelet agents for further in vivo experimental investigations.
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Affiliation(s)
- André Luiz Lourenço
- Programa de Pós-graduação em Patologia, Departamento de Patologia, Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense (UFF), Niterói CEP 24033-900, RJ, Brazil.
| | - Max Seidy Saito
- Programa de Pós-graduação em Patologia, Departamento de Patologia, Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense (UFF), Niterói CEP 24033-900, RJ, Brazil.
| | - Luís Eduardo Gomes Dorneles
- LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil.
| | - Gil Mendes Viana
- LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil.
| | - Plínio Cunha Sathler
- LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil.
| | | | - Marcelo de Pádula
- LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil.
| | | | - Aline Guerra Manssour Fraga
- LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil.
| | - Carlos Rangel Rodrigues
- ModMolQSAR, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil.
| | - Valeria Pereira de Sousa
- LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil.
| | - Helena Carla Castro
- LABiEMOL, Departamento de Biologia Celular e Molecular, Universidade Federal Fluminense (UFF), Niterói CEP 24033-900, RJ, Brazil.
| | - Lucio Mendes Cabral
- LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil.
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Cazacu I, Mogosan C, Loghin F. Safety issues of current analgesics: an update. ACTA ACUST UNITED AC 2015; 88:128-36. [PMID: 26528060 PMCID: PMC4576793 DOI: 10.15386/cjmed-413] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 03/17/2015] [Indexed: 12/18/2022]
Abstract
Pain represents a complex experience which can be approached by various medicines. Non-opioid and opioid analgesics are the most common drugs used to manage different types of pain. The increased attention nowadays to pain management entailed concomitantly more frequent adverse drug reactions (ADRs) related to analgesic use. Drug-drug interactions can be sometimes responsible for the adverse effects. However, a significant proportion of analgesic ADRs are preventable, which would avoid patient suffering. In order to draw the attention to analgesics risks and to minimize the negative consequences related to their use, the present review comprises a synthesis of the most important safety issues described in the scientific literature. It highlights the potential risks of the most frequently used analgesic medicines: non-opioid (paracetamol, metamizole, non-steroidal anti-inflammatory drugs) and opioid analgesics. Even if there is a wide experience in their use, they continue to capture attention with safety concerns and with potential risks recently revealed. Acknowledging potential safety problems represents the first step for health professionals in assuring a safe and efficient analgesic treatment with minimum risks to patients. Taking into consideration all medical and environmental factors and carefully monitoring the patients are also essential in preventing and early detecting analgesic ADRs.
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Affiliation(s)
- Irina Cazacu
- Department of Pharmacology, Physiology and Pathophysiology, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Cristina Mogosan
- Department of Pharmacology, Physiology and Pathophysiology, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Felicia Loghin
- Department of Toxicology, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Horváth VJ, Tabák GÁ, Szabó G, Putz Z, Koós CG, Lakatos P. [Cardiovascular side effects of non-steroidal anti-inflammatory drugs in the light of recent recommendations. Diclofenac is not more dangerous]. Orv Hetil 2015; 156:516-520. [PMID: 25796279 DOI: 10.1556/oh.2015.30120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/14/2024]
Abstract
Among their beneficial effects, non-steroidal anti-inflammatory drugs may also exert several side effects which depend on the dosage and the type of these medications. The most frequent gastrointestinal side effects usually develop shortly after the beginning of their administration, but others such as cardiovascular interactions (which are present much less frequently than gastrointestinal side effects) can also occur after the beginning of drug administration without a latency period. For a long-term treatment, non-steroidal anti-inflammatory drugs are most frequently used in the elderly population where patients typically have high cardiovascular risk and take other medicines, e.g. low dose acetylsalicylic acid that can interact with non-steroidal anti-inflammatory drugs; in this aspect diclofenac may cause less side effects. In this review, the authors briefly review cardiovascular side effects of non-steroidal anti-inflammatory drugs, the processes which potentially influence them, therapeutic consequences and their interaction with acetylsalicylic acid.
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Affiliation(s)
- Viktor József Horváth
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Belgyógyászati Klinika Budapest Korányi S. u. 2/A 1083
| | - Gy Ádám Tabák
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Belgyógyászati Klinika Budapest Korányi S. u. 2/A 1083
| | - Gergely Szabó
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Belgyógyászati Klinika Budapest Korányi S. u. 2/A 1083
| | - Zsuzsanna Putz
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Belgyógyászati Klinika Budapest Korányi S. u. 2/A 1083
| | | | - Péter Lakatos
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Belgyógyászati Klinika Budapest Korányi S. u. 2/A 1083
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Polzin A, Richter S, Schrör K, Rassaf T, Merx MW, Kelm M, Hohlfeld T, Zeus T. Prevention of dipyrone (metamizole) induced inhibition of aspirin antiplatelet effects. Thromb Haemost 2015; 114:87-95. [PMID: 25789542 DOI: 10.1160/th14-11-0922] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 01/23/2015] [Indexed: 12/31/2022]
Abstract
We have recently shown that dipyrone (metamizole), a non-opioid analgesic, can nullify aspirin (acetylsalicylic acid; ASA) antiplatelet effects in patients with coronary artery disease (CAD). In this study, we analysed the aspirin and dipyrone drug-drug interaction in order to identify strategies to prevent the dipyrone induced inhibition of asprin antiplatelet effects. Platelet function was measured by arachidonic acid-induced light-transmission aggregometry, thromboxane (TX) B2- formation by immunoassay. Dipyrone metabolite plasma levels were determined by high-performance-liquid-chromatography (HPLC). In seven healthy individuals, in vitro ASA (30 µM/ 100 µM/ 300 µM/ 1,000 µM) and dipyrone (10 µM) coincubation revealed, that the aspirin and dipyrone interaction can be overcome by increasing doses of aspirin. In 36 aspirin and dipyrone comedicated CAD patients, addition of ASA (30 µM/ 100 µM) in vitro inhibited, but did not completely overcome the dipyrone induced reduction of aspirin antiplatelet effects. Notably, the inhibition of thromboxane formation in aspirin and dipyrone comedicated CAD patients coincided with dipyrone plasma levels. In a cross-over designed study in four healthy individuals, we were able to prove that inhibition of aspirin (100 mg/ day) effects by dipyrone (750 mg/ day) was reversible. Furthermore, aspirin (100 mg/ day) medication prior to dipyrone (750 mg/ day) intake prevented the inhibition of antiplatelet effects by dipyrone in 12 healthy individuals. In conclusion, aspirin medication prior to dipyrone intake preserves antiplatelet effects, circumventing the pharmacodynamic drug-drug interaction at the level of cyclooxygenase-1.
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Affiliation(s)
- Amin Polzin
- Klinik für Kardiologie, Pneumologie und Angiologie, Moorenstrasse 5, 40225 Düsseldorf, Germany, Tel.: +49 211 18800, Fax: +49 211 18812, E-mail:
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Hohlfeld T, Schrör K. Inhibition of antiplatelet effects of aspirin by nonopioid analgesics. Clin Pharmacol Ther 2014; 97:131-4. [PMID: 25670517 DOI: 10.1002/cpt.21] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 09/30/2014] [Indexed: 11/05/2022]
Abstract
In patients undergoing coronary bypass grafting, we noticed that low-dose aspirin failed to inhibit platelet aggregation, potentially elevating the risk of thrombotic bypass occlusion. This "high on-treatment platelet reactivity" was reproducible in vitro and could be transferred with patient plasma or urine to aspirin-sensitive donor platelets, suggesting a drug/drug interaction. Loss of aspirin efficacy was associated with analgesia by dipyrone (metamizol) and initiated further study of the interaction between aspirin and other nonopioid analgesics.
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Affiliation(s)
- T Hohlfeld
- Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
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