Toborinone and olprinone, phosphodiesterase III inhibitors, inhibit human platelet aggregation due to the inhibition of both calcium release from intracellular stores and calcium entry

Q4 · MEDICINE

Article

Author: Shinji Nozuchi ; Yasufumi Nakajima ; Hiroshi Aoki ; Kyoko Kageyama ; Noriko Hiramatsu ; Toshiki Mizobe

PURPOSEWe investigated the inhibitory effects of toborinone and olprinone on human platelet aggregation and calcium mobilization.Abstract Copyright:METHODSWashed human platelets were preincubated with toborinone or olprinone, then exposed to 0.015 U.ml-1 of thrombin. Aggregation curves were measured using an aggregometer. Effects of toborinone or olprinone on changes in intracellular calcium concentration ([Ca2+]i) were measured fluorometrically using fura-2 acetoxymethyl ester (fura-2). Levels of intracellular cyclic 3",5"-adenosine monophosphate concentration ([cAMP]i) were also measured, using enzyme-linked immunosorbent assay (ELISA) techniques.RESULTSThe concentrations required to cause 50% inhibition of aggregation (IC50) induced by thrombin were 9.7 +/- 0.9 micro M for toborinone and 3.6 +/- 0.2 micro M for olprinone. Both drugs at IC50 significantly elevated [cAMP]i levels and significantly inhibited Ca2+ release from intracellular stores. Release of [Ca2+]i induced by thrombin was 272.9 +/- 87.1 nM, 153.3 +/- 28.7 nM, and 138.9 +/- 58.2 nM in the control, toborinone, and olprinone groups, respectively ( P < 0.02). Calcium influx through calcium channels in the plasma membrane was also suppressed by toborinone and olprinone.CONCLUSIONToborinone (9.7 micro M) and olprinone (3.6 micro M) inhibit human platelet aggregation, though these concentrations are higher than their therapeutic plasma concentrations. The inhibitory effects of both drugs are related to the inhibition of both Ca2+ release and Ca2+ entry through [cAMP]i elevation.

01 Dec 2002·The Journal of Clinical PharmacologyQ3 · MEDICINE

The Pharmacokinetics of Toborinone in Subjects with Congestive Heart Failure and Concomitant Renal Impairment and/or Concomitant Hepatic Impairment

Q3 · MEDICINE

Article

Author: Brinda Tammara ; Mami Kitani ; John M. Trang ; Gohachiro Miyamoto ; Steven L. Bramer

The pharmacokinetics of toborinone was studied in subjects with congestive heart failure (CHF) and concomitant renal and/or hepatic disease. At the time of admission, subjects were grouped based on estimated creatinine clearance and serum bilirubin. Glomerular filtration rate was assessed using iothalamate clearance. Hepatic function was assessed using the caffeine metabolism test and indocyanine green clearance. No significant differences were observed in mean toborinone pharmacokinetic parameters among the four study groups. Positive correlations were observed between toborinone clearance and the measured indices of renal and hepatic function: creatinine clearance, iothalamate renal clearance, paraxanthine/caffeine ratio, and indocyanine green clearance. Toborinone clearance decreased with decreasing creatinine clearance, decreasing glomerular filtration rate, decreasing demethylation metabolic activity, and decreasing hepatic blood flow, although no significant differences were observed in any mean toborinone pharmacokinetic parameters evaluated among the four study groups.

01 Aug 2002·European Journal of Heart FailureQ1 · MEDICINE

The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure—a meta‐regression analysis

Q1 · MEDICINE

Article

Author: Cleland, John G.F. ; Easthaugh, Joanne ; Thackray, Simon ; Freemantle, Nick

AbstractAimsTo review systematically the use of intravenous (IV) inotropic agents acting through the adrenergic signalling pathway, compared with placebo or an active agent, in patients with heart failure.MethodsStudies investigating the use of intravenous inotropes in patients with heart failure published between 1966 and 2000 were identified using MEDLINE, the Cochrane register and Embase databases. Reference lists from relevant papers and reviews were hand searched for further papers. In total, 21 trials, that included 632 patients receiving IV inotropic drugs, placebo or non‐treatment control, were identified. Drugs of the following classes were included, the β‐agonists; dobutamine, high‐dose (>2.5 μg/kg/min) dopamine, dopexamine and the phosphodiesterase (PDE) inhibitors; amrinone, milrinone, enoximone and toborinone. Sixteen trials (474 patients) contributed data from acute invasive haemodynamic studies of symptomatically severe heart failure. Five trials (158 patients) were based on intermittent inotropic therapy in an outpatient context.ResultsWith few exceptions, trials of intravenous inotropic agents were small and often failed to report clinically important outcomes. Compared to placebo, intravenous inotropic agents acting through the adrenergic system tended to increase mortality (odds ratio 1.50 (95% CI‐0.51 to 3.92) but this did not reach significance and insufficient data were available to determine whether symptoms improved. There appeared to be little difference in the effect of beta‐agonists compared to PDE inhibitors on patient outcomes but this could be attributed to the paucity of data.ConclusionsIntravenous inotropic agents acting through the adrenergic pathway are often used in patients with worsening heart failure to achieve arbitrary haemodynamic targets. Our analyses show that there is very little evidence that such treatment improves symptoms or patient outcomes and may not be safe. This highlights the need for further well designed randomised clinical trials.

100 Deals associated with Torborinone

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Indication	Highest Phase	Country/Location	Organization	Date
Heart Failure	NDA/BLA	JP	Otsuka Pharmaceutical Co., Ltd.	-
Heart Failure	NDA/BLA	-	Otsuka Holdings Co., Ltd.	-

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