A simple accurate method for concentration-QTc analysis in preclinical animal models.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The "One-Step" approach for QT analysis increases the sensitivity of nonclinical QTc analysis.

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.

Evaluation of the Efficacy and Safety of Antiplatelet Therapeutics in Rabbits.

Hemostasis is a multifactorial process that involves vasoconstriction of blood vessels, activation of the coagulation cascade, and platelet aggregation. Inappropriate activation of hemostatic processes can result in thrombosis and tissue ischemia. In patients at risk for thrombotic events, antiplatelet therapeutic agents inhibit platelet activation, thereby reducing the incidence of pathologic clot formation. Platelets are activated by several endogenous chemical mediators, including adenosine diphosphate, thrombin, and thromboxane. These activation pathways serve as attractive drug targets. The protocols described in this article are designed to evaluate the preclinical efficacy and safety of novel antiplatelet therapeutics in rabbits. Here, we provide two protocols for blood collection, two for determining platelet activation, and one for assessing bleeding safety. Together, these protocols can be used to characterize the efficacy and safety of antiplatelet agents for hemostasis. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Blood collection via the central ear artery Alternative Protocol 1: Blood collection via the jugular vein Basic Protocol 2: Platelet aggregation assessment via light transmission aggregometry Alternative Protocol 2: Platelet activation assessment via flow cytometry Basic Protocol 3: Determination of tongue bleeding time.

QT Ratio: A simple solution to individual QT correction.

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.

Pleiotropic effects of clopidogrel.

Clopidogrel is a widely prescribed prodrug with anti-thrombotic activity through irreversible inhibition of the P2Y12 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 P2Y12 receptor. Importantly, various non-hemostatic effects of clopidogrel therapy have been described. These non-hemostatic effects are perhaps unsurprising, as P2Y12 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 P2Y12 receptor-independent effects of clopidogrel treatment that may be mediated by understudied metabolites. In this review, we summarize both the P2Y12 receptor-mediated and non-P2Y12 receptor-mediated effects of clopidogrel and its metabolites in various tissues.

Improving corrected QT; Why individual correction is not enough.

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.

Clopidogrel treatment inhibits P2Y2-Mediated constriction in the rabbit middle cerebral artery.

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.

Contemporary use of and outcomes associated with ultra-low contrast volume in patients undergoing percutaneous coronary interventions.

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.

Significant Improvement of Antithrombotic Responses to Clopidogrel by Use of a Novel Conjugate as Revealed in an Arterial Model of Thrombosis.

Clopidogrel is a prodrug that requires bioactivation by cytochrome P450 (P450) enzymes to a pharmacologically active metabolite for antiplatelet action. The clinical limitations of clopidogrel are in large part due to its poor pharmacokinetics resulting from inefficient bioactivation by P450s. In this study, we determined the pharmacokinetics and pharmacodynamics of a novel conjugate of clopidogrel, referred to as ClopNPT, in animal models and we evaluated its potential to overcome the limitations of clopidogrel. Results from pharmacokinetic (PK) studies showed that ClopNPT released the active metabolite with a time to maximal plasma concentration of <5 minutes in C57BL/6 mice after either oral or intravenous administration, and plasma concentrations of the active metabolite reached Cmax values of 1242 and 1100 ng/ml after a 10-mg/kg oral dose and a 5-mg/kg intravenous dose, respectively. Furthermore, ClopNPT was highly effective in preventing arterial thrombosis in rabbits and mice after vascular injuries. Formation of occlusive thrombi was prevented by ClopNPT at the 1-mg/kg dose with no significant increase in tongue bleeding time, whereas clopidogrel was ineffective at the same dose. These results suggest that ClopNPT has favorable PK/pharmacodynamic properties that can potentially overcome the attenuated PK properties of clopidogrel and thus significantly improve the efficacy of antiplatelet therapy.

Sildenafil citrate for prophylaxis of nephropathy in an animal model of contrast-induced acute kidney injury.

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.

CYP-independent inhibition of platelet aggregation in rabbits by a mixed disulfide conjugate of clopidogrel.

Dual antiplatelet therapy with clopidogrel and aspirin has been the standard of care in the United States for patients with acute coronary syndromes (ACS) and/or undergoing percutaneous coronary interventions (PCI). However, the effectiveness of clopidogrel varies significantly among different sub-populations due to inter-individual variability. In this study we examined the antiplatelet potential of a novel mixed disulfide conjugate of clopidogrel with the aim to overcome the inter-individual variability. In the metabolic studies using human liver microsomes and cDNA-expressed P450s, we confirmed that multiple P450s are involved in the bioactivation of 2-oxoclopidogrel to H4, one of the diastereomers of the pharmacologically active metabolite (AM) possessing antiplatelet activity. Results from kinetic studies demonstrated that 2C19 is the most active in converting 2-oxoclopidogrel to H4 with a catalytic efficiency of 0.027 µM⁻¹min⁻¹ in the reconstituted system. On the basis of this finding, we were able to biosynthesise the conjugate of clopidogrel with 3-nitropyridine-2-thiol, referred to as clopNPT, and examined its antiplatelet activity in male New Zealand white rabbits. After administration as intravenous bolus at 2 mg/kg, the clopNPT conjugate was rapidly converted to the AM leading to the inhibition of platelet aggregation (IPA). Analyses of the blood samples drawn at various time points showed that intravenous administration of clopNPT led to ~70% IPA within 1 hour and the IPA persisted for more than 3 hours. Since the antiplatelet activity of clopNPT does not require bioactivation by P450s, the mixed disulfide conjugate of clopidogrel has the potential to overcome the inter-individual variability in clopidogrel therapy.

Formation, reactivity, and antiplatelet activity of mixed disulfide conjugates of clopidogrel.

In this work, we investigated the formation, reactivity, and antiplatelet activity of various mixed disulfide conjugates of clopidogrel. Our results showed that the production of the active metabolite (AM) from 2-oxoclopidogrel by human liver microsomes (HLMs) is greatly affected by the thiol reductants used. Among the 10 thiol compounds tested, glutathione (GSH) is most efficient in producing the AM at a rate of 167 pmoles AM/min/mg HLM. Interestingly, no AM but only the mixed disulfide conjugates were formed in the presence of 6-chloropyridazine-3-thiol (CPT), 2,5-dimethylfuran-3-thiol, and 3-nitropyridine-2-thiol (NPT). The mass spectrometry (MS) and MS(2) spectra of the conjugates of these thiol compounds confirmed the presence of a mixed disulfide bond linkage between the AM and the thiol reductants. Kinetic studies revealed that the mixed disulfide conjugates were capable of exchanging thiols with GSH to release the AM with second order rate constants ranging from 1.2 to 28 M(-1)s(-1). The mixed disulfide conjugates of CPT and NPT showed potent inhibition of platelet aggregation after pretreatment with 1 mM GSH, confirming that the AM is responsible for the antiplatelet activity of clopidogrel. Collectively, our results provide strong support for a cytochrome P450 (P450)-mediated bioactivation mechanism involving the initial formation of a glutathionyl conjugate, followed by thiol-disulfide exchange with another GSH molecule to release the AM. Furthermore, the stable mixed disulfide conjugates identified in this study provide a platform to quantitatively generate the therapeutic AM without the need for P450-mediated bioactivation. This property can be further explored to overcome the interindividual variability in clopidogrel therapy.

Oral pretreatment with liposomal glutathione attenuates reperfusion injury in rabbit isolated hearts.

Reactive oxygen species are a key mediator of myocardial reperfusion injury. Endogenous cellular defenses against reactive oxygen species often become overwhelmed after ischemia and reperfusion. Therefore, exogenous supplementation of various antioxidant compounds has been hypothesized to protect against reperfusion. Reduced glutathione (GSH) is an important endogenous antioxidant that affords protection against oxidative damage. Oral administration of GSH is limited due to poor gastrointestinal absorption. A liposomal preparation of glutathione (lipGSH) capable of oral administration was investigated for its ability to attenuate tissue injury and increase myocardial glutathione levels in an isolated heart model of reperfusion injury. Male, New Zealand white rabbits were assigned randomly among 4 groups as follows: control and daily oral administration of lipGSH for 3, 7, or 14 days. At completion of the dosing regimen, hearts were harvested and perfused in a retrograde manner with the use of a Langendorff apparatus. The hearts were subjected to 30 minutes of global ischemia followed by 60 minutes of reperfusion. Hearts from lipGSH-treated rabbits exhibited better recovery of left ventricular contractile function during reperfusion and had attenuated oxidative damage. Furthermore, hearts from lipGSH-treated animals had increased myocardial tissue levels of GSH demonstrating effective absorption of lipGSH.

Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1.

Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A(2) 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.

Disodium disuccinate astaxanthin prevents carotid artery rethrombosis and ex vivo platelet activation.

BACKGROUND/AIMS: The disodium disuccinate derivative of astaxanthin (DDA) is a carotenoid antioxidant under development for the treatment of ischemic cardiovascular events. Recent evidence suggests that reactive oxygen species (ROS) play an important role in platelet activation. This study seeks to investigate the effects of a reactive oxygen species quencher, DDA, in a canine model of carotid artery thrombosis. METHODS: After formation of an occlusive carotid thrombus, dogs were administered recombinant tissue plasminogen activator intra-arterially to achieve thrombolysis in the presence of either 0.9% NaCl solution or DDA (10-50 mg/kg i.v. infusion). Ex vivo platelet aggregation and tongue bleeding times were measured before and after drug administration. Residual thrombus mass was analyzed at the end of each experiment. RESULTS: The data indicated a dose- dependent reduction in the incidence of carotid artery rethrombosis. In addition, platelet aggregation and thrombus weights were dose-dependently inhibited by DDA. No change was recorded in tongue bleeding time among the treatment groups. CONCLUSIONS: The data demonstrate that at the doses used in this study, DDA significantly reduced the incidence of secondary thrombosis while maintaining normal hemostasis. The results suggest that upon further study, DDA may one day find utility in revascularization procedures.

Sulodexide: a renewed interest in this glycosaminoglycan.

Glycosaminoglycans (GAGs) are the most abundant group of heteropolysaccharides found in the body. These long unbranched molecules contain a repeating disaccharide unit. GAGs are located primarily in the extracellular matrix or on the surface of cells. These molecules serve as lubricants in the joints while at the same time providing structural rigidity to cells. Sulodexide is a highly purified glycosaminoglycan composed of a fast mobility heparin fraction as well as dermatan sulfate. Sulodexide differs from other glycosaminoglycans, like heparin, by having a longer half-life and a reduced effect on systemic clotting and bleeding. In addition, sulodexide demonstrates a lipolytic activity that is increased in comparison to heparin. Oral administration of sulodexide results in the release of tissue plasminogen activator and an increase in fibrinolytic activities. An increasing body of research has demonstrated the safety and efficacy of sulodexide in a wide range of vascular pathologies.

Disodium Disuccinate Astaxanthin (Cardax) attenuates complement activation and reduces myocardial injury following ischemia/reperfusion.

Carotenoids are a naturally occurring group of compounds that possess antioxidant properties. Most natural carotenoids display poor aqueous solubility and tend to form aggregates in solution. Disodium disuccinate astaxanthin (DDA; Cardax) is a water-dispersible synthetic carotenoid that rapidly and preferentially associates with serum albumin, thereby preventing the formation of supramolecular complexes and facilitating its efficacy after parenteral administration. This study investigated the ability of DDA to reduce inflammation and myocardial injury in a rabbit model of ischemia/reperfusion. DDA (50 mg/kg/day) or saline was administered i.v. for 4 consecutive days before the initiation of the protocol for induction of myocardial ischemia/reperfusion. On the 5th day, rabbits underwent 30 min of coronary artery occlusion, followed by a 3-h reperfusion period. Myocardial infarct size, as a percentage of the area at risk, was calculated for both groups. Infarct size was 52.5 +/- 7.5% in the vehicle-treated (n = 9) and 25.8 +/- 4.7% in the DDA-treated (n = 9) animals (p < 0.01 versus vehicle; mean myocardial salvage = 51%). To evaluate the anti-inflammatory effects of DDA, complement activity was assessed at the end of reperfusion using a red blood cell lysis assay. DDA administration significantly reduced (p < 0.01) the activation of the complement system in the serum. The current results, coupled with the well established antioxidant ability of carotenoids, suggest that the mechanism(s) of action by which DDA reduces the tissue damage associated with reperfusion injury may include both antioxidant and anticomplement components.

Sulodexide attenuates myocardial ischemia/reperfusion injury and the deposition of C-reactive protein in areas of infarction without affecting hemostasis.

Several glycosaminoglycans (GAGs) have been demonstrated to protect the ischemic heart against reperfusion injury, in part, by modulating activation of the complement cascade. The present study assessed the cardioprotective effects of sulodexide (KRX-101), a mixture of GAGs composed of 80% low-molecular mass heparin and 20% dermatan sulfate. KRX-101 differs from other GAGs (e.g., heparin) in that it has limited anticoagulant efficacy and can be administered orally. The experimental protocol was designed to determine whether KRX-101 could protect the ischemic myocardium. Anesthetized New Zealand white rabbits underwent 30 min of coronary artery occlusion. Intravenous doses of KRX-101 (0.5 mg/kg, n = 10) or drug diluent (n = 10) were administered at the end of regional ischemia and at each hour of reperfusion. Infarct size, as a percentage of the area at risk, was calculated for both groups. Myocardial infarct size was 31.3 +/- 4.1% in the vehicle- and 17.3 +/- 3.2% in the KRX-101-treated animals (p < 0.05 versus vehicle). Activated partial thromboplastin times determined at baseline (preischemia) and at each hour of reperfusion (n = 4) were not significantly different between vehicle- and KRX-101-treated groups (p = N.S.). Myocardial injury was further assessed by measuring serum levels of cardiac-specific troponin I. KRX-101 administration significantly reduced (p < 0.05) the serum concentration of troponin I during reperfusion. The results suggest that KRX-101 may be an effective adjunctive agent in myocardial revascularization procedures, without the risk of increased bleeding.

Commonalities in women's spirituality and women's health.

Both women's spirituality and women's health movements have grown dramatically in recent years. If clinicians understood in greater depth the commonalities between these two perspectives, then they would be better positioned to foster the health of women more fully. In this article, concepts of feminism, religion, spirituality, and women's health are described briefly. After identifying some assumptions, themes, and characteristics of both women's spirituality and women's health, the commonalities between these two perspectives are delineated. Next, processes critical to women's spirituality and women's health are proposed. Finally, implications for clinical practice are offered.