RESUMO
The article reports on an experiment which investigated the effect of increased classroom ventilation rate on the performance of children aged 10-12 years. The experiment was executed at two different schools (two classrooms at each school) as a double-blind 2 × 2 crossover intervention where four different performance tests were used as surrogates for short-term concentration and logical thinking. Only complete pairs of test responses were included in the within-subject comparisons of performance, and data were not corrected for learning and fatigue effects. Analysis of the total sample suggested the number of correct answers was improved significantly in four of four performance test, addition (6.3%), number comparison (4.8%), grammatical reasoning (3.2%), and reading and comprehension (7.4%), when the outdoor air supply rate was increased from an average of 1.7 (1.4-2.0) to 6.6 l/s per person. The increased outdoor air supply rate did not have any significant effect on the number of errors in any of the performance tests. Results from questionnaires regarding pupil perception of the indoor environment, reported Sick Building Syndrome symptoms, and motivation suggested that the study classroom air was perceived more still and pupil were experiencing less pain in the eyes in the recirculation condition compared to the fresh air condition.
Assuntos
Desempenho Acadêmico , Poluição do Ar em Ambientes Fechados/efeitos adversos , Dióxido de Carbono/efeitos adversos , Estudantes/psicologia , Ventilação/métodos , Poluição do Ar em Ambientes Fechados/análise , Dióxido de Carbono/análise , Criança , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Aprendizagem/efeitos dos fármacos , Masculino , Instituições Acadêmicas , Estações do Ano , Síndrome do Edifício Doente/psicologiaRESUMO
The demonstration that angiogenic growth factors can stimulate new blood vessel growth and restore perfusion in animal models of myocardial ischemia has led to the development of strategies designed for the local production of angiogenic growth factors in patients who are not candidates for conventional revascularization. The results of recent clinical trials of proangiogenesis gene therapy have been disappointing; however, significant limitations in experimental design, in particular in gene transfer strategies, preclude drawing definitive conclusions. In the REVASC study cardiac gene transfer was optimized by direct intramyocardial delivery of a replication-deficient adenovirus-containing vascular endothelial growth factor (AdVEGF121, 4 x 10(10) particle units (p.u.)). Sixty-seven patients with severe angina due to coronary artery disease and no conventional options for revascularization were randomized to AdVEGF121 gene transfer via mini-thoracotomy or continuation of maximal medical treatment. Exercise time to 1 mm ST-segment depression, the predefined primary end-point analysis, was significantly increased in the AdVEGF121 group compared to control at 26 weeks (P=0.026), but not at 12 weeks. As well, total exercise duration and time to moderate angina at weeks 12 and 26, and in angina symptoms as measured by the Canadian Cardiovascular Society Angina Class and Seattle Angina Questionnaire were all improved by VEGF gene transfer (all P-values at 12 and 26 weeks < or =0.001). However, if anything the results of nuclear perfusion imaging favored the control group, although the AdVEGF121 group achieved higher workloads. Overall there was no significant difference in adverse events between the two groups, despite the fact that procedure-related events were seen only in the thoracotomy group. Therefore, administration of AdVEGF121 by direct intramyocardial injections resulted in objective improvement in exercise-induced ischemia in patients with refractory ischemic heart disease.
Assuntos
Adenoviridae/genética , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Isquemia Miocárdica/terapia , Fator A de Crescimento do Endotélio Vascular/genética , Análise de Variância , Anti-Hipertensivos/uso terapêutico , Quimioterapia Combinada , Eletrocardiografia , Teste de Esforço , Feminino , Vetores Genéticos/genética , Coração/diagnóstico por imagem , Humanos , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/tratamento farmacológico , Neovascularização Fisiológica , Segurança , Tomografia Computadorizada de Emissão de Fóton Único , Transdução Genética/métodos , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
PURPOSE: This phase I study was performed to evaluate the safety and pharmacokinetics of escalating doses of Marimastat (British Biotech, Inc, Oxford, United Kingdom) in patients with advanced malignancies and to determine the phase II recommended dose to be used in subsequent studies. PATIENTS AND METHODS: A standard phase I design was used in this study, in which consecutive groups of three patients were treated with escalating doses of the study drug. Marimastat was administered orally at 25, 50, or 100 mg twice daily to consecutive groups of patients with advanced lung cancer. An additional three patients were added at the highest dose studied (100 mg orally twice daily) to assess whether the inflammatory polyarthitis observed at that dose level can be prevented by a concurrent administration of nonsteroidal antiinflammatory drugs (NSAIDS) and/or low-dose corticosteroids. Blood was drawn for safety monitoring, pharmacokinetic analysis, and plasma levels of metalloproteinase (MMP)-2 and MMP-9 (determined by zymography). A total of 12 patients were studied. RESULTS: The most significant toxicity at the highest dose studied (100 mg orally twice daily) was a symptomatic inflammatory polyarthritis that persisted for up to 8 weeks after discontinuation of the study drug and was dose-limiting. The estimated plasma elimination half-life of Marimastat was 4 to 5 hours. The mean maximum concentration (Cmax) at a reasonably well-tolerated dose (50 mg orally twice daily) was 196 ng/mL and was reached within 1 to 2 hours (Tmax) after administration. Areas under the curve (AUC) tended to correlate with the dose of Marimastat. Zymographic analysis of peripheral-blood ratios of activated proenzymatic forms of MMP-2 and -9 did not show any consistent patterns of change in MMP levels or in a degree of their activation during the course of treatment. CONCLUSION: Marimastat was well absorbed from the gastrointestinal tract, with high levels of the study drug detected in plasma within hours after drug administration. Plasma concentrations of Marimastat achieved at dose levels 2 and 3 (50 mg and 100 mg orally twice daily) were substantially higher than those required for MMP inhibition in vitro. The dose-limiting toxicity (DLT) was severe inflammatory polyarthritis, which seemed to be a cumulative toxicity.
Assuntos
Inibidores Enzimáticos/administração & dosagem , Ácidos Hidroxâmicos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Metaloendopeptidases/antagonistas & inibidores , Administração Oral , Idoso , Artrite/induzido quimicamente , Colagenases/sangue , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Gelatinases/sangue , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Ácidos Hidroxâmicos/farmacocinética , Masculino , Metaloproteinase 2 da Matriz , Metaloproteinase 9 da Matriz , Metaloendopeptidases/efeitos adversos , Metaloendopeptidases/sangue , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Matrix metalloproteinases (MMPs) are a homologous family of enzymes that are involved in tissue remodeling and morphogenesis. Collectively, these enzymes are capable of degrading all components of the extracellular matrix, and they play an important role in normal physiologic conditions, such as wound healing and other processes involving tissue remodeling. However, increased activity of these enzymes now has been observed in a number of different pathological conditions, and it has been hypothesized that such increased activity of MMPs might play a role in the pathogenesis of these conditions. Cancer is one such condition; extracellular matrices constitute the principal barrier to tumor growth and spread, and there is growing experimental evidence that malignant tumors utilize MMPs to overcome these barriers. Consequently, inhibitors of MMPs represent an attractive target for a new class of anticancer agents. Marimastat and batimastat are potent broad-spectrum inhibitors of all major MMPs and have been shown to prevent or reduce spread and growth of a number of different malignant tumors in numerous animal models. Both agents are now in advanced clinical testing in a number of different solid tumors in North America and Europe. The purpose of this paper is to review available preclinical and emerging clinical data, using batimastat and marimastat as prototype MMP inhibitors in the cancer area.
Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Ácidos Hidroxâmicos , Metaloendopeptidases/antagonistas & inibidores , Fenilalanina/análogos & derivados , Inibidores de Proteases/uso terapêutico , Tiofenos/uso terapêutico , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Feminino , Hemangioma/tratamento farmacológico , Humanos , Melanoma/tratamento farmacológico , Camundongos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Fenilalanina/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
There is increasing evidence that class III antiarrhythmic agents may be superior to class I agents for the long-term treatment of life-threatening ventricular tachyarrhythmias. This open study evaluated the acute electrophysiologic effects, antiarrhythmic efficacy, and safety of different doses of intravenous dofetilide, a new class III drug, in 50 patients with sustained monomorphic ventricular tachycardia inducible by programmed electrical stimulation who had previously been unsuccessfully treated with 0 to 7 (median 3) other drugs. Intravenous dofetilide was administered over 60 minutes at the following dose levels: 1.5, 3.0, 6.0, 9.0, and 15.0 micrograms/kg. Significant class III activity was apparent at doses of 3.0 to 15.0 micrograms/kg, as evidenced by dose-related prolongation of the QTc interval by 13.4% to 14.2%, ventricular effective refractory period by 7.9% to 20.6%, and ventricular functional refractory period by 7.3% to 25.0%. The corresponding mean +/- SD plasma dofetilide concentrations ranged from 1.45 +/- 0.52 to 6.48 +/- 1.31 ng/ml. There was no evidence of reverse use-dependence. At these electrophysiologically active dose levels, intravenous dofetilide suppressed (complete response) or slowed (partial response) inducible ventricular tachycardia in 17 of 41 patients (41%) compared with 0 of 9 patients receiving only 1.5 micrograms/kg. The response rate was fairly uniform among the groups receiving 3.0, 6.0, 9.0, and 15.0 micrograms/kg. Intravenous dofetilide was hemodynamically well tolerated. Torsades de pointes (which was self-limiting) developed in only 1 patient, who was allocated to receive 15.0 micrograms/kg. There were no other proarrhythmic episodes or serious adverse effects. Further evaluation of the therapeutic potential of dofetilide in the management of life-threatening ventricular arrhythmias is justified.
Assuntos
Antiarrítmicos/uso terapêutico , Fenetilaminas/uso terapêutico , Sulfonamidas/uso terapêutico , Taquicardia Ventricular/tratamento farmacológico , Idoso , Antiarrítmicos/administração & dosagem , Estimulação Elétrica , Eletrofisiologia , Europa (Continente) , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Fenetilaminas/administração & dosagem , Sulfonamidas/administração & dosagem , Taquicardia Ventricular/fisiopatologiaRESUMO
Monophasic action potentials (MAP) were simultaneously recorded from the right ventricular (RV) apex (RVA) and the outflow tract (RVOT) before and after an infusion of dofetilide in 10 patients with documented ventricular tachycardia. After the drug infusion, the MAP duration (MAPd), repolarization time, and corrected QT interval were significantly prolonged during sinus rhythm, RV pacing, and RV extra stimulation. The prolongation of MAPd at 90% repolarization during RV pacing at a cycle length of 500 ms was 31 +/- 6 ms (13%) and 26 +/- 7 ms (11%) at RVA and RVOT, respectively. The ventricular effective refractory period was significantly prolonged by 33 +/- 9 ms (13%) and 22 +/- 7 ms (9%) at driving cycle lengths 600 and 500 ms, respectively. The MAPd shortening with decreasing diastolic time intervals was significantly diminished by dofetilide in early extra beats during RV extra stimulation, suggesting a relatively more pronounced effect of this drug at the early diastolic phase. The dispersion of repolarization, defined as the difference in MAPd between RVA and RVOT, and the activation time were not significantly changed. In conclusion, acute administration of dofetilide in patients with ventricular tachycardia significantly prolonged the time intervals of ventricular repolarization and refractoriness in a parallel fashion, without affecting intraventricular conduction. The effect of dofetilide on MAPd prolongation appeared not to be reverse use-dependent in this study in humans. These results verify the selective class III antiarrhythmic property of dofetilide and warrant further studies in patients.
Assuntos
Antiarrítmicos/farmacologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Fenetilaminas/farmacologia , Bloqueadores dos Canais de Potássio , Sulfonamidas/farmacologia , Taquicardia Ventricular/fisiopatologia , Função Ventricular Direita/fisiologia , Potenciais de Ação/efeitos dos fármacos , Adulto , Idoso , Diástole/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Função Ventricular Direita/efeitos dos fármacosRESUMO
OBJECTIVE: To investigate the effect of long term oral magnesium treatment on incidence of cardiac events among survivors of an acute myocardial infarction. DESIGN: Double blind, placebo controlled parallel study in which patients were randomised to treatment or placebo. SETTING: Two coronary care units and corresponding outpatient clinics. SUBJECTS: 468 survivors of an acute myocardial infarction (289 men and 178 women) aged 31-92. INTERVENTIONS: One tablet of 15 mmol magnesium hydroxide or placebo daily for one year. MAIN OUTCOME MEASURES: Incidences of reinfarction, sudden death, and coronary artery bypass grafting in one year. RESULTS: There was no significant difference between treatment and placebo groups in the incidence of each of the three cardiac events, but when the events were combined and drop outs were excluded from calculations there was a significantly higher incidence of events in the treatment group (56/167 v 33/153; relative risk 1.55 (95% confidence interval 1.07 to 2.25); p = 0.02). When the timing of events was incorporated by means of a Kaplan-Meier plot the treatment group showed a significantly higher incidence of events whether drop outs were included or excluded (p < 0.025). CONCLUSION: Long term oral treatment with 15 mmol magnesium daily doses not reduce the incidence of cardiac events in survivors of an acute myocardial infarction and, indeed, seems to increase the risk of developing a cardiac event. Consequently, this treatment cannot be recommended as secondary prophylaxis for such patients.
Assuntos
Hidróxido de Magnésio/administração & dosagem , Infarto do Miocárdio/mortalidade , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Ponte de Artéria Coronária , Morte Súbita Cardíaca/prevenção & controle , Método Duplo-Cego , Feminino , Humanos , Assistência de Longa Duração , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/prevenção & controle , Recidiva , Fatores de RiscoAssuntos
Magnésio/uso terapêutico , Isquemia Miocárdica/tratamento farmacológico , Doença Aguda , Animais , Homeostase/efeitos dos fármacos , Humanos , Infusões Intravenosas , Magnésio/efeitos adversos , Magnésio/sangue , Deficiência de Magnésio/etiologia , Infarto do Miocárdio/sangue , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , Isquemia Miocárdica/sangueRESUMO
The effects of intravenous dofetilide on ventricular monophasic action potential duration and effective refractory period at the right ventricular apex and outflow tract were studied in 18 patients (aged 37 to 70 years) with ischemic heart disease. Six patients received low-dose dofetilide as a 3 micrograms/kg loading dose over 15 minutes and a 1.5 micrograms/kg maintenance dose over 45 minutes; 6 received high-dose dofetilide 6 + 3 micrograms/kg and 6 placebo. During atrial pacing at a cycle length of 800 ms high-dose dofetilide prolonged right ventricular apex monophasic action potential duration by 45 ms (16%) and the effective refractory period by 40 ms (16%). At the right ventricular outflow tract, monophasic action potential duration was prolonged by 45 ms (15%) and effective refractory period by 55 ms (21%). During atrial pacing at a cycle length of 500 ms high-dose dofetilide prolonged the right ventricular apex monophasic action potential duration by 40 ms (18%) and the effective refractory period by 43 ms (21%). The right ventricular outflow tract monophasic action potential duration was prolonged by 33 ms (14%) and effective refractory period by 45 ms (21%). Dofetilide produced no increase in the dispersion of repolarization between the 2 sites. During the maintenance infusion QTc prolongation by high-dose dofetilide averaged 43 ms (10%) with no increase of interlead QT dispersion. The effects of dofetilide on QT interval and effective refractory period are shown to be due to a direct effect on action potential duration with no effect on dispersion. No rate dependence of monophasic action potential prolongation was detected at these cycle lengths.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Angina Pectoris/fisiopatologia , Antiarrítmicos/uso terapêutico , Eletrocardiografia/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Fenetilaminas/uso terapêutico , Sulfonamidas/uso terapêutico , Função Ventricular Direita/efeitos dos fármacos , Adulto , Idoso , Antiarrítmicos/administração & dosagem , Função do Átrio Direito/efeitos dos fármacos , Nó Atrioventricular/efeitos dos fármacos , Estimulação Cardíaca Artificial , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Fenetilaminas/administração & dosagem , Placebos , Período Refratário Eletrofisiológico/efeitos dos fármacos , Sulfonamidas/administração & dosagemRESUMO
1. Short-chain fatty acid concentration was 180 mmol/l in the proximal colon and decreased to 108 mmol/l in the rectum. 2. Fermentation in chymus from different regions of the colon, showed the pattern of end products to reflect the substrate and not the site of the colon. 3. Isolated mucosa from proximal and distal colon had electroneutral sodium absorption of 4.8 +/- 0.2 and 2.9 +/- 0.8 mueq/cm2 hr in bicarbonate free media, which was abolished in the absence of chloride. 4. Electroneutral sodium absorption was enhanced by short-chain fatty acids in the proximal colon and could be described by Michaelis-Menten kinetics with Km 2.0-11 mmol/l and Jm 1.6-3.6 mueq/cm2 hr. In the distal colon the stimulation was smaller and propionate even inhibited sodium absorption. 5. Butyrate was absorbed in the proximal colon, whereas acetate and propionate, and butyrate in the distal colon had a flux ratio of one. 6. Amiloride (5 mmol/l) inhibited sodium absorption and net butyrate absorption.
Assuntos
Colo/metabolismo , Ácidos Graxos/metabolismo , Absorção Intestinal/fisiologia , Suínos/metabolismo , Animais , Ácidos Graxos/biossíntese , Técnicas In Vitro , Mucosa Intestinal/metabolismo , Sódio/metabolismoRESUMO
1. Pharmacokinetics of dofetilide were studied in man, dog, rat and mouse after single i.v. and oral doses of dofetilide or 14C-dofetilide. 2. Dofetilide was absorbed completely in all species. Low metabolic clearance in man resulted in complete bioavailability following oral administration. Higher metabolic clearance in rodents, and to a lesser extent dogs, resulted in decreased bioavailability because of first-pass metabolism. 3. Following i.v. administration, the volume of distribution showed only moderate variation in all species (2.8-6.3 l/kg). High plasma clearance in rodents resulted in short half-life values (mouse 0.32, male rat 0.5 and female rat 1.2 h), whilst lower clearance in dog and man gave longer terminal elimination half-lives (4.6 and 7.6 h respectively). 4. After single i.v. doses of 14C-dofetilide, unchanged drug was the major component excreted in urine of all species with several metabolites also present. 5. Metabolites identified in urine from all species were formed by N-oxidation or N-dealkylation of the tertiary nitrogen atom of dofetilide. 6. After oral and i.v. administration of 14C-dofetilide to man, parent compound was the only detectable component present in plasma and represented 75% of plasma radioactivity. No single metabolite accounted for greater than 5% of plasma radioactivity.
Assuntos
Antiarrítmicos/farmacocinética , Fenetilaminas/farmacocinética , Sulfonamidas/farmacocinética , Administração Oral , Animais , Antiarrítmicos/sangue , Antiarrítmicos/urina , Cães , Feminino , Humanos , Infusões Intravenosas , Injeções Intravenosas , Masculino , Camundongos , Fenetilaminas/sangue , Fenetilaminas/urina , Ratos , Ratos Sprague-Dawley , Sulfonamidas/sangue , Sulfonamidas/urinaRESUMO
Dofetilide (UK-68,798) is a new class III antiarrhythmic agent. In animal experiments it selectively prolongs the refractory periods parallel to the action potential duration without any influence on upstroke velocity or conduction parameters. The present double-blind, placebo-controlled study was designed to show the effect of dofetilide on basic electrophysiologic parameters in patients with coronary artery disease. Eighteen patients (aged 31 to 64 years) with symptoms of stable angina pectoris admitted for routine coronary angiography were recruited. They were randomly allocated to receive either placebo or 1 of 2 dose levels of dofetilide intravenously with 6 patients in each group. Paired electrophysiologic variables were compared before and after administration of dofetilide. Both active dose levels produced significant prolongations (p less than 0.05) of 10 to 23% in atrial effective refractory period, 6 to 16% in ventricular effective refractory period and 11 to 15% in ventricular functional refractory period. Atrial functional refractory period was prolonged by 14 to 22% at the high-dose level (p less than 0.05). No effect was observed on conduction parameters (PA, AH, HV, PR or QRS intervals), sinus cycle length or sinus node recovery. The selective prolongation of the refractory periods in both atrium and ventricle, combined with a lack of effect on cardiac conduction parameters, indicates that this drug could be useful in the treatment of both atrial and ventricular reentrant tachyarrhythmias and fibrillation.
Assuntos
Angina Pectoris/fisiopatologia , Antiarrítmicos/farmacologia , Eletrocardiografia/efeitos dos fármacos , Sistema de Condução Cardíaco/efeitos dos fármacos , Fenetilaminas/farmacologia , Sulfonamidas/farmacologia , Adulto , Análise de Variância , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Distribuição AleatóriaAssuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Flutter Atrial/tratamento farmacológico , Fenetilaminas/uso terapêutico , Sulfonamidas/uso terapêutico , Taquicardia Paroxística/tratamento farmacológico , Adulto , Idoso , Antiarrítmicos/efeitos adversos , Pressão Sanguínea , Relação Dose-Resposta a Droga , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenetilaminas/efeitos adversos , Sulfonamidas/efeitos adversosRESUMO
Dofetilide is a potent and selective class III antiarrhythmic agent that is under development for the treatment of re-entrant tachyarrhythmias (ventricular tachycardia/ventricular fibrillation, atrial fibrillation/atrial flutter, and paraoxysmal supraventricular tachycardia). In animal studies, dofetilide selectively inhibits the rapid component of the time-dependent outward potassium current (IKr) and therefore increases the effective refractory period and action potential duration without affecting the fast inward sodium current. Studies in dogs have shown that dofetilide (a) prolongs the effective refractory period in a dose-dependent manner, (b) elevates ventricular fibrillation threshold, (c) facilitates conversion of electrically induced ventricular fibrillation or fibrilloflutter to sinus rhythm, (d) does not influence conduction within the His-Purkinje system or within the myocardium, (e) does not impair cardiac contractility, and (f) reduces dispersion of ventricular repolarization. Dofetilide has been administered to healthy volunteers as well as to patients with ischemic heart disease or with supraventricular arrhythmias; the compound has generally been well tolerated. Side effects have occasionally been reported, but have generally been transient and mild and occur in placebo-treated subjects as well. No clinically significant changes in laboratory safety tests have been detected. The pharmacokinetic profile of dofetilide both in healthy volunteers and patients includes a linear dose-plasma concentration relationship and also a linear plasma concentration-QTc relationship. The terminal plasma elimination half-life is approximately 9-10 h and systemic bioavailability in the region of 100%. The elimination pattern is balanced, with 50% being excreted unchanged via the kidney, the remaining 50% being metabolized in the liver to inactive metabolites, with greater than 90% of circulating drug-related material being unchanged dofetilide. After intravenous administration of the compound, a slight hysteresis in the plasma drug level-QTc relationship has been detected. Pharmacodynamic data demonstrate dose- and concentration-dependent effects on myocardial repolarization as evidenced by prolongations of the QTc interval. This is reflected in significant prolongations in the effective and functional refractory periods and monophasic action potential duration throughout the myocardium. No effects on sinus node function, conduction parameters, or cardiac contractility have been detected in any of the clinical studies, supporting the contention that dofetilide is a highly selective class III antiarrhythmic agent.
Assuntos
Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Fenetilaminas/uso terapêutico , Sulfonamidas/uso terapêutico , Potenciais de Ação/efeitos dos fármacos , Animais , Eletrocardiografia/efeitos dos fármacos , Eletrofisiologia , Coração/fisiologia , Humanos , Fenetilaminas/metabolismo , Fenetilaminas/farmacocinética , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinéticaRESUMO
1. UK-68,798, a novel class III anti-arrhythmic agent was administered intravenously to twelve healthy volunteers in a placebo controlled, double-blind, dose-escalating study. 2. Doses of 5 and 10 micrograms kg-1 of UK-68,798 selectively and significantly prolonged the QT interval, with mean maximum changes of 35 and 107 ms respectively, without affecting other ECG intervals. 3. There were dose-related increases in AUC but clearance (23 l h-1), terminal elimination half-life (8 h) and volume of distribution (245 l) were found to be independent of dose with low levels of intra- and inter-patient variability. 4. UK-68,798 has electrophysiological effects indicative of selective class III anti-arrhythmic activity and merits further assessment in clinical studies.
Assuntos
Antiarrítmicos/farmacologia , Fenetilaminas/farmacologia , Sulfonamidas/farmacologia , Adulto , Antiarrítmicos/farmacocinética , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Fenetilaminas/farmacocinética , Sulfonamidas/farmacocinéticaRESUMO
1. The pharmacokinetic and pharmacodynamic properties of UK-68,798, a novel selective potential class III antiarrhythmic agent, were studied in 18 patients with coronary artery disease. Three groups of four patients received intravenous doses of 1.5, 3.0 and 4.5 micrograms kg-1 respectively over 10 min. 2. UK-68,798 caused a mean increase in electrocardiographic QTc interval of 41, 40 and 81 ms, and in uncorrected QT interval of 36, 52 and 83 ms at the three dose levels. There were no significant effects on heart rate, blood pressure, PR interval and QRS duration. UK-68,798 was well tolerated with no significant adverse effects. 3. A dosing regimen using a loading infusion of two thirds of the total dose over 15 min with the remainder given over the following 45 min in six patients produced stable plasma concentrations and lengthening in QTc during the maintenance infusion. 4. There was a linear correlation between plasma concentration and change in QTc. The drug exhibited first-order kinetics with a mean clearance of 4.7 +/- 1.2 ml min-1 kg-1 and a mean terminal plasma half-life of 9.7 h. 5. UK-68,798 warrants further study as a selective potential Class III antiarrhythmic agent.
Assuntos
Antiarrítmicos/farmacocinética , Fenetilaminas/farmacocinética , Sulfonamidas/farmacocinética , Adulto , Idoso , Antiarrítmicos/efeitos adversos , Antiarrítmicos/uso terapêutico , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/fisiopatologia , Eletrocardiografia , Feminino , Meia-Vida , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Fenetilaminas/efeitos adversos , Fenetilaminas/uso terapêutico , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêuticoRESUMO
Short-chain fatty acids are produced in the human colon by bacterial fermentation of dietary fibers and other saccharides escaping absorption in the small bowel. Short-chain fatty acid concentrations were determined together with production rates in 6- and 24-h incubations of intestinal outputs from 56 patients with various types of intestinal resections. Concentrations and 6- and 24-h production rates in feces from 9 healthy persons (controls; median +/- SD) were 98.9 +/- 21.4 mmol/L and 17.2 +/- 5.1 and 9.3 +/- 1.5 mmol/L.h, respectively. Colectomized patients with short bowel syndrome had extremely low concentrations (0.8 mmol/L) compared with controls (p less than 10-5), patients with ileostomy (p = 0.003), and ileal reservoirs (p less than 10-5), and showed low 6- and 24-h production rates (1.5 and 0.9 mmol/L.h, respectively; p less than 10-5 vs. controls). Short-chain fatty acids in ileostomic digesta (11.1 mmol/L) were decreased (p = 0.011) compared with outputs from ileal reservoirs (51.5 mmol/L), although production rates were in the same order of magnitude--all below control values (p less than 0.001). Patients partially colectomized and patients with small bowel bypass or short bowel syndrome with preserved colon had normal fecal concentrations with decreased production rates of short-chain fatty acids vs. controls (p less than 0.01). Only minor changes in ratios between individual acids were found. Reciprocal values of short-chain fatty acid concentrations correlated to volumes of outputs from both small intestine (r = 0.86, p less than 10-6) and colon (r = 0.79, p less than 10-6) when results were cumulated. It is concluded that partial resections of colon and the small bowel do not influence the fecal concentration level of short-chain fatty acids as long as colon is not totally resected.
Assuntos
Colo/metabolismo , Ácidos Graxos Voláteis/metabolismo , Fezes/análise , Intestinos/cirurgia , Adulto , Idoso , Feminino , Conteúdo Gastrointestinal/análise , Humanos , Absorção Intestinal , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Fatores de TempoRESUMO
The literature is reviewed with the aim of comparing the effect of resuscitation with colloid solutions with that of crystalloid solutions in the following patient categories: patients undergoing major elective abdominal surgery, patients in hypovolemic shock due to acute trauma and patients in septic shock. None of the clinical trials have documented that resuscitation with colloids is superior to that of crystalloids alone as regards mortality or frequency of complications. On the contrary, colloid resuscitation appears to be detrimental in patients with traumainduced hypovolemic shock with a higher incidence of pulmonary and cardiac complications as compared to resuscitation with crystalloids alone. This is contrary to what is expected from the Starling equation and the discrepancy between the theoretical and clinical findings is discussed. Furthermore, resuscitation with colloids is about 50 times more expensive than resuscitation with crystalloids. On the basis of the clinical data and the higher cost of colloids, the authors recommend cessation of the use of colloids in the abovementioned conditions.
Assuntos
Hidratação , Choque Séptico/terapia , Choque/terapia , Coloides , Humanos , Equilíbrio HidroeletrolíticoRESUMO
In a double-blind, placebo-controlled study, 47 patients with ischemic heart disease and acute myocardial infarction were allocated to 3 months' treatment with peroral magnesium (15 mmol/d) or placebo. Before, during, and after treatment, blood samples were taken to determine serum concentrations of cholesterol; triglyceride; high-density, low-density, and very-low-density lipoprotein; apolipoprotein A1 and B; and magnesium. We found a 13% increase in molar ratio of apolipoprotein A1:apolipoprotein B after magnesium treatment, as compared with a 2% increase in the placebo group (for mean differences between changes of the magnesium and the placebo groups). This increase was caused by a decrease in apolipoprotein B concentrations, which were reduced by 15% from 1.44 to 1.23 mmol/L in the magnesium group as compared with a slight increase in the placebo group. Triglyceride, and thereby very-low-density lipoprotein concentrations decreased by 27% after magnesium treatment (from 2.41 to 1.76 mmol/L, and from 1.1 to 0.79 mmol/L, respectively) as compared with much smaller decrements in the placebo group. Likewise, we found tendencies toward an increase in high-density lipoprotein cholesterol and in high-density lipoprotein cholesterol ratio/(low-density lipoprotein cholesterol:very-low-density lipoprotein cholesterol) after magnesium treatment. The observed findings support the hypothesis that magnesium deficiency might be involved in the pathogenesis of ischemic heart disease by altering the blood lipid composition in a way that disposes to atherosclerosis.