Clopidogrel and Low-Dose Aspirin, Alone or Together, Reduce Risk of Colorectal Cancer.

BACKGROUND & AIMS: The antiplatelet effect of low-dose aspirin, via inhibition of cyclooxygenase-1, might contribute to its ability to reduce the risk of colorectal cancer (CRC). Antiplatelet agents with a different mechanism, such as clopidogrel, might have the same effects. We aimed to quantify the effects of low-dose aspirin and clopidogrel on the risk of CRC in a Mediterranean population. METHODS: We performed a nested case-control study using a primary care database (Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria) in Spain. We collected data, from 2001 through 2014, on 15,491 incident cases of CRC and 60,000 randomly selected individuals (controls), frequency-matched to cases by age, sex, and year. To estimate the association between exposure to different antiplatelet agents and the risk of colorectal cancer, we built multiple logistic regression models and computed the adjusted-odds ratios (AORs) and their respective 95% CIs. RESULTS: Use of low-dose aspirin was associated with a reduced risk of CRC overall (AOR, 0.83; 95% CI, 0.78-0.89) and in patients receiving treatment for more than 1 year (AOR, 0.79; 95% CI, 0.73-0.85). Use of clopidogrel was associated with a decreased risk of CRC overall (AOR, 0.8; 95% CI, 0.69-0.93) and in patients receiving treatment for more than 1 year (AOR, 0.65; 95% CI, 0.55-0.78). Dual antiplatelet therapy had the same effect as either drug taken as monotherapy. No modification by sex or age was observed. CONCLUSIONS: In a nested case-control study of a primary care database in Spain, we found clopidogrel use, alone or in combination with low-dose aspirin, to reduce the risk of CRC by 20% to 30%, a magnitude similar to that of low-dose aspirin alone. These data support the concept that inhibiting platelets is an effective strategy for prevention of CRC.

EVI1 upregulates PTGS1 (COX1) and decreases the action of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia cells.

Tyrosine kinase inhibitors (TKIs) are highly effective in treating chronic myelogenous leukemia (CML). However, primary and acquired drug resistance to TKIs have been reported. In this study, we used RNA sequencing followed by RQ-PCR to show that the proto-oncogene EVI1 targets the drug-metabolizing gene PTGS1 in CML. The PTGS1 promoter element had an EVI1 binding site, and CHIP assay confirmed its presence. Data from a publicly available CML microarray dataset and an independent set of CML samples showed a significant positive correlation between EVI1 and PTGS1 expression in CML. Downregulation of EVI1 in K562 cells and subsequent treatment with TKIs resulted in a lower IC50 in the control cells. Furthermore, combined inhibition of BCR-ABL with imatinib and PTGS1 with FR122047 (PTGS1 inhibitor) synergistically reduced the viability of imatinib-resistant K562 cells. We conclude that elevated EVI1 expression contributes to TKIs resistance and that combined inhibition of PTGS1 and BCR-ABL may represent a novel therapeutic approach.

Aspirin Actions in Treatment of NSAID-Exacerbated Respiratory Disease.

Non-steroidal Anti-inflammatory drugs (NSAID)-exacerbated respiratory disease (N-ERD) is characterized by nasal polyposis, chronic rhinosinusitis, adult-onset asthma and hypersensitive reactions to cyclooxygenase-1 (COX-1) inhibitors. Among the available treatments for this disease, a combination of endoscopic sinus surgery followed by aspirin desensitization and aspirin maintenance therapy has been an effective approach. Studies have shown that long-term aspirin maintenance therapy can reduce the rate of nasal polyp recurrence in patients with N-ERD. However, the exact mechanism by which aspirin can both trigger and suppress airway disease in N-ERD remains poorly understood. In this review, we summarize current knowledge of aspirin effects in N-ERD, cardiovascular disease, and cancer, and consider potential mechanistic pathways accounting for the effects of aspirin in N-ERD.

o-Hydroxycinnamic derivatives as prospective anti-platelet candidates: in silico pharmacokinetic screening and evaluation of their binding sites on COX-1 and P2Y12 receptors.

Background The high prevalence of thrombotic abnormalities has become a major concern in the health sector. This is triggered by uncontrolled platelet aggregation, which causes complications and death. The problem becomes more complicated because of the undesirable side effects of the drugs currently in use, some of which have reportedly become resistant. This study aims to evaluate the potency of o-hydroxycinnamic acid derivatives (OCA1a-22a) and their pharmacokinetic properties and toxicity for them to be developed as new antiplatelet candidates. Methods In silico analysis of pharmacokinetics was carried out using pKCSM. Molecular docking of the compounds OCA 1a-22a was performed using the Molegro Virtual Docker. In silico evaluation of the potency of biological activity was done by measuring the bonding energy of each tested compound to the target receptor i.e. COX-1 and P2Y12, as the Moldock score (MDS). Results pKCSM analyses showed that more than 90% of OCA 1a-22a are absorbed through the intestine and distributed in plasma. Most tested compounds are not hepatotoxic, and none is mutagenic. An evaluation of the COX-1 receptor showed that OCA 2a-22a have lower binding energy compared to aspirin, which is the COX-1 inhibitor used today. So, it can be predicted that OCA 2-22a have stronger activity. Interactions with P2Y12 show lower MDS than aspirin, but slightly higher than ibuprofen, which is the standard ligand. Conclusions ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile prediction shows that OCA 1a-22a have the potential to be developed as oral preparations. OCA 1a-22a have strong potential to interact with COX-1 and P2Y12 receptors, so they are prospective anti-platelet candidates.

Cyclooxygenase-1 (COX-1) and COX-1 Inhibitors in Cancer: A Review of Oncology and Medicinal Chemistry Literature.

Prostaglandins and thromboxane are lipid signaling molecules deriving from arachidonic acid by the action of the cyclooxygenase isoenzymes COX-1 and COX-2. The role of cyclooxygenases (particularly COX-2) and prostaglandins (particularly PGE2) in cancer-related inflammation has been extensively investigated. In contrast, COX-1 has received less attention, although its expression increases in several human cancers and a pathogenetic role emerges from experimental models. COX-1 and COX-2 isoforms seem to operate in a coordinate manner in cancer pathophysiology, especially in the tumorigenesis process. However, in some cases, exemplified by the serous ovarian carcinoma, COX-1 plays a pivotal role, suggesting that other histopathological and molecular subtypes of cancer disease could share this feature. Importantly, the analysis of functional implications of COX-1-signaling, as well as of pharmacological action of COX-1-selective inhibitors, should not be restricted to the COX pathway and to the effects of prostaglandins already known for their ability of affecting the tumor phenotype. A knowledge-based choice of the most appropriate tumor cell models, and a major effort in investigating the COX-1 issue in the more general context of arachidonic acid metabolic network by using the systems biology approaches, should be strongly encouraged.

Platelet count and associated morbidities in VLBW infants with pharmacologically treated patent ductus arteriosus.

OBJECTIVE: Characterize the diagnosis of PDA and the distribution of pretreatment platelet count in pharmacologically managed PDA in infants ≤1500 g and assess the relationship of platelet count to serious morbidities. STUDY DESIGN: This is a retrospective, observational study. In 40 hospitals, data were collected on PDA, including pretreatment platelet count. Distribution of platelet count was examined. The association of platelet count and clinical outcomes of IVH, NEC and PDA closure prior to discharge were examined. Chi-square test was used to compare outcomes by platelet count groups. RESULTS: There were 311 patients treated with medically treated PDA. Pretreatment platelet counts were categorized as 0-119 K, 120-199 K, 200-299 K, >300 K. Incidence and grade of IVH were not significantly different by platelet group. Across all groups: No IVH 62-83%, Grades 1-2 IVH 13-25%, Grades 3-4 IVH 2-13%. NEC occurred in 0-11% of all patients studied. PDA closure rate was 33-45%. CONCLUSION: PDA closure was not significantly affected by platelet count. Platelet count was not a statistically significant factor for development of IVH and NEC in infants born <1500 g with pharmacologically treated PDA.

1,2-Diaryl-2-hydroxyiminoethanones as dual COX-1 and ß-amyloid aggregation inhibitors: biological evaluation and in silico study.

To find out new agents for treating inflammatory-involved diseases such as Alzheimer's disease, a series of 1,2-diaryl-2-hydroxyiminoethanones containing vicinal diaryl pharmacophore of COX inhibitors were tested by a set of in vitro, in vivo, and computational studies. The in vivo study of compounds indicated their prominent anti-inflammatory ability at the doses of 10 and 20 mg/kg comparable to celecoxib (10 mg/kg). Further in vitro COX-1/COX-2 evaluations revealed that 4-methoxy derivative 3 had a high selective COX-1 inhibitory activity (COX-1, IC50=0.12 µm, SI>833). To evaluate their potential use against Alzheimer's disease, in vitro evaluation of ß-amyloid fibril formation using Aß(1-40) and Aß(1-42) peptides was performed. The evaluation of their antiaggregation ability gave impressive results and comparable to rifampicin and indomethacin. Conformational study of compound 3 and subsequent docking of its restrained analogs on both active sites of COX-1 and COX-2 could provide a proof of its COX-1 selectivity as well as molecular dynamic simulation could elucidate and give more insight into the amyloid disaggregation mechanisms leading to rational design of inhibitors.

Assessment of common nonsteroidal anti-inflammatory medications by whole blood aggregometry: a clinical evaluation for the perioperative setting.

OBJECTIVE: To help define the perioperative risk related to commonly used non-aspirin NSAIDs with whole blood platelet aggregometry. METHODS: Twelve healthy volunteers were recruited. Two cyclooxygenase (COX)-1 inhibitors (ibuprofen and naproxen) and two COX-2 inhibitors (meloxicam and celecoxib) were administered, and daily whole blood platelet aggregometry studies were obtained until studies showed no platelet inhibition. Aspirin was studied at the conclusion of the study. RESULTS: Ibuprofen had no inhibitory effect on platelet aggregation in all women and no inhibitory effect in 83% of men at 24 hours. All platelet function had returned to normal at 48 hours. The inhibitory effect of naproxen on platelets was absent at 48 hours in 83% of the women and 50% of men. By 72 hours all platelet studies had returned to normal. Meloxicam and celecoxib did not cause any overall inhibitory effect on platelet aggregation. CONCLUSIONS: Ibuprofen and naproxen have a mild inhibitory effect on platelet aggregation compared with aspirin and this effect is undetectable by 48 hours and 72 hours, respectively. Meloxicam and celecoxib show essentially no inhibitory effect on platelet aggregation. These findings suggest that there is little bleeding risk related to platelet aggregation at 24 hours in patients who take COX-2 inhibitors and at 72 hours for those who take COX-1 inhibitor medications.