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The overall aim of this study is to compare and contrast the design of the two remaining working examples of early twentieth-century transporter bridges in the UK, namely, those at Newport and Middlesbrough. With the aid of modern finite-element analysis, the behaviour of the structures under loading is investigated, likely modes of failure determined and the efficiency of each structure evaluated. The important horizontal load component due to wind at the exposed locations of the bridges is examined using 'current blockage', ideas transferred from recent work on wave-current-structure interaction for space-frame structures in offshore engineering. This article is part of the theme issue 'Environmental loading of heritage structures'.
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The social niche specialization hypothesis predicts that group-living animals should specialize in particular social roles to avoid social conflict, resulting in alternative life-history strategies for different roles. Social niche specialization, coupled with role-specific life-history trade-offs, should thus generate between-individual differences in behaviour that persist through time, or distinct personalities, as individuals specialize in particular nonoverlapping social roles. We tested for support for the social niche specialization hypothesis in cooperative personality traits in wild female meerkats (Suricata suricatta) that compete for access to dominant social roles. As cooperation is costly and dominance is acquired by heavier females, we predicted that females that ultimately acquired dominant roles would show noncooperative personality types early in life and before and after role acquisition. Although we found large individual differences in repeatable cooperative behaviours, there was no indication that individuals that ultimately acquired dominance differed from unsuccessful individuals in their cooperative behaviour. Early-life behaviour did not predict social role acquisition later in life, nor was cooperative behaviour before and after role acquisition correlated in the same individuals. We suggest that female meerkats do not show social niche specialization resulting in cooperative personalities, but that they exhibit an adaptive response in personality at role acquisition.
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Comportamento Cooperativo , Herpestidae/fisiologia , Modelos Biológicos , Animais , Feminino , Herpestidae/psicologia , Predomínio SocialRESUMO
OBJECTIVE: Based on programs implemented in 2011-2013 in three Canadian provinces to improve the support paramedics provide to people receiving palliative care, the Canadian Partnership Against Cancer and Healthcare Excellence Canada provided support and funding from 2018 to 2022 to spread this approach in Canada. The study objectives were to conduct an economic evaluation of "the Program" compared to the status quo. METHODS: A probabilistic decision analytic model was used to compare the expected costs, the quality-adjusted life years (QALYs) and the return on investment associated with the Program compared to the status quo from a publicly funded healthcare payer perspective. Effectiveness data and Program costs, expressed in 2022 Canadian dollars, from each jurisdiction were supplemented with literature data. Probabilistic sensitivity analyses varying key model assumptions were conducted. RESULTS: Analyses of 5416 9-1-1 calls from five jurisdictions where paramedics provided support to people with palliative care needs between April 1, 2020 and March 31, 2022 indicated that 60% of the 9-1-1 calls under the Program enabled people to avoid transport to the emergency department and receive palliative care at home. Treating people at home saved paramedics an average of 31 min (range from 15 to 67). The Program was associated with cost savings of $2773 (95% confidence interval [CI] $1539-$4352) and an additional 0.00069 QALYs (95% CI 0.00024-0.00137) per 9-1-1 palliative care call. The Program return on investment was $4.6 for every $1 invested. Threshold analyses indicated that in order to be cost saving, 33% of 9-1-1 calls should be treated at home under the Program, the Program should generate a minimum of 97 calls per year with each call costing no more than $2773. CONCLUSION: The Program was cost-effective in the majority of the scenarios examined. These results support the implementation of paramedic-based palliative care at home programs in Canada.
RéSUMé: OBJECTIFS: En fonction des programmes mis en Åuvre en 2011-2013 dans trois provinces canadiennes pour améliorer le soutien que les ambulanciers paramédicaux fournissent aux personnes recevant des soins palliatifs. le Partenariat canadien contre le cancer et Excellence des soins de santé Canada a fourni un soutien et du financement de 2018 à 2022 pour diffuser cette approche au Canada. Les objectifs de l'étude étaient d'effectuer une évaluation économique du « programme ¼ par rapport au statu quo. MéTHODES: Un modèle probabiliste d'analyse décisionnelle a été utilisé pour comparer les coûts prévus, les années de vie ajustées en fonction de la qualité (AVAQ) et le rendement du capital investi associés au Programme par rapport au statu quo du point de vue des payeurs de soins de santé financés par l'État. Les données sur l'efficacité et les coûts du Programme, exprimés en dollars canadiens de 2022, de chaque administration ont été complétées par des données documentaires. Des analyses probabilistes de sensibilité ont été effectuées en fonction de diverses hypothèses clés du modèle. RéSULTATS: Des analyses de 5416 appels 9-1-1 provenant de cinq administrations où des ambulanciers paramédicaux ont fourni du soutien aux personnes ayant des besoins en soins palliatifs entre le 1er avril 2020 et le 31 mars 2022 ont indiqué que 60 % des 9Les appels 1-1 dans le cadre du Programme ont permis aux gens d'éviter le transport vers les urgences et de recevoir des soins palliatifs à domicile. Le traitement à domicile a permis aux ambulanciers paramédicaux d'économiser en moyenne 31 minutes (de 15 à 67 minutes). Le programme a permis de réaliser des économies de 2 773 $ (intervalle de confiance [IC] de 95 %, de 1 539 $ à 4 352 $) et de 0,00069 AVAQ supplémentaires (IC à 95 %, de 0,00024 à 0,00137) par appel de soins palliatifs 9-1-1. Le rendement du capital investi du Programme était de 4,6 $ pour chaque dollar investi. Les analyses des seuils ont indiqué que pour réaliser des économies, 33 % des appels 9-1-1 devraient être traités à domicile dans le cadre du Programme, le Programme devrait générer un minimum de 97 appels par année, chaque appel ne dépassant pas 2773 $. CONCLUSION: Le Programme a été rentable dans la majorité des scénarios examinés. Ces résultats appuient la mise en Åuvre de programmes de soins palliatifs paramédicaux à domicile au Canada.
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The T2K experiment presents new measurements of neutrino oscillation parameters using 19.7(16.3)×1020 protons on target (POT) in (anti-)neutrino mode at the far detector (FD). Compared to the previous analysis, an additional 4.7×1020 POT neutrino data was collected at the FD. Significant improvements were made to the analysis methodology, with the near-detector analysis introducing new selections and using more than double the data. Additionally, this is the first T2K oscillation analysis to use NA61/SHINE data on a replica of the T2K target to tune the neutrino flux model, and the neutrino interaction model was improved to include new nuclear effects and calculations. Frequentist and Bayesian analyses are presented, including results on sin2θ13 and the impact of priors on the δCP measurement. Both analyses prefer the normal mass ordering and upper octant of sin2θ23 with a nearly maximally CP-violating phase. Assuming the normal ordering and using the constraint on sin2θ13 from reactors, sin2θ23=0.561-0.032+0.021 using Feldman-Cousins corrected intervals, and Δm322=2.494-0.058+0.041×10-3eV2 using constant Δχ2 intervals. The CP-violating phase is constrained to δCP=-1.97-0.70+0.97 using Feldman-Cousins corrected intervals, and δCP=0,π is excluded at more than 90% confidence level. A Jarlskog invariant of zero is excluded at more than 2σ credible level using a flat prior in δCP, and just below 2σ using a flat prior in sinδCP. When the external constraint on sin2θ13 is removed, sin2θ13=28.0-6.5+2.8×10-3, in agreement with measurements from reactor experiments. These results are consistent with previous T2K analyses.
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In social mammals, social integration is generally assumed to improve females' reproductive success. Most species demonstrating this relationship exhibit complex forms of social bonds and interactions. However, female eastern grey kangaroos (Macropus giganteus) exhibit differentiated social relationships, yet do not appear to cooperate directly. It is unclear what the fitness consequences of such sociability could be in species that do not exhibit obvious forms of cooperation. Using 4 years of life history, spatial and social data from a wild population of approximately 200 individually recognizable female eastern grey kangaroos, we tested whether higher levels of sociability are associated with greater reproductive success. Contrary to expectations, we found that the size of a female's social network, her numbers of preferential associations with other females and her group sizes all negatively influenced her reproductive success. These factors influenced the survival of dependent young that had left the pouch rather than those that were still in the pouch. We also show that primiparous females (first-time breeders) were less likely to have surviving young. Our findings suggest that social bonds are not always beneficial for reproductive success in group-living species, and that female kangaroos may experience trade-offs between successfully rearing young and maintaining affiliative relationships.
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Many authors have proposed that inbreeding destabilizes developmental processes. This destabilization may be reflected by increased fluctuating asymmetry (FA) in inbred compared to relatively outbred populations, but many studies have failed to find such differences. We measured the left and right wings of a large number of individual Drosophila melanogaster from two genetically distinct populations to estimate changes in FA caused by inbreeding. The large sample size and experimental design allowed removal of potentially confounding directional asymmetry (DA) and measurement error terms. Trait means in the two populations were essentially unchanged by inbreeding (less than 0.5% smaller in both populations). Inbred lines showed higher signed FA variances (16 and 38% higher, significantly so in one population) and higher unsigned FA means (3.7 and 13.2%, significantly increased in one population). Significant DA was found in both populations, although the pattern differed between populations. DA did not change due to inbreeding.
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Drosophila melanogaster/genética , Asas de Animais/química , Animais , Padronização Corporal , Drosophila melanogaster/anatomia & histologia , Drosophila melanogaster/química , Drosophila melanogaster/crescimento & desenvolvimento , Endogamia , Modelos Genéticos , Asas de Animais/anatomia & histologia , Asas de Animais/crescimento & desenvolvimentoRESUMO
BACKGROUND: Experimental studies have demonstrated that 32P radioactive stents reduce neointimal formation at 28 days in porcine iliac and coronary arteries. Our objective was to determine the long-term dose-response effects of 1.0- to 12.0-microCi 32P radioactive stents in a porcine atherosclerotic coronary model. METHODS AND RESULTS: Control (n=19) and 1.0- to 12.0-microCi 32P radioactive (n=43) stents (total, n=62) were implanted in the coronary arteries of 31 miniature swine at 28 days after creation of a fibrocellular plaque by overstretch balloon injury and cholesterol feeding. Angiography and histomorphometry were performed at 6 months. Stent thrombosis occurred in 3 radioactive (7.7%) and no control stents (P=0.54). On histology, the mean neointimal area and the percent in-stent stenosis correlated positively with increasing stent activity (r=0.64, P<0.001). The mean neointimal area (mm2) for the stents with >/=3.0 microCi 32P (3.57+/-1.21) was significantly greater than that for the nonradioactive stents (1.78+/-0.68, P<0.0001). The neointima of the stents with >/=3.0 microCi 32P was composed of smooth muscle cells, matrix proteoglycans, calcification, foam cells, and cholesterol clefts. CONCLUSIONS: Continuous low-dose-rate irradiation delivered by high-activity (32)P radioactive stents promotes the formation of an "atheromatous" neointima after 6 months in this experimental model. These data may be useful for predicting late tissue responses to radioactive stents in human coronary arteries.
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Doença da Artéria Coronariana/terapia , Vasos Coronários/efeitos da radiação , Músculo Liso Vascular/diagnóstico por imagem , Radioisótopos de Fósforo/uso terapêutico , Stents , Animais , Angiografia Coronária , Trombose Coronária/etiologia , Vasos Coronários/patologia , Relação Dose-Resposta à Radiação , Músculo Liso Vascular/patologia , Stents/efeitos adversos , Suínos , Porco MiniaturaRESUMO
BACKGROUND: Paclitaxel can inhibit vascular smooth muscle proliferation in vitro, and early studies suggest that paclitaxel may be useful in preventing restenosis. Early and late intimal growth and local vascular pathological changes associated with paclitaxel delivered via stents have not been fully explored. METHODS AND RESULTS: Localized drug delivery was accomplished with balloon-expandable stainless steel stents coated with a cross-linked biodegradable polymer, chondroitin sulfate and gelatin (CSG), containing various doses of paclitaxel. CSG-coated stents with paclitaxel (42.0, 20.2, 8.6, or 1.5 microgram of paclitaxel per stent), CSG-coated stents without paclitaxel, and uncoated stents (without paclitaxel or CSG) were deployed in the iliac arteries of New Zealand White rabbits, which were killed 28 days after implant. Mean neointimal thickness at stent strut sites was reduced 49% (P<0.0003) and 36% (P<0.007) with stents containing 42.0 and 20.2 microgram of paclitaxel per stent, respectively, versus CSG-coated stents without paclitaxel. However, histological findings suggested incomplete healing in the higher-dose (42.0 and 20.2 microgram) paclitaxel-containing stents consisting of persistent intimal fibrin deposition, intraintimal hemorrhage, and increased intimal and adventitial inflammation. Stents coated with CSG alone (without paclitaxel) had similar neointimal growth as uncoated stents. In a separate group of rabbits killed at 90 days, neointimal growth was no longer suppressed by CSG-coated stents containing 42.0 or 21.0 microgram of paclitaxel CONCLUSIONS: CSG coating appears to be a promising medium for localized drug delivery. Paclitaxel polymer-coated stents reduce neointima formation but are associated with evidence of incomplete healing at 28 days. However, neointimal suppression was not maintained at 90 days.
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Inibidores da Angiogênese/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Paclitaxel/farmacologia , Stents , Inibidores da Angiogênese/farmacocinética , Animais , Divisão Celular/efeitos dos fármacos , Sulfatos de Condroitina , Relação Dose-Resposta a Droga , Fibrina/efeitos dos fármacos , Fibrina/metabolismo , Gelatina , Hemorragia/induzido quimicamente , Hemorragia/patologia , Artéria Ilíaca/efeitos dos fármacos , Artéria Ilíaca/metabolismo , Artéria Ilíaca/patologia , Inflamação/induzido quimicamente , Inflamação/patologia , Masculino , Paclitaxel/sangue , Paclitaxel/farmacocinética , Polímeros , Coelhos , Fatores de Tempo , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/metabolismo , Túnica Íntima/patologiaRESUMO
BACKGROUND: The purpose of this study was to determine the efficacy of stent-based delivery of sirolimus (SRL) alone or in combination with dexamethasone (DEX) to reduce in-stent neointimal hyperplasia. SRL is a potent immunosuppressive agent that inhibits SMC proliferation by blocking cell cycle progression. METHODS AND RESULTS: Stents were coated with a nonerodable polymer containing 185 microgram SRL, 350 microgram DEX, or 185 microgram SRL and 350 microgram DEX. Polymer biocompatibility studies in the porcine and canine models showed acceptable tissue response at 60 days. Forty-seven stents (metal, n=13; SRL, n=13; DEX, n=13; SRL and DEX, n=8) were implanted in the coronary arteries of 16 pigs. The tissue level of SRL was 97+/-13 ng/artery, with a stent content of 71+/-10 microgram at 3 days. At 7 days, proliferating cell nuclear antigen and retinoblastoma protein expression were reduced 60% and 50%, respectively, by the SRL stents. After 28 days, the mean neointimal area was 2.47+/-1.04 mm(2) for the SRL alone and 2.42+/-1.04 mm(2) for the combination of SRL and DEX compared with the metal (5.06+/-1.88 mm(2), P<0.0001) or DEX-coated stents (4.31+/-3.21 mm(2), P<0.001), resulting in a 50% reduction of percent in-stent stenosis. CONCLUSIONS: Stent-based delivery of SRL via a nonerodable polymer matrix is feasible and effectively reduces in-stent neointimal hyperplasia by inhibiting cellular proliferation.
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Antibacterianos/farmacologia , Doença das Coronárias/prevenção & controle , Sistemas de Liberação de Medicamentos/métodos , Sirolimo/farmacologia , Stents , Túnica Íntima/efeitos dos fármacos , Animais , Materiais Biocompatíveis , Western Blotting , Quimiocina CCL2/análise , Doença das Coronárias/metabolismo , Doença das Coronárias/terapia , Vasos Coronários/química , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Dexametasona/farmacologia , Modelos Animais de Doenças , Cães , Sinergismo Farmacológico , Feminino , Hiperplasia/prevenção & controle , Interleucina-6/análise , Masculino , Polímeros , Antígeno Nuclear de Célula em Proliferação/análise , Proteína do Retinoblastoma/análise , Suínos , Túnica Íntima/química , Túnica Íntima/patologiaRESUMO
OBJECTIVES: This study was performed to define the evolution of lesion morphology and its relation to thrombus formation and smooth muscle cell proliferation after experimental coronary stent placement. BACKGROUND: Restenosis after percutaneous revascularization may develop because of thrombus accumulation and smooth muscle cell proliferation. In animal models of restenosis, thrombus may assume a significant role in neointimal formation by providing an absorbable matrix into which smooth muscle cells proliferate. METHODS: Twenty-eight oversized stents were placed in the coronary arteries of 23 juvenile domestic pigs. The histologic degree of vessel injury, lesion morphometry and smooth muscle cell proliferation measured by immunolocalization with a monoclonal antibody to proliferating cell nuclear antigen (PCNA) were assessed at 24 h and 7, 14 and 28 days after stent placement. RESULTS: The area of thrombus was minimal at 24 h ([mean +/- SE] 0.44 +/- 0.12 mm2). Neointimal area at 7 days (0.72 +/- 0.20 mm2) was similar to the area of thrombus, followed by a significant increase at 14 days (3.15 +/- 0.39 mm2) and 28 days (3.30 +/- 0.28 mm2) (p < 0.0036, 24 h and 7 days vs. 14 and 28 days). At 14 and 28 days, neointimal thickness correlated with the histologic degree of vessel injury (p < 0.003). In arteries with severe injury, the increase in neointimal thickness is accounted for by replacement of the damaged media. The smooth muscle cell proliferation index was 18.6 +/- 3.5% at 7 days compared with 9.6 +/- 1.3% by 14 days (p = 0.0247) and declined to 1.1 +/- 0.97% by 28 days (p < 0.008, 7 and 14 days vs. 28 days). CONCLUSIONS: Early thrombus formation is minimal, and thrombus accounts for a small portion of subsequent neointimal formation. Smooth muscle cell proliferation and matrix formation are the major factors relating to neointimal formation in this proliferative model of restenosis. The evolution of neointimal formation after coronary stenting shows maximal smooth muscle cell proliferation at 7 days, with a decline to low levels by 28 days. Therefore, these data may be useful for developing effective therapies for restenosis.
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Doença das Coronárias/patologia , Trombose Coronária/patologia , Vasos Coronários/lesões , Músculo Liso Vascular/patologia , Stents , Animais , Divisão Celular/fisiologia , Vasos Coronários/patologia , Antígeno Nuclear de Célula em Proliferação/análise , Recidiva , Suínos , Fatores de Tempo , Túnica Íntima/patologia , Túnica Média/patologiaRESUMO
OBJECTIVES: This study evaluated the delivery characteristics and vascular response to placement of a novel balloon-expandable stent in swine with experimentally induced atherosclerosis. BACKGROUND: The Multi-Link stent is a balloon-expandable stainless steel stent with an interconnected ring structure designed to provide a high degree of compressive resistance while preserving longitudinal flexibility. The placement characteristics and vascular response to this stent in atherosclerotic coronary arteries have not been characterized. METHODS: We tested the delivery characteristics and vascular response to the Multi-Link stent in 19 miniature swine with experimentally induced coronary atherosclerosis created in 37 coronary artery segments by overstretch balloon injury and high cholesterol diet. Quantitative coronary angiography was used to define stent performance characteristics, such as lesion dilation and compressive resistance. Pathologic assessment of the stented arteries was used to evaluate the immediate and long-term vascular response to stent placement. RESULTS: Nineteen (95%) of 20 stents were successfully implanted in the left anterior descending (n = 11), left circumflex (n = 7) or right (n = 1) coronary artery. The baseline angiographic minimal lumen diameter of the stented coronary segment was 2.48 +/- 0.09 mm (reference diameter 2.87 +/- 0.06 mm, mean +/- SE) and increased to 2.82 +/- 0.05 mm (p < 0.001) after stent placement. The balloon-inflated stent diameter was 2.98 +/- 0.06 mm with minimal recoil to a final minimal lumen diameter of 2.82 +/- 0.06 mm at 15 min after implantation (p = 0.001). Angiographic and histologic follow-up at 72 h (n = 7), 14 days (n = 4) and 56 days (n = 8) demonstrated that all stents were patent, without evidence of migration, intraluminal filling defects or side branch occlusion. At 56 days, mean neointimal thickness was significantly greater at the stent wire sites in the region of the plaque where the media was absent than the stent wire sites, where the internal elastic lamina was intact with underlying normal media (0.48 +/- 0.01 vs. 0.27 +/- 0.02 mm, p < 0.0001). Compared with the nonstented atherosclerotic lesions, after 56 days the stented vessels had a mildly reduced lumen area when normalized to the proximal reference vessel (2.81 +/- 0.27 vs. 2.68 +/- 0.30 mm2, p = 0.07). The mean change in the area within the external elastic lamina relative to a normal proximal reference segment was significantly greater in stented vessels (1.45 +/- 0.34 mm2) than nonstented atherosclerotic vessels (0.44 +/- 0.28 mm2, p = 0.033). CONCLUSIONS: Morphologic data confirm that the principal beneficial effect of stent placement is vessel expansion and attenuation of constrictive remodeling. In vessels with eccentric atherosclerotic fibrocellular plaques, the presence of normal media underlying the stent determines the degree of neointimal formation. These data may be useful in understanding the mechanism of stent restenosis in patients with prior percutaneous transluminal coronary angioplasty.
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Angioplastia Coronária com Balão/métodos , Doença da Artéria Coronariana/terapia , Stents , Túnica Íntima/patologia , Angioplastia Coronária com Balão/efeitos adversos , Animais , Doença da Artéria Coronariana/patologia , Hiperplasia , SuínosRESUMO
PURPOSE: The objective of this paper was to provide an update on the clinical and experimental evaluation of radioactive stents for the prevention of restenosis. MATERIALS AND METHODS: Direct ion implantation of 32P onto the surface of a 15-mm length balloon expandable stainless-steel Palmaz-Schatz stent was employed to render this commercially available vascular stent radioactive. 32Phosphorous, a pure beta-particle-emitting radioisotope, was selected because of its short half-life (14.3 days) and limited range of tissue penetration (3-4 mm). The vascular response to radioactive 7-mm length Palmaz-Schatz stents with activities 0.14 to 23 microCi of 32P were evaluated in animal models of arterial injury and restenosis. The Phase-1 isostent for restenosis intervention study (IRIS trial) was a nonrandomized safety trial designed to evaluate the use of a low activity 32P (0.5 to 1.5 microCi) 15-mm length Palmaz-Schatz stent for the treatment of de novo or restenosis native coronary arterial lesions. RESULTS: In the porcine coronary restenosis model, at < or =0.5 microCi and > or =3.0 microCi stent activities, there was a 30% reduction in the neointimal and percent area stenosis as compared to nonradioactive stents. The 1.0 microCi stents, however, had nearly 2-fold greater neointimal formation and more luminal narrowing than the control stents. In the Phase 1 IRIS trial, 57 patients with symptomatic de novo or restenosis native coronary lesions have been treated with low activity (0.5 to 1.5 microCi) 32P Palmaz-Schatz coronary stents. Fifty-seven stents were successfully implanted without a major procedural complication (death, urgent coronary bypass, Q-wave myocardial infarction). There were no cases of stent thrombosis, target vessel revascularization, or other adverse events in the first 30 days after implant. CONCLUSION: The early clinical results with a low-activity 32P Palmaz-Schatz radioactive stent demonstrate sufficient procedural and 30-day event-free survival to warrant consideration of additional clinical studies to determine the safety and efficacy of this therapy for the prevention of restenosis. Future studies will focus on optimal stent design for delivery of radiation, and will further evaluate safe and effective dosing strategies.
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Stents , Doenças Vasculares/prevenção & controle , Animais , Constrição Patológica/prevenção & controle , Radioisótopos de Fósforo/uso terapêutico , Recidiva , Suínos , Porco Miniatura , Grau de Desobstrução VascularRESUMO
PURPOSE: The objective of this article is to describe the methods used to manufacture a radioactive stent and to review the experimental data on this therapy designed to improve arterial patency rates after stent placement. MATERIALS AND METHODS: Surface activation in a cyclotron and ion implantation techniques are used to render commercially available vascular stents radioactive. beta-Particle-emitting stents, most commonly 32P, were employed because of their short half-life (14.3 days) and limited range of tissue penetration (3-4 mm). The function and vascular response to these 32P radioactive stents with varying activities (range 0.14-23 microCi) was evaluated in several animal models of arterial injury and restenosis. RESULTS: In porcine iliac arteries, beta-particle-emitting stents with an initial activity of 0.14 microCi reduced neointimal formation 37% at 28 days after implant. On histology, the neointima consisted of smooth muscle cells and a proteoglycan-rich matrix. Scanning electron microscopy demonstrated complete endothelialization of the stent. beta-Particle-emitting stents with an initial activity of 3-23 microCi inhibited neointimal smooth muscle cell proliferation at 28 days in a porcine coronary restenosis model. The neointima within these high-activity stents consisted of fibrin, erythrocytes, and only rare smooth muscle cells. Studies with 1-year follow-up after implantation of a radioactive stent with a composition of gamma- and beta-particle-emitting radionuclides 55,56,57Co, 52Mg, and 55Fe and an initial activity of 17.5 microCi demonstrated almost complete inhibition of neointimal proliferation in a rabbit model. CONCLUSION: Endovascular irradiation delivered via a radioactive stent reduces neointimal formation and improves luminal patency without increasing the risk for stent thrombosis in experimental models of restenosis. The optimal radiation dose is unknown. At stent activities >3 microCi of 32P, the inhibition of neointimal formation is due to direct radiation affects on proliferating smooth muscle cells. At ultra-low activities (0.14 microCi), beta-particle irradiation reduces neointimal formation possibly by impairing cell proliferation or migration. This novel therapy may have a significant impact on preventing stent restenosis, and requires further investigation.
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Braquiterapia/instrumentação , Vasos Coronários/efeitos da radiação , Endotélio Vascular/efeitos da radiação , Artéria Ilíaca/efeitos da radiação , Músculo Liso Vascular/efeitos da radiação , Stents , Animais , Vasos Coronários/patologia , Endotélio Vascular/patologia , Desenho de Equipamento , Artéria Ilíaca/patologia , Músculo Liso Vascular/patologia , Radioisótopos de Fósforo , Suínos , Grau de Desobstrução VascularRESUMO
We have synthesized a series of stereoisomeric 6,7-benzomorphan derivatives with modified N-substituents and determined their ability to antagonize the N-methyl-D-aspartate (NMDA) receptor-channel complex in vitro and in vivo. The ability of the compounds to displace [3H]-MK-801 from the channel site of the NMDA receptor in rat brain synaptosomal membranes and to inhibit NMDA-induced lethality in mice was compared with their ability to bind to the mu opioid receptor. Examination of structure-activity relationships showed that the absolute stereochemistry is critically important for differentiating these two effects. (-)-1R,9 beta,2"S-enantiomers exhibited a higher affinity for the NMDA receptor-channel complex than for the mu opioid receptor. The aromatic hydroxy function was also found to influence the specificity of the compounds. Shift of the hydroxy group from the 2'-position to the 3'-position significantly increased the affinity for the NMDA receptor-channel complex and considerably reduced the affinity for the mu opioid receptor. From this series of 6,7-benzomorphan derivatives, the compound 15cr.HCl [(2R)-[2 alpha, 3(R*),6 alpha]-1,2,3,4,5,6-hexahydro-3-(2-methoxypropyl)-6,11,11-trimethyl -2,6-methano-3-benzazocin-9-ol hydrochloride] was chosen as the optimum candidate for further pharmacological investigations.
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Benzomorfanos/síntese química , Benzomorfanos/farmacologia , Canais Iônicos/antagonistas & inibidores , Derivados da Morfina/síntese química , Derivados da Morfina/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Benzomorfanos/química , Ligação Competitiva , Membrana Celular/metabolismo , Córtex Cerebral/metabolismo , Cristalografia por Raios X , Di-Hidromorfina/metabolismo , Maleato de Dizocilpina/metabolismo , Canais Iônicos/fisiologia , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Derivados da Morfina/química , N-Metilaspartato/metabolismo , N-Metilaspartato/toxicidade , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Sinaptossomos/metabolismoRESUMO
The preparation of 1,4-dihydropyridines containing (heterocyclylmethoxy)methyl groups in the 2-position is described and the structural identification of certain of the compounds using 1H NMR spectroscopic methods is reported. The calcium antagonist activity of the compounds on rat aorta is listed and is compared with the negative inotropic potency as determined by using a Langendorff-perfused guinea pig heart model. Several compounds are more potent than nifedipine and show greater selectivity for the vasculature over the heart. One compound, 2-[(2-amino-4-hydroxypyrimidin-6-yl)methoxy]-4- (2,3-dichlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl- 1,4-dihydropyridine (27, UK-56,593), was identified as a potent (IC50 = 1.6 x 10(-9) M), tissue-selective calcium antagonist which proved to have a markedly longer duration of action (greater than 4.5 h) than nifedipine in the anesthetized dog on intravenous administration.
Assuntos
Bloqueadores dos Canais de Cálcio/síntese química , Di-Hidropiridinas/síntese química , Músculo Liso Vascular/fisiologia , Contração Miocárdica/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Circulação Coronária/efeitos dos fármacos , Di-Hidropiridinas/farmacologia , Cães , Cobaias , Técnicas In Vitro , Indicadores e Reagentes , Estrutura Molecular , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Potássio/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The synthesis of a series of 1,4-dihydropyridines which have N-linked heterocycles at the terminus of an ethoxymethyl chain at the 2-position is described. The calcium antagonist activity on rat aorta of this class of DHPs is compared with their negative inotropic activity as determined by using a Langendorff-perfused guinea pig heart model. The compounds examined show a wide range of selectivity for vascular over cardiac tissue, with those analogues which possess an amide group at the terminus of the 2-substituent proving the most selective. From the in vitro data obtained for a series of 1,2,3-triazoles, it is possible to conclude that the SARs for binding to the calcium channels in vascular and cardiac tissue are different. One of the compounds, 2-amino-1-[2-[[4-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-5- (methoxycarbonyl)-6-methyl-1,4-dihydropyrid-2-yl]methoxy]ethyl]-4( 3H)- imidazolone (20b, UK-55,444), was identified as a potent (IC50 = 8 x 10(-9) M) calcium antagonist which is 40-fold selective for vascular over cardiac tissue and which has a significantly longer duration of action (greater than 3 h) than nifedipine in the anesthetized dog on intravenous administration.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Di-Hidropiridinas/farmacologia , Imidazóis/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Di-Hidropiridinas/síntese química , Cães , Cobaias , Imidazóis/síntese química , Técnicas In Vitro , Músculo Liso Vascular , Miocárdio , Especificidade de Órgãos , Ratos , Relação Estrutura-Atividade , Fatores de TempoRESUMO
The preparation of a series of 1,4-dihydropyridines (DHPs) which have polar, acyclic, nonbasic substituents on an ethoxymethyl chain at the 2-position is described. In addition, in order to assess the effects of incorporating a basic center into DHPs of this type, a series of glycinamides were also prepared. The calcium antagonist activity on rat aorta of both these classes of DHP is compared with their negative inotropic activity as determined by using a Langendorff perfused guinea pig heart model. A number of the compounds evaluated have activity of the same order as nifedipine although those with more extended substituents have lower potency, particularly when a basic substituent is present. The compounds examined displayed a wide variation in selectivity for vascular over cardiac tissue. A number of structure-activity relationship trends were identified and possible explanations to account for the differences in selectivity observed are advanced. One of the compounds, 2-[[2-[[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6- methyl-1,4-dihydropyrid-2-yl]methoxy]ethyl]amino]acetamide (26, UK-51,656), was identified as a potent (IC50 = 4 x 10(-9) M) calcium antagonist which is 20-fold selective for vascular over cardiac tissue and which has a markedly longer duration of action (greater than 5 h) than nifedipine in the anesthetized dog on intravenous administration. The pharmacokinetic half-life of 26 was established as 4.7 h and possible explanations are advanced to account for 26 having a shorter plasma half-life than amlodipine and a longer plasma half-life than felodipine.
Assuntos
Bloqueadores dos Canais de Cálcio/síntese química , Di-Hidropiridinas/síntese química , Receptores Nicotínicos/metabolismo , Animais , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio , Fenômenos Químicos , Química , Di-Hidropiridinas/farmacocinética , Di-Hidropiridinas/farmacologia , Cães , Técnicas In Vitro , Contração Muscular/efeitos dos fármacos , Músculo Liso , Ratos , Relação Estrutura-Atividade , Fatores de Tempo , VasodilatadoresRESUMO
Hippocampal slices were transiently exposed to an oxygen- and glucose-free environment which causes a pronounced drop of both ATP and creatine phosphate, an anoxic depolarization, and an incomplete recovery of synaptically evoked population spike in the CA1 region after 1 h (48.5 +/- 3.6% of baseline values). This recovery could be markedly enhanced by the application of N-methyl-D-aspartate receptor antagonists. To examine the influence of metabotropic glutamate receptors on neuronal recovery from hypoxia/hypoglycemia, we applied various antagonists and agonists of the metabotropic glutamate receptors to the bath during the interval from 20 min before to 10 after hypoxia/hypoglycemia. The metabotropic glutamate receptor antagonists (+)-alpha-methyl-4-carboxyphenylglycine and L-2-3- amino-phosphonopropionic acid were both able to enhance the population spike recovery significantly. However, the mixed metabotropic glutamate receptor agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid also exhibited a protective effect on population spike recovery, leaving the anoxic depolarization and N-methyl-D-aspartate responses during the hypoxia/hypoglycemia untouched. With the help of more subtype-specific agonists, we found that an activation of phospholipase C coupled (class 1) metabotropic glutamate receptors prior to hypoxia/hypoglycemia may be responsible for the protective effect seen with 1S, 3R-1-aminocyclopentane-1,3-dicarboxylic acid, because the specific class 1 metabotropic glutamate receptor agonist trans-azetidine-2,4-dicarboxylic acid appeared to be highly protective, but only if it was applied 20 min before the hypoxia/hypoglycemia. An activation of class 2 metabotropic glutamate receptors by (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine, which inhibits adenylyl cyclase activity, led to a marked deterioration of the population spike recovery and even to a total prevention of the protective effect of the N-methyl-D-aspartate agonist D-2-amino-5-phosphonopentanoic acid. Our data suggest that prior activation of class 1 metabotropic glutamate receptors is beneficial, while their activation during hypoxia/hypoglycemia is detrimental. Furthermore, the activation of class 2 metabotropic glutamate receptors decreases the recovery from hypoxia/hypoglycemia.
Assuntos
Hipocampo/metabolismo , Hipoglicemia/patologia , Hipóxia Encefálica/patologia , Neurônios/fisiologia , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Animais , Cicloleucina/análogos & derivados , Cicloleucina/farmacologia , Eletrofisiologia , Metabolismo Energético/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Técnicas In Vitro , Masculino , N-Metilaspartato/antagonistas & inibidores , Fosfocreatina/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Ratos , Ratos WistarRESUMO
The platelet aggregation that occurred in whole blood in response to several aggregating agents (collagen, arachidonic acid, adenosine diphosphate, adrenaline and thrombin) was measured using an Ultra-Flo 100 Whole Blood Platelet Counter. The amounts of thromboxane B2 produced were measured by radioimmunoassay. The effects of various inhibitors of thromboxane synthesis and the effects of apyrase, an enzyme that destroys adenosine diphosphate, were determined. Platelet aggregation was always accompanied by the production of thromboxane B2, and the amounts produced depended on the nature and concentration of the aggregating agent used. The various inhibitors of thromboxane synthesis--aspirin and flurbiprofen (cyclo-oxygenase inhibitors), BW755C (a cyclo-oxygenase and lipoxygenase inhibitor) and dazoxiben (a selective thromboxane synthase inhibitor)--did not markedly inhibit aggregation. Results obtained using apyrase showed that adenosine diphosphate contributed to the aggregation process, and that its role must be acknowledged when devising means of inhibiting platelet aggregation in vivo.
Assuntos
Difosfato de Adenosina/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Tromboxano A2/farmacologia , 4,5-Di-Hidro-1-(3-(Trifluormetil)Fenil)-1H-Pirazol-3-Amina , Difosfato de Adenosina/sangue , Apirase/farmacologia , Ácido Araquidônico , Ácidos Araquidônicos/farmacologia , Aspirina/farmacologia , Colágeno/farmacologia , Inibidores de Ciclo-Oxigenase , Epinefrina/farmacologia , Flurbiprofeno/farmacologia , Humanos , Imidazóis/farmacologia , Técnicas In Vitro , Inibidores de Lipoxigenase , Pirazóis/farmacologia , Trombina/farmacologia , Tromboxano A2/sangue , Tromboxano-A Sintase/antagonistas & inibidoresRESUMO
Whole blood, allowed to clot at 37 degrees C in glass tubes, synthesized thromboxane A2 (TxA2) as determined by radioimmunoassay for thromboxane B2 (TxB2). The time course for TxB2 synthesis showed no further increase after 60 min and the concentration of TxB2 in serum obtained from 60 normal subjects positively correlated with the whole blood platelet count in EDTA anticoagulated blood from the same donor. Patients with chronic renal failure produced less serum TxB2 than age- and sex-matched controls; they also had lower haematocrits. After re-calculating TxB2 production as a function of platelet count and haematocrit all but one of the patients fell in the range of values obtained for controls. These results suggest that chronic renal failure may not be associated with a cyclooxygenase defect and that clotted whole blood TxB2 production should be expressed as a function of platelet count and haematocrit.