An Investigation Into the Effects of Intravenous Lipid Emulsion (ILE) on the Pharmacokinetic and Pharmacodynamic Properties of Metoprolol.
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Change in heart rate from baseline compared between study days
研究概览
简要总结
The aim of this study is to investigate whether intravenous lipid emulsion is effective in attenuating the clinical effects of a cardioactive drug, exemplified by the beta-blocking agent metoprolol. In addition, the investigators will clarify how intravenous lipid emulsion affects the pharmacokinetic parameters of metoprolol.
详细描述
Overdose or poisonings with cardioactive drugs can have serious consequences. In recent years, intravenous lipid emulsion has emerged as a possible treatment option in otherwise treatment-resistant cardiovascular collapse caused by poisonings with cardio-active drugs.
Experimental evidence obtained from animal studies has been indicating a beneficial effect of intravenous lipid emulsion in the treatment of poisoning with various cardio-toxic medications. Based on these findings, the first reported cases on the use of intravenous lipid emulsion in the treatment of human cardiotoxicity caused by poisonings with local anesthetics were published in 2006. Subsequently, a steadily increasing number of case reports concerning the use of intravenous lipid emulsion in resuscitation and treatment of various medications poisonings have been published. Often patients had either cardiac arrest or severe circulatory failure treated according to guidelines for advanced life support prior to lipid emulsion therapy. It is noteworthy that a common observation following bolus infusion of lipid emulsion has been a rapid hemodynamic stabilization of the patient.
Despite an increasing use of intravenous lipid emulsion in the treatment of the poisoned patient, the mechanism behind lipid rescue has not been elucidated. The most widely accepted hypothesis, the "lipid sink/sponge" model, suggests that intravenous lipid emulsion entraps xenobiotics intravascularly, thereby preventing them from reaching sites of toxicity. Additionally, intravenous lipid emulsion may redistribute xenobiotics to areas of higher lipid content. However, other mechanisms of actions of lipid emulsion, supported by observations from animal experiments, are vasoconstrictive and cardio-tonic effects. These effects could be secondary to direct activation of sodium, potassium or calcium channels in the myocardium, or alternatively fatty acid-induced modulation of the metabolic properties of mitochondria. Both mechanisms could result in hemodynamic stabilization. The potential beneficial effects of lipid emulsion on hemodynamic instability beyond the lipid sink have led to the notion that intravenous lipid emulsion could be valuable in the treatment of poisonings with non-lipophilic xenobiotics.
At present, it remains however unclear to what extent the evidence concerning resuscitation of the poisoned patient with lipid emulsion may reflect publication bias. To our knowledge, only one controlled human trial has been conducted at present. In a randomized crossover study, Litonius et al. investigated the effects of lipid emulsion on plasma concentrations of bupivacaine in eight healthy subjects. It was found that lipid emulsion lowered the total plasma concentrations of bupivacaine. This was attributed to an altered distribution and contradicted so the above hypothesis of a lipid sink-mechanism as the fraction of non-lipid bound bupivacaine was unchanged. The mechanism by which lipid emulsion may attenuate the effects of cardio toxic xenobiotics must therefore still be regarded as undecided. This lack of evidence calls for further human studies in order to elucidate the pharmacokinetic and pharmacodynamic consequences of intravenous lipid emulsion. The purpose of this double blind, randomized placebo-controlled crossover clinical trial is to investigate the effects of intravenous lipid emulsion on the pharmacokinetic and pharmacodynamic properties of the adrenoceptor antagonist metoprolol in a human model of beta blocker overdose.
The study includes a total of five visits; a screening visit and four trial days. At the screening visit, anthropometric data (weight, height, blood pressure and pulse) is measured. Additionally, blood samples are collected in accordance with exclusion criteria. A spot urine sample measuring the albumin/creatinine ratio is collected and an electrocardiogram (ECG) is recorded to verify normality of heart rhythm and electrical impulses. In addition, an investigator carries out a clinical examination. Based on the clinical examination, urine and blood tests and ECG measurement, the investigator assesses whether the trial participant meet all inclusion criteria and no exclusion criteria.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 20 Years 至 30 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •healthy male.
排除标准
- •Abnormal blood levels of sodium, potassium, creatinine, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, albumin, bilirubin, hemoglobin, HbA1c, cholesterol fractions.
- •Abnormal urine albumin to creatinine ratio.
- •Abnormal function of CYP2D6 metabolism (ultrarapid or slow metabolizer)
- •Any heart disease or hypertension
- •Sinoatrial block
- •Second or third degree atrioventricular block
- •Heart failure
- •profound bradycardia or hypotension
- •sinoatrial node disease
- •metabolic acidosis
- •untreated pheochromocytoma
- •chronic obstructive pulmonary disease
- •intermittent claudicatio
- •Allergy to egg, soy or peanut protein and allergy to any active or inactive ingredients contained in metoprolol (Seloken) or the lipid emulsion (Intralipid)
- •Raynaud's syndrome
- •Prinzmetal's angina
研究组 & 干预措施
Metoprolol-Lipid emulsion
intervention 1: metoprolol Intervention 2: intravenous lipid emulsion
干预措施: metoprolol (Drug)
Metoprolol-Lipid emulsion
intervention 1: metoprolol Intervention 2: intravenous lipid emulsion
干预措施: intravenous lipid emulsion (Drug)
Metoprolol - normal saline
intervention 1: metoprolol intervention 2: Sodium chloride 0.9% solution - lipid emulsion dummy
干预措施: metoprolol (Drug)
Metoprolol - normal saline
intervention 1: metoprolol intervention 2: Sodium chloride 0.9% solution - lipid emulsion dummy
干预措施: Sodium chloride 0.9% solution - lipid emulsion dummy (Drug)
Normal saline-Lipid emulsion
intervention 1: Sodium chloride 0.9% solution - metoprolol dummy intervention 2: intravenous lipid emulsion
干预措施: intravenous lipid emulsion (Drug)
Normal saline-Lipid emulsion
intervention 1: Sodium chloride 0.9% solution - metoprolol dummy intervention 2: intravenous lipid emulsion
干预措施: Sodium chloride 0.9% solution - metoprolol dummy (Drug)
Normal saline-normal saline
intervention 1: Sodium chloride 0.9% solution - metoprolol dummy intervention 2: Sodium chloride 0.9% solution - lipid emulsion dummy
干预措施: Sodium chloride 0.9% solution - lipid emulsion dummy (Drug)
Normal saline-normal saline
intervention 1: Sodium chloride 0.9% solution - metoprolol dummy intervention 2: Sodium chloride 0.9% solution - lipid emulsion dummy
干预措施: Sodium chloride 0.9% solution - metoprolol dummy (Drug)
结局指标
主要结局
Change in heart rate from baseline compared between study days
时间窗: From baseline to + 120 minutes.
Arterial catheter connected to a pressure transducer records heart rate (beats per minute).
次要结局
- Peak plasma concentration (Cmax) of paracetamol on days with co-administration of intravenous lipid emulsion compared to days with lipid emulsion placebo.(0, +10, +20, +30, +40, +50, +60, +90, +120 minutes post metoprolol dose.)
- Area under the plasma concentration versus time curve (AUC) of metoprolol on days with co-administration of intravenous lipid emulsion compared to days with lipid emulsion placebo.(0, +10, +20, +30, +40, +50, +60, +90, +120 minutes post metoprolol dose.)
- Peak Plasma Concentration (Cmax) of metoprolol on days with co-administration of intravenous lipid emulsion compared to days with lipid emulsion placebo.(+0, +10, +20, +30, +40, +50, +60, +90, +120 minutes post metoprolol dose.)
- Area under the plasma concentration versus time curve (AUC) of paracetamol on days with co-administration of intravenous lipid emulsion compared to days with lipid emulsion placebo.(0, +10, +20, +30, +40, +50, +60, +90, +120 minutes post metoprolol dose.)
- Time to peak plasma concentration (Tmax) of paracetamol on days with co-administration of intravenous lipid emulsion compared to days with lipid emulsion placebo.(0, +10, +20, +30, +40, +50, +60, +90, +120 minutes post metoprolol dose.)
- Percent change in plasma levels of standard biochemical measurements from baseline compared between study days.(Changes at +30 and +60 minutes from baseline.)
- Time to peak plasma concentration (Tmax) of metoprolol on days with co-administration of intravenous lipid emulsion compared to days with lipid emulsion placebo.(+0, +10, +20, +30, +40, +50, +60, +90, +120 minutes post metoprolol dose.)
- Cardiac conductivity between days with metoprolol and/or intravenous lipid emulsion compared with placebo.(T-10, T-5, T 0, T 10, T 20, T 30, T 40, T 50, T 60, T 90, T 120 minutes.)
- Effects of metoprolol and lipid emulsion on stroke volume compared to days with placebo.(T-10, T-5, T 0, T 10, T 20, T 30, T 40, T 50, T 60, T 90, T 120 minutes.)
- Effect of metoprolol on systolic, diastolic and mean arterial pressure on days with co-administration of intravenous lipid emulsion compared to days with placebo.(T-10, T-5, T 0, T 10, T 15, T 20, T 30, T 40, T 50, T 60, T 90, T100, T110, T 120 minutes.)
- Change in systolic, diastolic and mean arterial pressure from baseline compared between study days.(Changes at +5, +10, +15, +20, +30, +40, +50, +60, +90, +95, +100, +105, +110, +115, +120 minutes from baseline.)
- Change in stroke volume (ml) from baseline compared between study days.(Changes at +5, +10, +15, +20, +30, +40, +50, +60, +90, +95, +100, +105, +110, +115, +120 minutes from baseline.)
- Change in heart rate from baseline compared between study days.(Changes at +5, +10, +15, +20, +30, +40, +50, +60, +90, +95, +100, +105, +110, +115, +120 minutes from baseline.)
研究者
Mikkel Bring Christensen
MD, PhD
University Hospital Bispebjerg and Frederiksberg