RESUMO
Non-toxic doses of tetrakis-mu-3,5-diisopropylsalicylatodicopper(II) [Cu(II)2(3,5-DIPS)4] have been found to have anti-inflammatory, analgesic, anti-ulcer, anti-colitis, anti-convulsant, anti-cancer, anti-mutagenic, anti-carcinogenic, and anti-diabetic activities and, in addition, facilitates recovery from lethal irradiation and ischemia-reperfusion injuries. The goal of this research was to determine the time-dependent tissue distribution and persistence of 67Cu and the 14C labeled salicylate ligand, carboxy-14C-3, 5-diisopropylsalicylate [3,5-DIP(carboxy-14C)S], following subcutaneous administration of a 50 micromole per kilogram of body mass dose of double labeled tetrakis-mu-3,5-diisopropyl[carboxy-14C]salicylatodiaquo [67Cu]dicopper(II) 67Cu(II)4[3,5-DIP(carboxy-14C)S]4. This compound was administered to nine groups of six 20 gram female C57BL/6 mice and blood, liver, kidney, intestine, lung, thymus, femur, muscle, spleen, and brain tissues removed and analyzed for 67Cu and 14C at 0.5, 1, 3, 6, 12, 24, 48, 72, and 96 hours after treatment. These data were then analyzed using a pharmacokinetic model simulation program. Both 67Cu and 14C were found in all tissues as well as urine and feces at 0.5 hour after administration. As anticipated, 67Cu entered the liver storage pool; it was conserved by the kidneys, and subsequently underwent release in maintaining 67Cu levels in all other tissues. While the presence of 67Cu correlated with the presence of the salicylate ligand, 3,5-DIP (carboxy-14C)S, early in the course of this experiment, the ligand was lost via ligand exchange and could not be measured in blood, kidney, intestine, lung, thymus, spleen, and brain after 24 hours following administration. However, 3,5-DIP(carboxy-14C)S persisted in liver, femur, and muscle throughout the 5-day period of study. It is suggested that marked lipophilicity accounts for its very rapid distribution to all tissues wherein it undergoes ligand exchange as 67Cu is incorporated into Cu-dependent enzymes and proteins and persists in tissues based upon physiological demand for Cu in meeting normal biochemical requirements.
Assuntos
Anti-Inflamatórios/farmacocinética , Salicilatos/farmacocinética , Animais , Anti-Inflamatórios/síntese química , Radioisótopos de Carbono , Radioisótopos de Cobre , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Salicilatos/síntese química , Fatores de Tempo , Distribuição TecidualRESUMO
If a dam springs several leaks, there are various ways to respond. One could assiduously plug the holes, for instance. Or one could correct the underlying weaknesses, a more sensible approach. When it comes to corporate governance, for too long we have relied on the first approach. But the causes of many governance problems lie well below the surface--specifically, in critical relationships that are not structured to support the players involved. In other words, the very foundation of the system is flawed. And unless we correct the structural problems, surface changes are unlikely to have a lasting impact. When shareholders, management, and the board of directors work together as a system, they provide a powerful set of checks and balances. But the relationship between shareholders and directors is fraught with weaknesses, undermining the entire system's equilibrium. As the authors explain, the exchange of information between these two players is poor. Directors, though elected by shareholders to serve as their agents, aren't individually accountable to the investors. And shareholders--for a variety of reasons--have failed to exert much influence over boards. In the end, directors are left with the Herculean task of faithfully representing shareholders whose preferences are unclear, and shareholders have little say about who represents them and few mechanisms through which to create change. The authors suggest several ways to improve the relationship between shareholders and directors: Increase board accountability by recording individual directors' votes on key corporate resolutions; separate the positions of chairman and CEO; reinvigorate shareholders; and give boards funding to pay for outside experts who can provide perspective on crucial issues.
Assuntos
Comércio/organização & administração , Ética nos Negócios , Conselho Diretor/organização & administração , Responsabilidade Social , Comércio/ética , Conselho Diretor/economia , Conselho Diretor/ética , Humanos , Relações Interprofissionais/ética , Afiliação Institucional/ética , Inovação Organizacional , Estados UnidosRESUMO
Antihypertensive drugs can have different effects on central and brachial blood pressures, which may affect outcomes. Nitric oxide donors have acute effects on central blood pressure but have not been assessed with renin-angiotensin system blockade. Thirteen patients with prehypertensive/Stage 1 hypertension were randomized to five single-dose treatments separated by ≤4 days using a double-blind, crossover study design: angiotensin receptor blocker (ARB) losartan 100 mg, isosorbide mononitrate (ISMN) 60 mg, losartan 100 mg + ISMN 15 mg, losartan 100 mg + ISMN 60 mg, and placebo. Central and brachial blood pressures were measured throughout 10 hours. Mean placebo-subtracted decrease from baseline in augmentation index (AIx) approximately 1% for losartan 100 mg, 26% for ISMN 60 mg, 19% for losartan 100 mg + ISMN 15 mg, and 24% for losartan 100 mg + ISMN 60 mg. Administered with losartan 100 mg or alone, ISMN lowered AIx, demonstrating that acute effects of a nitrate donor are much larger than those of an ARB even when administered with an ARB. Differences from placebo were statistically significant except for losartan 100 mg. AIx is a good biomarker of acute hemodynamic effects of nitric oxide in prehypertensive/Stage 1 hypertension.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Hipertensão/tratamento farmacológico , Dinitrato de Isossorbida/análogos & derivados , Losartan/administração & dosagem , Doadores de Óxido Nítrico/administração & dosagem , Pré-Hipertensão/tratamento farmacológico , Idoso , Pressão Sanguínea , Artéria Braquial , Estudos Cross-Over , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Frequência Cardíaca , Humanos , Dinitrato de Isossorbida/administração & dosagem , Masculino , Pessoa de Meia-IdadeRESUMO
Precision and accuracy of the quantitative magnetic resonance (QMR) system for measuring fat in phantoms and total body fat (TBF) in humans were investigated. Measurements were made using phantoms: oil, beef with water, beef with oil, and humans with oil and water. TBF(QMR) in humans was compared with TBF by a four-compartment model (TBF(4C)). The coefficient of variation (CV) for replicate TBF(QMR) was 0.437%. QMR fat was lower at 23 °C vs. 37 °C. The fat increase in QMR phantom studies was consistent with the oil increase. When oil was added with humans, the increase in TBF(QMR) was >250 g for the initial 250 g of oil. With additional oil increments, the increase in TBF(QMR) was consistent with the amount of oil added. When water was added with humans, the TBF(QMR) increased independent of the amount of water added. TBF(QMR) was significantly less (mean ± s.e.) than TBF(4C) (females: -0.68 ± 0.27 kg, males: -4.66 ± 0.62 kg; P = 0.0001), TBF(BV) (females: -1.90 ± 0.40 kg; males: -5.68 ± 0.75 kg; P = 0.0001), and TBF(D2O) for males, but greater for females (1.19 ± 0.43 kg vs. -3.69 ± 0.81 kg for males; P = 0.0003). TBF(QMR) was lower than TBF(iDXA) with the difference greater in males (P = 0.001) and decreased with age (P = 0.011). The strong linear relationships between TBF(QMR) and TBF(4C), TBF(BV), and TBF(D2O) with slopes consistent with unity suggest that modifications are required to improve the accuracy. Should the latter be accomplished, QMR holds promise as a highly precise, rapid, and safe, noninvasive method for estimating the amount of and changes in TBF in overweight and severely obese persons.
Assuntos
Tecido Adiposo/patologia , Adiposidade , Pesos e Medidas Corporais/métodos , Espectroscopia de Ressonância Magnética/métodos , Obesidade/patologia , Adulto , Viés , Água Corporal , Pesos e Medidas Corporais/normas , Feminino , Humanos , Espectroscopia de Ressonância Magnética/instrumentação , Masculino , Pessoa de Meia-Idade , Imagens de Fantasmas , Fatores Sexuais , Adulto JovemRESUMO
PURPOSE: Ritonavir is a powerful inhibitor of cytochrome P450 3A (CYP3A) that metabolizes many antiretrovirals. We examined the effect of ritonavir and of chronic viral hepatitis (CVH) status on CYP3A activity. METHODS: Twenty-six HIV-positive men (13 with CVH, 16 on chronic ritonavir-based highly active antiretroviral therapy) received oral and intravenous midazolam, a probe for CYP3A phenotypic activity. RESULTS: CYP3A activity was expressed as oral clearance of the midazolam probe. In HIV-positive subjects not on ritonavir, CYP3A activity (mean +/- SD) did not differ between subjects by CVH (no CVH, controls: 28.5 +/- 9.0 vs. CVH+: 23.2 +/- 6.2 mL/min/kg, not significant). In those on ritonavir (R), CYP3A activity was 7% of controls (R: 2.1 +/- 0.8 vs. no R 28.5 +/- 9.0 mL/min/kg, P < 0.0004). CYP3A activity in subjects on ritonavir and with CVH was further reduced to 4% of controls (no CVH, R+ 2.1 +/- 0.8 vs. R+, CVH+ 1.0 +/- 0.4 mL/min/kg, P < 0.006). CONCLUSIONS: Ritonavir markedly decreases CYP3A activity. In the presence of CVH, ritonavir-based therapy further reduces CYP3A activity by half. Coinfection with CVH impairs CYP3A activity in the presence of the CYP3A inhibitor ritonavir.