Abstract-Both angiotensin-converting enzyme (ACE) inhibitors and 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors have been shown to decrease cardiovascular morbidity and mortality. Results from clinical trials have suggested that HMG-CoA reductase inhibition might exert a beneficial effect independent of its lipid-lowering effect, and ACE inhibition may exert a benefit independent of blood-pressure lowering. To test the hypothesis that such an effect might be mediated by alteration in platelet reactivity, we studied 55 monkeys receiving both, 1, or neither of the ACE inhibitor fosinopril and the HMG-CoA reductase inhibitor pravastatin. Platelet responsiveness to collagen and to the thrombin receptor agonist (TRA) SFLRRN-NH 2 was determined by aggregometry. For each agonist, the maximum rate and extent of aggregation were measured for each dose, and the concentration required for half-maximal response (C 50 ) was determined. Each drug, when given alone, slightly decreased the dose of agonist required to produce 50% response in the rate and extent of platelet aggregation relative to control. The combination of the 2 drugs, however, produced a significant increase in the dose of TRA required to produce 50% response in the rate and extent of aggregation relative to either drug alone or the control group. This was not true for collagen. The magnitude of the change relative to the control group, 47% for rate and 30% for extent of aggregation, could confer considerable protection by changing the threshold for thrombin-induced platelet aggregation and, thus, decrease thrombosis. (Arterioscler Thromb Vasc Biol. 1998;18:1643-1646.)Key Words: angiotensin-converting enzyme inhibitors Ⅲ platelet aggregation Ⅲ 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors C ardiovascular disease is the leading cause of death in the United States. 1 Most of the morbidity and mortality of this disease results from the rupture of atherosclerotic plaques in the vessel wall. This event leads to exposure of the thrombogenic inner components of the plaque to circulating blood, resulting in platelet activation and aggregation and activation of the coagulation system. Subsequently, a thrombus forms.2 The use of angiotensin-converting enzyme (ACE) inhibitors and lipid-lowering drugs has decreased cardiovascular morbidity and mortality below that expected from the resulting mild reduction in blood pressure and minor reduction in severity of coronary stenosis.2-4 Therefore, in addition to their well-known actions, these drugs probably have other protective effects on the processes that lead to cardiovascular disease and thrombosis. It is possible that these drugs may affect platelet function.In this randomized trial, we studied platelet responsiveness to collagen and a thrombin receptor agonist (TRA) in monkeys that were treated with an ACE inhibitor, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, both drugs, or neither drug. Methods MaterialsThe highly purified peptide TRA SFLRRN-NH 2 (PMIS387) wa...
The absence of VWF cleaving protease activity (VWFcp, ADAMTS13) has recently been identified as a central component in the pathogenesis of TTP. Several assays for the measurement of ADAMTS13 activity have been described, but most are cumbersome and employ techniques not easily adapted to routine laboratories. Thus, ADAMTS13 assays are available at only a few reference or research laboratories. Prompt identification of absent or impaired ADAMTS13 activity could prove invaluable to clinical decision-making regarding diagnosis and treatment of suspected TTP patients. We describe an assay for ADAMTS13 that uses a commercial source of VWF substrate and obviates dialysis for sample and substrate preparation. Patient and normal plasma are prepared by desalting over Micro-Spin columns, and barium is added to activate the cleaving protease. Humate-Pâ is prepared over a desalting column and reconstituted in urea prior to use as the exogenous VWF substrate. Desalted plasma is mixed with prepared substrate, and digestion is carried out at 37 C. Maximum sensitivity to very low levels of enzyme activity is achieved by using undiluted plasma and allowing digestion to proceed for 14 hr. The extent of VWF multimer cleavage is then demonstrated by Western blot. We used this assay to analyze VWF cleaving protease activity in plasma samples from 30 patients treated at our institution for TTP. Plasma from patients lacking ADAMTS13 was incubated with PNP and then analyzed by the same methods to determine the presence of an inhibitor. Our results indicate that the assay is suitable for providing timely information regarding ADAMTS13 activity for the diagnosis and treatment of patients with suspected TTP. Am.
TPS12151 Background: Pain is a common symptom among cancer patients and often is inadequately treated. Treatment guidelines recommend patients have access to behavioral interventions that educate about pain and pain management. Pain coping skills training (PCST) accomplishes these goals through teaching cognitive and behavioral coping skills shown to reduce pain. When delivered in in-person, PCST can substantially improve chronic pain conditions. Yet, these interventions are underused due to myriad barriers (high costs, shortage of therapists, travel needs). There is a critical need for improved options to help reduce cancer-related pain and related impairment that should include evidence-based PCST interventions capable of overcoming access barriers. To address this need, we developed a web-based PCST program using a novel expert systems approach that retains critical features of in-person PCST in an automated program that requires no therapist. PainTRAINER, is an 8-week, interactive PCST program using tailoring algorithms, a knowledge database, and a virtual coach to guide development of essential skills for coping with chronic pain. Methods: With funding from the NIH HEAL Initiative, we have undertaken a randomized, prospective, comparative effectiveness trial through the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base to determine the impact of painTRAINER on pain outcomes when compared to Enhanced Usual Care (EUC). Participants have a documented diagnosis of invasive cancer who are undergoing anticancer therapy or within 5 years of completing all cancer therapy. Participants must report cancer-related pain most days of the week of 4 or greater on the PROMIS Pain Intensity Scale; with pain of new onset or significantly exacerbated since cancer diagnosis. All participants receive usual care provided by their physician along with pain education materials. PainTRAINER arm participants have access to the painTRAINER program and a tutorial on how to use the program, and complete the painTRAINER modules on their own (1 session/week for 8 weeks). To enhance study access, patients without internet availability are provided a WiFi/cellular-enabled tablet during the intervention period. This trial examines short- and long-term outcomes measured immediately post-intervention and 3- and 6- months post-intervention. Primary outcomes are: pre- to post-intervention change in pain interference/severity. Secondary outcomes are: pain severity/interference at 3- and 6-month follow-up, opioid/analgesic use, health-related quality of life, and pain management self-efficacy. Qualitative interviews are conducted with a random sample of diverse participants who have completed the painTRAINER, and all who exit the study early, to subjectively assess experiences with pain and the clinical trial. Enrollment for this trial has begun (n = 36 of 456 patients enrolled) and is ongoing at 12 sites. Clinical trial information: NCT04462302.
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