Background
The risk of contrast‐induced acute kidney injury (CI‐AKI) increases in a nonlinear fashion with increasing volume of contrast media. Prior studies recommend limiting contrast volume to ...less than three times the estimated creatinine clearance (CC). Recently, a number of operators have reported successful percutaneous coronary intervention (PCI) using even lower volumes of contrast.
Objectives
To evaluate the prevalence and outcomes associated with ultra‐low contrast volume among patients undergoing PCI.
Methods
We assessed the prevalence and outcomes associated with use of ultra‐low contrast volume among 75 393 patients undergoing PCI in Michigan between July 2014 and June 2017 in the BMC2 (Blue Cross Blue Shield of Michigan Cardiovascular Consortium) registry. Ultra‐low contrast volume was defined as contrast volume less than or equal to the patient's estimated CC. Patients receiving dialysis at the time of the procedure were excluded.
Results
Ultra‐low contrast volume was used in 13% of procedures with the majority of these patients being at low risk of renal complications. Compared with patients who received a contrast volume between one and three times the CC, use of ultra‐low volume of contrast was associated with a significantly lower incidence of AKI (aOR 0.682, 95% CI 0.566–0.821, P < 0.001) and a lower incidence of need for dialysis (aOR = 0.341, 95% CI 0.165–0.704, P = 0.003). These benefits were most evident in the patients with a high baseline predicted risk of AKI.
Conclusions
A small but clinically significant number of patients are treated with ultra‐low contrast volume. Ultra‐low contrast volume use is associated with a significant reduction in the incidence of AKI or need for dialysis. It may be prudent to consider this new threshold when performing PCI on patients who are at an increased risk of AKI.
Pleiotropic effects of clopidogrel Kuszynski, Dawn S.; Lauver, D. Adam
Purinergic signalling,
09/2022, Letnik:
18, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Clopidogrel is a widely prescribed prodrug with anti-thrombotic activity through irreversible inhibition of the P2Y
12
receptor on platelets. It is FDA-approved for the clinical management of ...thrombotic diseases like unstable angina, myocardial infarction, stroke, and during percutaneous coronary interventions. Hepatic clopidogrel metabolism generates several distinct metabolites. Only one of these metabolites is responsible for inhibiting the platelet P2Y
12
receptor. Importantly, various non-hemostatic effects of clopidogrel therapy have been described. These non-hemostatic effects are perhaps unsurprising, as P2Y
12
receptor expression has been reported in multiple tissues, including osteoblasts, leukocytes, as well as vascular endothelium and smooth muscle. While the “inactive” metabolites have been commonly thought to be biologically inert, recent findings have uncovered P2Y
12
receptor-independent effects of clopidogrel treatment that may be mediated by understudied metabolites. In this review, we summarize both the P2Y
12
receptor-mediated and non-P2Y
12
receptor-mediated effects of clopidogrel and its metabolites in various tissues.
Contrast-induced acute kidney injury (CIAKI) is one of the commonest complications associated with contrast media (CM). Although the exact etiology of CIAKI remains unclear, one hypothesis involves ...vasoconstriction of afferent arterioles resulting in renal ischemia. Increased renal blood flow, therefore, might represent an attractive target for the treatment of CIAKI. In this study we evaluated the protective effects of the phosphodiesterase type 5 (PDE5) inhibitor, sildenafil citrate, in a rabbit model of CIAKI. New Zealand white rabbits were used due to their susceptibility to CIAKI. To evaluate the effects of sildenafil, the drug was administered before CM infusion and repeatedly throughout the remainder of the experiment (6 mg/kg, p.o.). Animals were sacrificed after 48 hours and kidneys were prepared for histological evaluation. Intravenous administration of CM produced marked kidney injury. Serum creatinine concentrations were elevated within two hours of the infusion and remained elevated for the duration of the experiment. Histological evaluation of the kidneys revealed significant tubular necrosis. The effects of the CM were dose dependent. Treatment with sildenafil was associated with lesser degree of histological injury, attenuation in markers of acute kidney injury (48 hour creatinine 1.54±0.21 versus 4.42±1.31 mg/dl, p<0.05) and reduction in electrolyte derangement (percent change in serum K+ at 48 hours 2.55±3.80% versus 15.53±4.47%, p<0.05; serum Na+ at 48 hours -0.14±0.26% versus -1.97±1.29%, p = 0.20). The results suggest a possible role for PDE5 inhibitors in the treatment of CIAKI and warrant further evaluation to determine the exact mechanism of protection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In preclinical cardiovascular safety pharmacology studies, statistical analysis of the rate corrected QT interval (QTc) is the focus for predicting QTc interval changes in the clinic. Modeling of a ...concentration/QTc relationship, common clinically, is limited due to minimal pharmacokinetic (PK) data in nonclinical testing. It is possible, however, to relate the average drug plasma concentration from sparse PK samples over specific times to the mean corrected QTc. We hypothesize that averaging drug plasma concentration and the QTc-rate relationship over time provides a simple, accurate concentration-QTc relationship bridging statistical and concentration/QTc modeling.
Cardiovascular telemetry studies were conducted in non-human primates (NHP; n = 48) and canines (n = 8). Pharmacokinetic samples were collected on separate study days in both species. Average plasma concentrations for specific intervals (CAverage0-X) were calculated for moxifloxacin in canines and NHP using times corresponding to super-intervals for the QTc data statistical analysis. The QTc effect was calculated for each super-interval using a linear regression correction incorporating QT and HR data from the whole super-interval. The concentration QTc effects were then modeled.
In NHP, a 10.9 ± 0.06 ms (mean ± 95% CI) change in QTc was detected at approximately 1.5× the moxifloxacin plasma concentration that causes a 10 ms QTc change in humans, based on a 0-24 h super-interval. When simulating a drug without QT effects, mock, no effect on QTc was detected at up to 3× the clinical concentration. Similarly, in canines, a 16.6 ± 0.1 ms change was detected at 1.7× critical clinical moxifloxacin concentration, and a 0.04 ± 0.1 ms change was seen for mock.
While simultaneous PK and QTc data points are preferred, practical constraints and the need for QTc averaging did not prevent concentration-QTc analyses. Utilizing a 0-24 h super-interval method illustrates a simple and effective method to address cardiovascular questions when preclinical drug exposures exceed clinical concentrations.
Clopidogrel is an effective purinergic 2Y12 receptor (P2Y12) antagonist used to prevent arterial thrombosis, but its use is associated with adverse bleeding. Clinical studies have demonstrated that ...clopidogrel users have an increased risk of cerebral microbleeds and intracerebral hemorrhage. Our previous studies suggest that non-platelet mechanisms mediate these adverse bleeding events; we hypothesize that clopidogrel or one of its metabolites interacts with blood vessels directly to cause bleeding. New Zealand white rabbits (1.9–2.7 kg) were treated orally with vehicle or clopidogrel (3 or 10 mg/kg) for three days. On the fourth day, the rabbits were anesthetized for blood collection and then euthanized. The brain was collected, and the middle cerebral arteries were isolated. We used light transmission aggregometry and pressure myography to elucidate the mechanisms of the off-target effects associated with clopidogrel treatment. We confirmed that inhibition of P2Y12 activation by clopidogrel inhibited ADP-induced platelet aggregation but had no impact on P2Y12-independent arachidonic acid- or collagen-induced platelet aggregation. Analysis of middle cerebral arteries from clopidogrel treated rabbits showed that clopidogrel did not affect P2Y4, P2Y6, and P2Y14 receptor-mediated contraction but attenuated the contractile response after P2Y2 receptor activation. Further analysis determined P2Y2-mediated constriction was endothelium-dependent. Vasoconstriction is a primary component of hemostasis, and impaired vasoconstriction can prolong bleeding. These results suggest clopidogrel inhibits the endothelial P2Y2 receptor in the middle cerebral artery, which provides a mechanistic explanation for the adverse cerebral bleeding associated with the drug.
Display omitted
•Clopidogrel pretreatment does not significantly inhibit mean myogenic tone generation in MCAs, but reduces the percentage of MCAs that generated tone•Clopidogrel significantly inhibits vasoconstriction resulting from P2Y2 receptor activation•P2Y2-mediated vasoconstriction is endothelium-dependent in the rabbit MCA
Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A₂ formed by platelets from AA via ...cyclooxygenase-1 (COX-1) mediates thrombosis. COX-1 and COX-2 are both targets of nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) including aspirin whereas COX-2 activity is preferentially blocked by COX-2 inhibitors called coxibs. COXs are homodimers composed of identical subunits, but we have shown that only one subunit is active at a time during catalysis; moreover, many nsNSAIDS bind to a single subunit of a COX dimer to inhibit the COX activity of the entire dimer. Here, we report the surprising observation that celecoxib and other coxibs bind tightly to a subunit of COX-1. Although celecoxib binding to one monomer of COX-1 does not affect the normal catalytic processing of AA by the second, partner subunit, celecoxib does interfere with the inhibition of COX-1 by aspirin in vitro. X-ray crystallographic results obtained with a celecoxib/COX-1 complex show how celecoxib can bind to one of the two available COX sites of the COX-1 dimer. Finally, we find that administration of celecoxib to dogs interferes with the ability of a low dose of aspirin to inhibit AA-induced ex vivo platelet aggregation. COX-2 inhibitors such as celecoxib are widely used for pain relief. Because coxibs exhibit cardiovascular side effects, they are often prescribed in combination with low-dose aspirin to prevent thrombosis. Our studies predict that the cardioprotective effect of low-dose aspirin on COX-1 may be blunted when taken with coxibs.
Whether a compound prolongs cardiac repolarization independent of changes in beat rate is a critical question in drug research and development. Current practice is to resolve this in two steps. ...First, the QT interval is corrected for the influence of rate and then statistical significance is tested. There is renewed interest in improving the sensitivity of nonclinical corrected QT interval (QTc) assessment with modern studies having greater data density than previously utilized. The current analyses examine the effects of moxifloxacin or vehicle on the QT interval in nonhuman primates (NHPs) using a previously described one-step method. The primary end point is the statistical sensitivity of the assessment. Publications suggest that for a four animal crossover (4 × 4) in NHPs the minimal detectable difference (MDD) is greater than or equal to 10 ms, whereas in an eight animal crossover the MDD is ~6.5 ms. Using the one-step method, the MDD for the four animal NHP assessments was 3 ms. In addition, the one-step model accounted for day-to-day differences in the heart rate and QT-rate slope as well as drug-induced changes in these parameters. This method provides an increase in the sensitivity and reduces the number of animals necessary for detecting potential QT change and represents "best practice" in nonclinical QTc assessment in safety pharmacology studies.
Preclinical risk assessment of drug-induced arrhythmias is critical for drug development and relies on heart rate corrected QT interval (QT) prolongation as a biomarker for arrhythmia risk. However, ...the methods used to correct QT vary in complexity and don't account for all changes in the QT-rate relationship. Thus, we developed the novel Ratio QT correction method which characterizes that relationship at each timepoint using the ratio between QT, adjusted for a species-specific constant, and rate (RR interval). This ratio represents the slope between the intercept and the datapoint being corrected, which is then used in a linear equation like individual methods. A unique correction coefficient for each datapoint avoids assuming static relationships. We hypothesize that the simple and dynamic nature of the Ratio method will provide more consistent rate correction and error reduction compared to Bazett's and individual regression methods. Comparisons were made using ECG data from non-human primates (NHPs) treated with dofetilide or moxifloxacin, separated into small groups (n = 4). The methods were compared based on corrected QT vs RR slopes, standard error, and minimal detectable difference (MDD) for each method. The Ratio method resulted in smaller corrected QT-rate relationship slopes than Bazett's, more closely matching those of individual methods. It produced similar or lower MDDs compared to individual and Bazett's correction, respectively, with more consistent reduction in standard error. This simple and effective method has the potential for easy translatability across species.
Improving corrected QT; Why individual correction is not enough Ether, Nicholas D.; Jantre, Sanket R.; Sharma, Dhruv B. ...
Journal of pharmacological and toxicological methods,
January-February 2022, 2022 Jan-Feb, 2022-01-00, 20220101, Letnik:
113
Journal Article
Recenzirano
Odprti dostop
The use of QT-prolongation as a biomarker for arrhythmia risk requires that researchers correct the QT-interval (QT) to control for the influence of heart rate (HR). QT correction methods can vary ...but most used are the universal correction methods, such as Bazett's or Van de Water's, which use a single correction formula to correct QT-intervals in all the subjects of a study. Such methods fail to account for differences in the QT/HR relationship between subjects or over time, instead relying on the assumption that this relationship is consistent. To address these changes in rate relationships, we test the effectiveness of linear and non-linear individual correction methods. We hypothesize that individual correction methods that account for additional influences on the rate relationship will result in more effective and consistent correction. To increase the scope of this study we use bootstrap sampling on ECG recordings from non-human primates and beagle canines dosed with vehicle control. We then compare linear and non-linear individual correction methods through their ability to reduce HR correlation and standard deviation of corrected QT values. From these results, we conclude that individual correction methods based on post-treatment data are most effective with the linear methods being the best option for most cases in both primates and canines. We also conclude that the non-linear methods are more effective in canines than primates and that accounting for light status can improve correction while examining the data from the light periods separately. Individual correction requires careful consideration of inter-subject and intra-subject variabilities.
Introduction: Tunica media extracellular matrix (ECM) remodeling is well understood to occur in response to elevated blood pressure, unlike the remodeling of other tunicas. We hypothesize that ...perivascular adipose tissue (PVAT) is responsive to hypertension and remodels as a protective measure. Methods: The adventitia and PVAT of the thoracic aorta were used in measuring ECM genes from 5 pairs of Dahl SS male rats on 8 or 24 weeks of feeding from weaning on a control (10% Kcal fat) or high-fat (HF; 60%) diet. A PCR array of ECM genes was performed with cDNA from adventitia and PVAT after 8 and 24 weeks. A gene regulatory network of the differentially expressed genes (DEGs) (HF 2-fold > con) was created using Cytoscape. Results: After 8 weeks, 29 adventitia but 0 PVAT DEGs were found. By contrast, at 24 weeks, PVAT possessed 47 DEGs while adventitia had 3. Top DEGs at 8 weeks in adventitia were thrombospondin 1 and collagen 8a1. At 24 weeks, thrombospondin 1 was also a top DEG in PVAT. The transcription factor Adarb1 was identified as a regulator of DEGs in 8-week adventitia and 24-week PVAT. Conclusion: These data support that PVAT responds biologically once blood pressure is elevated.
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