Coadministration Of Aspirin Research Articles

Safety, tolerability, pharmacokinetics and pharmacodynamics of milvexian with aspirin and/or clopidogrel in healthy participants

Milvexian, an oral activated Factor XI (FXIa) inhibitor, is in clinical studies where it may be combined with antiplatelet agents, including aspirin and/or clopidogrel, to prevent thromboembolic diseases. This phase I trial assessed safety, pharmacokinetics, and pharmacodynamics of milvexian coadministration with aspirin and/or clopidogrel in healthy participants through 3 drug-drug interaction studies using a 3-period, 3-treatment, crossover design. A total of 113 participants were randomized to receive milvexian (200 mg; twice daily for 5 days) or matched placebo coadministered with once-daily aspirin (325 mg for 5 days) and/or clopidogrel (Day 1: 300 mg; Days 2–5: 75 mg). Milvexian was safe and well tolerated, with and without aspirin and/or clopidogrel. Eight mild bleeding adverse events (AEs) were reported in 5 of 113 participants across various treatment arms. Peak and total exposures of milvexian were similar with or without clopidogrel and/or aspirin. Exposure-dependent prolongation of activated partial thromboplastin time and reduction of FXI clotting activity by milvexian were similar with coadministration of aspirin and/or clopidogrel. Milvexian, with or without coadministration of aspirin and/or clopidogrel, did not affect bleeding time or platelet aggregation. Administration of milvexian alone or with aspirin and/or clopidogrel was safe and well tolerated without increased incidence of AEs, including bleeding. Pharmacokinetic and pharmacodynamic effects of milvexian, including bleeding time, were similar with or without aspirin and/or clopidogrel.ClinicalTrials.gov Identifier: NCT03698513.

Pharmacodynamic and Pharmacokinetic Drug Interactions between Fexuprazan, a Novel Potassium-Competitive Inhibitor, and Aspirin, in Healthy Subjects

Acid-reducing agents are commonly used for the prevention of aspirin-induced gastrointestinal complications such as peptic ulcers. As a novel potassium-competitive acid blocker, fexuprazan is expected to prevent aspirin-induced gastrointestinal complications. This randomized, open-label study aimed to evaluate the pharmacodynamic and pharmacokinetic interactions between aspirin and fexuprazan in healthy Koreans. Subjects randomized to the aspirin group received 500 mg aspirin in combination with 80 mg fexuprazan. For the fexuprazan group, fexuprazan 80 mg was administered alone and then in combination with aspirin 500 mg. Platelet aggregation inhibited by aspirin and the pharmacokinetic parameters of aspirin and fexuprazan were compared between monotherapy and combination therapy. A total of 22 subjects completed the study. The platelet aggregation-inhibitory activity and systemic exposure to aspirin were not significantly affected by fexuprazan coadministration. The systemic exposure of fexuprazan was decreased up to 20% by aspirin coadministration, which was not regarded as clinically meaningful considering the previously reported exposure-response relationship. In conclusion, there were no clinically relevant pharmacodynamic or pharmacokinetic interactions between aspirin and fexuprazan. This finding suggests the potential of fexuprazan for the prevention of aspirin-induced gastrointestinal complications, serving as a baseline for optimizing its therapeutic application with aspirin.

A randomized, cross-over study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of milvexian with single and dual antiplatelet therapy in healthy participants

Abstract Background According to scientific evidence, modulation of Factor XI (FXI) function may provide a novel mechanism for systemic anticoagulation without increasing the risk of clinically relevant bleeding in a variety of conditions associated with a high risk of thrombotic events. Milvexian (BMS-986177/JNJ-70033093) is an oral small molecule that binds reversibly to and inhibits the active form of FXI (FXIa) with high affinity and selectivity. Depending on the patient population, milvexian is expected to provide benefit to patients as replacement or add on therapy to current guideline-recommended antithrombotic agents which include aspirin and/or clopidogrel. Purpose This DDI study aimed to investigate the safety and to identify possible pharmacokinetic (PK) or pharmacodynamic (PD) interaction of milvexian when co-administered with aspirin and/or clopidogrel. Methods The study consisted of 3 parts, each of which was a single DDI study using a randomized, 3-period, 3-treatment crossover design. Six unique treatment sequences were utilized in the study. Milvexian was placebo controlled and blinded when co-administered with aspirin and clopidogrel (Part 1), with clopidogrel (Part 2), or with aspirin (Part 3). In each case the subjects crossed over to milvexian monotherapy. Subjects were randomly assigned into 1 part of the study only. Results Overall, multiple dose milvexian 200 mg given BID for 5 days with and without dual antiplatelet therapy (clopidogrel given as 300 mg on Day 1 followed by 4 days of 75 mg clopidogrel, and aspirin 325 mg once daily given for 5 days) was safe and well tolerated. There were 8 mild bleeding adverse events (AEs) reported from 5 subjects in various treatment groups; no trend towards increased bleeding potential was observed when milvexian was co-administered with dual antiplatelet therapy or separately with aspirin or clopidogrel. After co-administration of aspirin and clopidogrel with milvexian, peak (Cmax) and total exposure [AUC(TAU)] of milvexian were reduced 17% and 15%, respectively, on Day, 1 but were not changed on Day 5, compared to milvexian administered alone. After co-administration of clopidogrel or aspirin separately with milvexian, peak and total exposures of milvexian were not changed, compared to milvexian administered alone. Exposure-dependent prolongation of activated partial thromboplastin time (aPTT) and reduction of Factor XI clotting activity (FXIc) were observed with milvexian administration. Effects were similar when milvexian was administered alone or in combination with aspirin and/or clopidogrel. Conclusion This Phase 1 study in healthy adults demonstrated administration of milvexian alone or in combination with aspirin and/or clopidogrel was not associated with a trend towards AE's including bleeding. Milvexian steady-state exposure and PD effects were similar when milvexian was administered alone or in combination with aspirin and/or clopidogrel. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bristol Myers Squibb and Janssen Pharmaceuticals

Formulation Development and Evaluation of a Novel Emulsion Composition Embracing Aspirin and Glycerol in the Treatment of Ischemic Stroke

An ischemic stroke occurs when the blood supply to part of the brain is interrupted or reduced, preventing brain tissue from getting oxygen and nutrients. Brain cells begin to die in minutes. Ischemic stroke can be treated by using Antiplatelet drug such as aspirin as an immediate treatment which may prevent blood clots and improve recovery after stroke. Glycerol is also used as it decreases the edema in ischemic stroke. The aim of the present investigation is to develop a novel formulation of oil in Glycerol emulsion comprising aspirin in the treatment of ischemic stroke and in vitro evaluation. The oil in glycerol emulsion was prepared by high shear homogenization and prepared emulsions were evaluated for particle size, drug content, in vitro drug release and stability. Based on log P values of aspirin, olive oil is selected as oil phase and tween 80 was used as emulsifying agent. Total 10 formulations F1to F10 were prepared and among these, in F1-F6 phase separation was observed within 24 hrs whereas F8 to F10 were stable for one week and later creaming was observed and it is re-dispersible. The particle size was determined by optical microscopy and the average particle size for F8, F9 and F10 were 6.04, 3.38 and 7.8 µm respectively. Drug content was determined as 68±3.95%,108±5.816%, 103±4.61% respectively in compositions F8, F9 and F10. Rate of drug release followed first order kinetics and an immediate burst release effect was observed within 15 minutes. It is concluded that olive oil and glycerol emulsions containing aspirin is prepared successfully and evaluated. It is a promising formulation approach for co administration of aspirin and glycerol in the treatment of ischemic stroke. The formulations were physically and chemically stable. In vivo application of this formulation will be done in suitable animal models in future.

The Comparison of Antioxidant Effect of Aspirin, Metformin, Atorvastatin and Captopril Co-administration in the Heart and Kidney Tissues of Diabetic Rats.

The present study investigated the effects of co-administration of aspirin, metformin, atorvastatin and captopril on serum lipid profile and oxidative stress in the heart and kidney of streptozotocin-induced diabetic rats. In this study, rats were randomly divided into the following eleven groups: control (Cont.), and diabetic (D), as well as 9 groups that were treated with metformin (M, 300 mg/kg) or aspirin (ASA, 120 mg/kg) alone or in different combinations with captopril (C, 50 mg/kg), or atorvastatin (AT, 40 mg/kg), as follows: (D + M), (D + ASA), (D + M + ASA), (D + M + C), (D + M + AT), (D + M + C + ASA), (D + M + C + AT), (D + M + AT + ASA), and (D + M + C + AT + ASA). The rats in treatment groups daily received drugs by gavage for six weeks. Finally, serum lipid profile and levels of oxidative markers in the heart and kidney tissues were evaluated. In diabetic rats, blood levels of glucose, cholesterol, TG (triglyceride), LDL (low-density lipoprotein), MDA (malondialdehyde) and AIP (atherogenic index of plasma) significantly increased but those of HDL (high-density lipoprotein) and total thiol as well as SOD (superoxide dismutase) and CAT (catalase) activities significantly decreased. Treatment with different combinations of C, ASA, AT and M significantly ameliorated these parameters. This study showed that co-administration of ASA, M, C and AT, could improve glucose and lipid metabolism and oxidative stress markers in the kidneys and heart tissues of diabetic rats more markedly than the administration of these drugs alone.

A descriptive study of antithrombotic medication patterns in adult patients with recent venous thromboembolism.

Objectives:The objective of this study is to describe the most common self-reported antithrombotic therapy utilization patterns in a national cohort of patients with recent venous thromboembolism (VTE).Methods:Extant data from a national online survey administered to 907 patients 18 years of age or older with VTE in the last two years were analyzed. Patients’ self-reported antithrombotic usage patterns used during three phases of treatment for the most recent VTE episode were summarized using descriptive statistics.Results:The following overall antithrombotic usage patterns were identified: warfarin (38.7%), direct oral anticoagulants (DOACs) (26.1%), switching between warfarin and DOACs (13.3%), aspirin only (8.7%), switching between different DOACs (4.5%), injectable anticoagulants only (3.9%), and no treatment (4.7%). Extended antithrombotic therapy beyond 90 days was reported by 65.7% of patients. Aspirin coadministration with anticoagulant therapy occurred for 33.7%.Conclusions:In this national sample of recent VTE sufferers warfarin therapy remains the most used anticoagulant followed closely by DOAC therapy. Switching between warfarin and DOACs and between different DOACs was common which could indicate adverse events or affordability issues. Aspirin coadministration with anticoagulant therapy was present in 1 of 3 patients and is a potential medication safety intervention for anticoagulation providers.

Co-administration of aspirin and adipose-derived stem cell conditioned medium improves the functional recovery of the optic pathway in a lysolecithin-induced demyelination model.

IntroductionBased on beneficial effects of aspirin and mesenchymal stem cells (MSCs) on myelin repair, in a preset study, effects of co-administration of aspirin and conditioned medium from adipose tissue-derived stem cells (ADSC-CM) on functional recovery of optic pathway, demyelination levels, and astrocytes’ activation were evaluated in a lysolecithin (LPC)-induced demyelination model of optic chiasm.MethodsLPC (1%, 2 µL) was injected into the rat optic chiasm and animals underwent daily intraperitoneal (i.p.) injections of ADSCs-CM and oral gavage of aspirin at a dose of 25 mg/kg for 14 days post LPC injection. The conductivity of visual signals was assessed using visual evoked potential recordings (VEPs) before LPC injection and on days 7 and 14 post lesion. Immunostaining against PDGFRα as oligodendrocyte precursor cells marker, MOG as mature myelin marker, and GFAP as astrocyte marker was performed on brain sections at day 14 post LPC injection. FluoroMyelin staining was also used to measure the extent of demyelination areas.ResultsOur results showed that administration of ADSCs-CM and aspirin significantly reduced the latency of VEP waves in LPC receiving animals. In addition, demyelination levels and GFAP expressing cells were attenuated while the number of oligodendrocyte precursor cells significantly increased in rats treated with ADSCs-CM and aspirin.ConclusionOverall, our results suggest that co-administration of ADSCs-CM and aspirin improves the functional recovery of optic pathway through amelioration of astrocyte activation and attenuation of demyelination level.

Co-Administration of Aspirin and L-DOPA Against 6-OHDA-Induced Dopamine Neurotoxicity

Background: At present, L-DOPA remained the gold standard therapy for motor symptoms of Parkinson's disease (PD) patients. However, prolonged administration of L-DOPA led to the development of dyskinesia. Aspirin, a non-steroidal anti-inflammatory drug (NSAID), has been widely used to relieve pain and inflammation. Recent studies indicated that aspirin produced neuroprotection against DA neuronal loss in PD animal model. Methods: Rats lesioned with 6-hydroxydopamine (6-OHDA) in substantia nigra were employed and treated with L-DOPA and aspirin for 21 days. The movement disorders elicited by L-DOPA were determined by the abnormal involuntary movements (AIM) scores analysis. Finding: In 6-OHDA lesioned rat PD model, aspirin or L-DOPA evoked DA neuroprotection 7 days after treatment. Co-administration of aspirin and L-DOPA still conferred neuroprotection. In addition, aspirin attenuated the development of LID, as evidenced by the decreased AIM scores without interfering with L-DOPA efficacy 21 days after treatment. Furthermore, aspirin combined with L-DOPA inhibited microglia and astroglia activation and the subsequent neuroinflammatory responses. Importantly, aspirin didn't produce side effects during this neuroprotection. Interpretation: These results suggest that aspirin might have beneficial potential to attenuate L-DOPA efficacy and alleviate LID in PD. Funding Statement: National Natural Science Foundation of China (No. 81760658), foundation for High-level Innovative Talents of Guizhou Province (No. 20164027), Shijingshan's Tutor Studio of Pharmacology (No. GZS-201607), Innovation Research Group project of Education Department of Guizhou Province (No. 2016038), foundation for Excellent Young Talents of Zunyi Medical University (No.201603). Declaration of Interests: The authors have declared no any conflict of interests. Ethics Approval Statement: All animal experiments were performed in accordance with Chinese Guidelines of Animal Care and Welfare, and the present study was approved by the Animal Care and Use Committee of Zunyi Medical University (Zunyi, China).

Expression of Metallothionein after Administration of Aspirin, Vitamin C or Zinc Supplement in the DMH Induced Colon Carcinoma in Rat

Background:Chemoprevention refers to the use of specificnatural or synthetic chemical agents to suppress the development and progression to carcinoma. The purpose of this study was to assess the effect of aspirin, vitamin C or zinc on the metallothionein (MT) mRNA gene expression as well as MT protein content byimmunohistochemistry andradioimmunoassay (RIA) in 1, 2-dimethyl hydrazine (DMH) induced cancerous colonic tissuein rats.Methods:Rats were randomly divided into three groups, group 1 (aspirin), group 2 (vitamin C) group 3 (zinc), each of which was further sub divided into two groups and given subcutaneous injections of DMH (30 mg/kg body weight) twice a week for 3 months and sacrificed at either 4 months (A-precancer model) or at 6 months (B-cancer model). The control groups were administered 0.5 ml saline subcutaneously. All the 3 groups were simultaneouslyadministered aspirin, vitamin Cor zinc supplement respectively from the beginning till the end of the study.Results:It was observed that rats co-treated with aspirin, vitamin C or zinc resulted in a significant increase in the colonic MT mRNA expression in the precancer and cancer model as compared to the saline only controls. MT protein expression showed a 60%, 64% and 78% immunopositivity in the co-treated groups respectively. The mean MT content in the precancer and the cancer model was restored to near normal levels in all the three co-treated groups.Conclusion:These results suggest that co-administration of aspirin, vitamin C or zinc resulted in a significant increase in MT mRNA gene expression, MT protein expression and MT protein content which could possibly be one of the reasons for a chemo protective effect against progression to colonic cancer in a chemically induced DMH model in rat. Zinc supplement had a greater effect on metallothionein expression than aspirin or vitamin C.

Activation of catalase via co-administration of aspirin and pioglitazone: Experimental and MLSD simulation approaches

Aspirin (ASP) and pioglitazone (PGL) are the most common drugs that are widely used by diabetic patients to control the blood sugar and hinder cardiovascular diseases. The interaction between PGL and ASP is one of the important medical issues to clarify the safety of co-administration of these drugs. In the present study, the effect of co-administered ASP with PGL was investigated on the structure and catalytic function of catalase as a potential target in the liver. Based on our data, co-administration of ASP-PGL significantly enhanced the catalase activity in comparison with PGL alone. However, ASP does not have any effects on the catalytic function of catalase. Moreover, the dialysis measurement and CD spectroscopy study revealed that binding of ASP to catalase could increase the stability of catalase-PGL complex. Based on the obtained data, it is shown that the binding of ASP to catalase led to increase the affinity of catalase to PGL. Binding analysis showed that the association constant of catalase-PGL was reduced considerably in the presence of ASP from 12.19 ± 0.1 × 106 M−1 to 6.4 ± 0.2 × 106 M−1 at 298 K. Multiple ligands simultaneous docking (MLSD) also confirmed an increase in the binding affinity of PGL to catalase.

Effect of Aspirin Coadministration on the Safety of Celecoxib, Naproxen, or Ibuprofen

BackgroundThe safety of nonsteroidal anti-inflammatory drug (NSAID) and aspirin coadministration is uncertain. ObjectivesThe aim of this study was to compare the safety of combining NSAIDs with low-dose aspirin. MethodsThis analysis of the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen) trial included 23,953 patients with osteoarthritis or rheumatoid arthritis at increased cardiovascular risk randomized to celecoxib, ibuprofen, or naproxen. The on-treatment population was used for this study. Outcomes included composite major adverse cardiovascular events, noncardiovascular death, gastrointestinal or renal events, and components of the composite. Cox proportional hazards models compared outcomes among NSAIDs stratified by aspirin use following propensity score adjustment. Kaplan-Meier analysis was used to compare the cumulative probability of events. ResultsWhen taken without aspirin, naproxen or ibuprofen had greater risk for the primary composite endpoint compared with celecoxib (hazard ratio [HR]: 1.52; 95% confidence interval [CI]: 1.22 to 1.90, p <0.001; and HR: 1.81; 95% CI: 1.46 to 2.26; p <0.001, respectively). Compared with celecoxib, ibuprofen had more major adverse cardiovascular events (p < 0.05), and both ibuprofen and naproxen had more gastrointestinal (p < 0.001) and renal (p < 0.05) events. Taken with aspirin, ibuprofen had greater risk for the primary composite endpoint compared with celecoxib (HR: 1.27; 95% CI: 1.06 to 1.51; p < 0.01); this was not significantly higher with naproxen (HR: 1.18; 95% CI: 0.98 to 1.41; p = 0.08). Among patients on aspirin, major adverse cardiovascular events were similar among NSAIDs, and compared with celecoxib, ibuprofen had more gastrointestinal and renal events (p < 0.05), while naproxen had more gastrointestinal events (p < 0.05), without a difference in renal events. Similar results were seen on adjusted Kaplan-Meier analysis. ConclusionsCelecoxib has a more favorable overall safety profile than naproxen or ibuprofen when taken without aspirin. Adding aspirin attenuates the safety advantage of celecoxib, although celecoxib is still associated with fewer gastrointestinal events than ibuprofen or naproxen and fewer renal events than ibuprofen. (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen [PRECISION]; NCT00346216)

Development and Validation of UHPLC-MS/MS for Simultaneous Determination of Scutellarin and Salicylic Acid in Rat Plasma: Application to Herb-Drug Pharmacokinetic Interaction Study

Dengzhanxixin injection (DI) product has been clinically proven to be effective for treating cardio-cerebrovascular disease. Furthermore, herb-drug interactions between the DI product and drugs that are commonly co-administered, such as aspirin, must be explored to ensure safe clinical use. A reliable ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for simultaneous determination of scutellarin and salicylic acid (SA) in rat plasma. The proposed method has been successfully applied to pharmacokinetic studies on analytes in rats afteri.g. administration of aspirin alone, i.v. administration of DI alone or a combination of both (i.g .: 10 mg kg-1 aspirin,i.v .: 4 mL kg-1 DI). Both SA and scutellarin exhibited a two-compartment model pharmacokinetic profile. Aspirin did not change the concentration-time course for scutellarin, but DI decreased the peak plasma concentration and the area under the SA curve. This study indicates that co-administration of aspirin and DI can cause an apparent herb-drug pharmacokinetic interaction in rats.

A non-interventional retrospective cohort study of the interaction between methotrexate and proton pump inhibitors or aspirin

Methotrexate (MTX) is an antifolate drug, which is frequently used in the treatment of cancer. Proton pump inhibitors (PPIs) could delay the elimination of plasma MTX in high-dose MTX therapy by inhibition of tubular secretion, which could lead to MTX toxicity. However, the evidence of the clinical relevance of this drug-drug interaction is inconsistent. No previous studies into the effect of low dose aspirin on the elimination of MTX in high-dose therapy have been performed. Therefore, we evaluated the interaction between MTX and PPIs or aspirin. We conducted a non-interventional retrospective cohort study in patients treated with high dose MTX (≥500mg/m2 or >1000mg), between 2009 and 2016 at the OLVG ("Onze Lieve Vrouwe Gasthuis, Oost") in Amsterdam, the Netherlands. Patients were included if MTX concentrations were determined at 24, 48 or 72hours after high dose MTX treatment. We categorised the cycles of high dose MTX therapy into delayed elimination or normal elimination. Differences in patient characteristics and MTX dosing regimen were compared between all groups by X2-test, Fisher's exact probability test or Mann-Whitney U-test. In total, 89 high dose MTX cycles were included. Delayed MTX elimination was observed in 27 (30.3%) cycles. Co-administration of a PPI was significantly more frequent in the delayed elimination group than in the normal elimination group (P<0.001). There was no statistical effect observed by co-administration of aspirin. The use of PPIs during high dose MTX treatment can lead to delayed MTX elimination. Discontinuation of PPIs during high dose MTX treatment is recommended. Co-administration of aspirin did not influence the elimination of MTX, but further research is needed.

Riociguat (BAY 63-2521) and aspirin: a randomized, pharmacodynamic, and pharmacokinetic interaction study.

In preclinical studies, drugs that increase cyclic guanosine monophosphate levels have been shown to influence platelet function/aggregation; however, the effect of riociguat on human platelets is unclear. Aspirin, a platelet inhibitor, is likely to be given concomitantly in patients receiving riociguat. It is therefore important to establish clinically whether (1) riociguat affects platelet function and (2) aspirin and riociguat interact. This randomized, open-label, crossover study investigated potential pharmacodynamic and pharmacokinetic interactions between these drugs in healthy male volunteers (N = 18). There were 3 treatment regimens: a single morning dose of riociguat 2.5 mg, aspirin 500 mg on 2 consecutive mornings, and both treatments together, with riociguat given on the second morning. Fifteen participants were available for pharmacodynamic/pharmacokinetic analysis. There was no effect of riociguat alone on bleeding time, platelet aggregation, and serum thromboxane B2 levels. The effects of aspirin on these parameters were not influenced by concomitant administration of riociguat. The pharmacokinetic profile of riociguat showed interindividual variability, which was independent of aspirin coadministration. Six of 17 participants available for safety evaluation reported at least 1 treatment-emergent adverse event. All adverse events were of mild severity, apart from 1 report of moderate headache. No serious adverse events occurred. In conclusion, riociguat demonstrated no clinically relevant pharmacodynamic or pharmacokinetic interactions with aspirin at the doses used in this study in healthy men; coadministration of riociguat and aspirin should therefore not require any dose adjustment for either drug.

Pharmacokinetic and pharmacodynamic interactions of aspirin with warfarin in beagle dogs

1. Warfarin and aspirin are widely used in a wide spectrum of thromboembolic and atherothrombotic diseases. Despite the potential efficacy of warfarin–aspirin therapy, the safety and side effect of combined therapy remains unclear.2. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic interactions between warfarin and aspirin in beagles after single and multiple doses.3. Coadministration of aspirin had no significant effects on the area under the plasma concentration time curve (AUC0–t) and maximum plasma concentration (Cmax) of R- and S-warfarin after a single dose of warfarin, but significantly increase the AUC0–t and Cmax and dramatically decrease the clearance (CL) of R- and S-warfarin after multiple dose of warfarin. Accordingly, there was a slight increase in the AUEC0–t and Emax of activated partial thromboplastin time (aPTT), prothrombin time (PT) and international normalized ratio (INR) after multiple dose of warfarin.4. Coadministration of warfarin had no markedly effects on the AUC0–t and Cmax of aspirin and its metabolite salicylic acid after single or multiple dose of aspirin. Meanwhile, the AUEC0–t and Emax of inhibition of platelet aggregation (IPA) were not significantly affected by warfarin.5. Our animal study indicated that coadministration of aspirin with warfarin can cause significant pharmacokinetic and pharmacodynamic drug–drug interactions in beagles. However, more studies are urgently needed to assess related information of warfarin–aspirin drug interactions in healthy volunteers or patients.

Co-administration of aspirin and allogeneic adipose-derived stromal cells attenuates bone loss in ovariectomized rats through the anti-inflammatory and chemotactic abilities of aspirin.

IntroductionOsteoporosis is a syndrome of excessive skeletal fragility characterized by the loss of mass and deterioration of microarchitecture in bone. Single use of aspirin or adipose-derived stromal cells (ASCs) has been recognized recently to be effective against osteoporosis. The goal of the study was to evaluate the osteogenic effects of the co-administration of aspirin and allogeneic rat adipose-derived stromal cells (rASCs) on ovariectomized (OVX)-induced bone loss in rats. The underlying mechanisms were investigated in vitro and in vivo.MethodsFirstly, allogeneic rASCs were isolated and cultured, and the conditioned medium (CM) from the maintenance of rASCs was collected. Secondly, the OVX rats were administrated CM, rASCs, aspirin (ASP) or rASCs + ASP, respectively. Twelve weeks later, the anti-inflammatory and osteogenic effects were assessed by micro-CT, undecalcified histological sections, dynamic histomorphometric analyses and serologic assays for biochemical markers. Finally, a Transwell migration assay in vitro and cell-trafficking analyses in vivo were used to explore the effects of aspirin on rASC migration.ResultsSystemic administration of aspirin and rASCs attenuated OVX-induced bone loss better than single use of aspirin or ASCs (p < 0.05, respectively). Next, we analyzed the underlying mechanisms of the anti-inflammatory and chemotactic abilities of aspirin. Aspirin suppressed serum levels of the pro-inflammatory cytokines on tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), and the anti-inflammatory ability was positively associated with bone morphometry. Also, aspirin exhibited excellent chemotactic effects in vitro and accelerated the homing of allogeneic rASCs into bone marrow during early in vivo stages.ConclusionsCo-administered aspirin and allogeneic ASCs can partially reverse OVX-induced bone loss in rats. This effect appears to be mediated by the anti-inflammatory and chemotactic abilities of aspirin.

Pharmacokinetic Evaluation of Administration of Losartan with Aspirin in Healthy Volunteers

Losartan and aspirin are often used concomitantly in patients with heart failure, ischemic heart disease and hypertension. Objectives: To investigate whether aspirin co-administration affects losartan bioavailability. Methods: 1) Twenty-four healthy volunteers from both sexes were recruited. Volunteers received a single 50 mg losartan with or without a 81 mg aspirin tablet. Blood samples were obtained at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.33, 2.67, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12 hour post-dosing. The concentrations of losartan were analyzed by LC-MSMS. Clearance (Cl) and T1/2 were used to evaluate a possible drug-drug interaction. Cmax and AUC0-8 were used to evaluate whether co-administration interferes on the bioavailability process. Results: From the losartan plasma concentrations vs. time curves the following pharmacokinetic parameters were obtained: ASC0-8 hours, AUCinf, Cmax, Cl, Vd, Tmax, Ke and T1/2. No significant differences were observed in T1/2 (p-value = 0.431), Cl (p-value = 0.554), AUC0-8 hours (p-value = 0.590), Cmax (p-value = 0.987) and Vd (p-value = 0.647). Conclusions: Since there is no significant difference in losartan bioavailability and elimination when coadministered with aspirin, we conclude that there is no pharmacokinetic interaction between both drugs. The finding is important since it reassures the safe use of combining AAS to losartan treatment.

The effect of cilostazol and aspirin pre-treatment against subsequent transient focal cerebral ischemia in rat

Objectives:Among several anti-platelet drugs to prevent recurrent stroke, cilostazol has shown various effects besides its anti-platelet activity. We examined whether 7 days of oral administration of cilostazol protects against subsequent cerebral ischemia, and whether or not the effect of combination therapy with aspirin is more protective.Methods:We used Sprague-Dawley (SD) rats and assigned them to four groups: vehicle, aspirin, cilostazol, and aspirin plus cilostazol combination therapy. After oral administration of anti-platelets for 7 days, we performed transient middle cerebral artery occlusion (MCAO) for 90 minutes, and examined infarct volume, neurological symptoms, and regional cerebral blood flow (rCBF). Immunostaining of Bax, Bcl-2, TUNEL, 4-HNE, 8-OHdG, and COX-2 was performed 24 hours after ischemia.Results:The cilostazol group and the combination therapy group showed significant decreases of infarct volume and significant improvements of rCBF during ischemia, compared with the vehicle or aspirin group. Significant decreases of Bax, TUNEL, 8-OHdG, and 4-HNE expression in the combination therapy group, compared with those in the vehicle or aspirin group, were shown in the boundary zone. COX-2 expression was unexpectedly increased in the combination therapy group.Discussion:Aspirin co-administration did not inhibit this effect. The addition of the oral administration of cilostazol either alone or with aspirin administration may be beneficial for subsequent cerebral ischemic damage in terms of reducing infarct volume, improving rCBF during ischemia, inhibiting the apoptotic pathway, and reducing oxidative stress.

CVS to phase out tobacco sales, launch smoking cessation program

Calling the decision "simply the right thing to do for the good of our customers and our company," CVS Caremark will stop selling all tobacco products at its more than 7,600 CVS/pharmacy locations by October 1. The February 5 announcement came a week after the U.S. Surgeon General issued renewed warnings about tobacco use on the 50th anniversary of the Surgeon General's landmark report linking smoking and poor health.

Aspirin Decreases Systemic Exposure to Clopidogrel Through Modulation of P-Glycoprotein But Does Not Alter Its Antithrombotic Activity

Decreased oral clopidogrel absorption caused by induction of intestinal permeability glycoprotein (P-gp) expression after aspirin administration was observed in rats. This study evaluated the effect of aspirin coadministration on the pharmacokinetics/pharmacodynamics of clopidogrel in humans. A single 75-mg dose of clopidogrel was orally administered before and after 2 and 4 weeks of once-daily 100-mg aspirin administration in 18 healthy volunteers who were recruited based on CYP2C19 and PON1 genotypes. Plasma concentrations of clopidogrel and its active metabolite, H4, and relative platelet inhibition (RPI) were determined. The P-gp microRNA miR-27a increased by up to 7.67-fold (P = 0.004) and the clopidogrel area under the concentration-time curve (AUC) decreased by 14% (P > 0.05), but the AUC of H4 remained unchanged and RPI increased by up to 15% (P = 0.002) after aspirin administration. These findings indicate low-dose aspirin coadministration may decrease clopidogrel bioavailability but does not decrease its efficacy.