Pharmacokinetics and Pharmacodynamics of Intravenous OPC‐18790 in Humans: A Novel Nonglycosidic Inotropic Agent

Ohnishi, Akihiro; Toyoki, T; Ohno, Toshiyuki; Takeshige, Yoshiko; Fujita, Tsuyoshi; Kodama, Kazuhisa; Mishima, Masayoshi; Hirayama, Atsushi; Kitani, Mami; Miyamoto, Gohhachiro; Odomi, Masatoshi; Tanaka, Teruji

doi:10.1002/j.1552-4604.1994.tb03983.x

Cited by 8 publications

(2 citation statements)

References 11 publications

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“…Therefore, it is concluded that the vascular relaxing effects of toborinone may be mediated by both the PDE III inhibitory action and the weak adrenaline α-receptor blocking activities. In clinical trials, 19 the therapeutic plasma concentration of toborinone was about 800 ng/ml after 60 min of continuous intravenous infusion at 10 µg/kg per min. This concentration is approximately equivalent to the EC 50 values obtained in this study.…”

Section: Discussionmentioning

confidence: 99%

Vascular Relaxant Effects of Toborinone on the Isolated Canine Internal Mammary Artery

2001

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Section: Discussionmentioning

confidence: 99%

Vascular Relaxant Effects of Toborinone on the Isolated Canine Internal Mammary Artery

2001

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“…The drug's mechanism of action includes an inhibitory action on phosphodiesterase III, an inhibitory action on the potassium channel, and a prolonging effect on action potential duration. Previous studies have shown toborinone to have beneficial hemodynamic effects in animals [2] and in normal volunteers [3] without increasing myocardial oxygen consumption and in dilated cardiomyopathy without changing heart rate [4]. We therefore investigated the effectiveness, usefulness, and safety of this drug for the treatment of heart failure occurring immediately after extracorporeal circulation (ECC) in cardiac surgery, and the relationship between infusion volume and hemodynamics was also examined.…”

Section: Introductionmentioning

confidence: 99%

Study on the Effectiveness of Toborinone (OPC-18790) in the Treatment of Heart Failure in Patients Following Cardiac Surgery

Hirata¹,

Akamatsu

et al. 2011

Arzneimittelforschung

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Toborinone ((+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-qui nolinone, CAS 128667-95-8, OPC-18790), a novel cardiotonic agent with an inhibitory action on phosphodiesterase, is known to have a potent positive inotropic action with no positive chronotropic effect. The effectiveness of this drug in the treatment of heart failure occurring immediately after extracorporeal circulation (ECC) in cardiac surgery was investigated. The study was conducted in 12 patients with valvular heart disease showing a cardiac index (CI) of below 2.8 l/min/m2 and/or pulmonary capillary wedge pressure (PCWP) or pulmonary arterial diastolic pressure (PAD) of above 8 mmHg immediately after extracorporeal circulation. In group A (n = 6), toborinone was infused at a rate of 40 micrograms/kg/min for the first 5 min and then at 10 micrograms/kg/min for 85 min. In group B (n = 6), the drug was infused at a rate of 10 micrograms/kg/min for the entire 90 min. CI, mean systemic arterial pressure (mSAP), mean pulmonary artery pressure (mPAP), CVP, PCWP, and heart rate were measured at 5, 15, 30, 60, and 90 min after the start of infusion. The infusion volume required to maintain a constant PCWP was also estimated. In group A, CI increased rapidly and significantly from the baseline of 2.48 +/- 0.23 l/min/m2 to 3.57 +/- 1.07 l/min/m2 at 5 min after the start of infusion, and at that time mSAP was slightly decreased. In group B, CI increased gradually from the baseline of 2.53 +/- 0.18 l/min/m2 to 3.08 +/- 0.34 l/min/m2 at 15 min after the start of infusion, but almost no change was seen in mSAP. During the first 30 min, group A required a significantly larger infusion volume (983 +/- 395 ml) than group B (475 +/- 184 ml). From 30 to 90 min after the start of infusion, CI remained increased to similar levels in both groups and mSAP levels were also similar. There were no significant differences between the two groups in any other parameter. Continuous infusion of toborinone appears to be effective for treating heart failure occurring immediately after ECC in cardiac surgery. Initial loading at a rate of 40 micrograms/kg/min rapidly increased CI but was accompanied by mild hypotension. Constant infusion at 10 micrograms/kg/min brought about a more gradual effect that was similar to that of loading at 40 micrograms/kg/min, but without inducing hypotension. Thus, infusion at 10 micrograms/kg/min is considered preferable in order to avoid a larger-than-necessary infusion volume.

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Clinical Pharmacokinetics of Drugs in Patients with Heart Failure

2013

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Heart failure is one of the leading causes of death in developed countries, and its prevalence is expected to increase further in the coming years. While the pharmacokinetic changes observed in patients with heart failure have been reviewed twice in Clinical Pharmacokinetics, approximately a quarter century has passed since the latest article was published in 1988. Since then, many important classes of agents (e.g. ACE inhibitors, angiotensin receptor antagonists and inotropes) have been introduced for the treatment of heart failure. The aim of the present article is to update the information regarding the pharmacokinetics of these drugs. For this purpose we have made a systematic survey of literature using MEDLINE, EMBASE and Japan Centra Revuo Medicina (in Japanese) and found a total of 111 relevant publications for 58 drugs. Heart failure is a pathophysiological state where the damaged heart, from whatever causes, no longer pumps enough blood for the needs of body tissues at rest or during the normal daily activities. The spectrum of heart failure ranges from acute decompensated heart failure (including circulatory shock) to chronic compensated or decompensated heart failure. Because hypoperfusion of organs may influence drug absorption from the gastrointestinal tract, distribution into tissues and elimination either by the liver or kidneys, it is conceivable that the pharmacokinetics of many drugs may be altered in patients with heart failure. The pharmacokinetic changes of drugs in these patients in the light of a physiologically based pharmacokinetic model are discussed, since this model can interpret altered pharmacokinetics in terms of changes in the binding of drugs in plasma and tissue, blood flow to drug-eliminating organs and intrinsic activity of drug elimination. Pharmacokinetic changes of drugs after intravenous administration are described here in Part 1 and those after oral administration will be discussed in Part 2 in a later issue of the Clinical Pharmacokinetics. Reviewing the retrieved data, it was considered that patients with asymptomatic or compensated chronic heart failure seem to have no or minimal alterations in the pharmacokinetics of parenterally administered drugs as long as there was no concurrent liver and/or kidney dysfunction. In contrast, it was found that the systemic clearance of at least six drugs (i.e. milrinone, carperitide, molsidomine, theophylline, ciclosporin and hydralazine) was reduced after intravenous administration by 50 % or more in patients with acute decompensated heart failure or chronic severe heart failure (New York Heart Association class III or IV) as compared with healthy subjects. Because there is a paucity of information regarding the pharmacokinetics of drugs in patients with severe heart failure, close attention should be paid to monitoring the efficacy of these agents and their associated adverse effects.

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Pharmacokinetics and Pharmacodynamics of Intravenous OPC‐18790 in Humans: A Novel Nonglycosidic Inotropic Agent

Cited by 8 publications

References 11 publications

Vascular Relaxant Effects of Toborinone on the Isolated Canine Internal Mammary Artery

Vascular Relaxant Effects of Toborinone on the Isolated Canine Internal Mammary Artery

Study on the Effectiveness of Toborinone (OPC-18790) in the Treatment of Heart Failure in Patients Following Cardiac Surgery

Clinical Pharmacokinetics of Drugs in Patients with Heart Failure

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