Pertti J. Pentikäinen

Pharmacodynamics and Safety of a New Calcium Sensitizer, Levosimendan, and Its Metabolites during an Extended Infusion in Patients with Severe Heart Failure

Levosimendan is a new calcium sensitizer developed for the short‐term intravenous treatment of congestive heart failure. The aims of the present open‐label, nonrandomized study were to determine the tolerability, hemodynamic effects, and the basic pharmacokinetics of levosimendan and its metabolites during an extended continuous infusion of levosimendan. Twenty‐four patients with New York Heart Association (NYHA) III‐IV heart failure in two groups of 12 patients were exposed to either 0.05 μg/kg/min or 0.1 μg/kg/min of levosimendan for 7 days. Heart rate and blood pressure were measured, and blood samples for the determination of plasma concentrations of the parent drug and its metabolites were drawn daily during the infusion and the 10 to 15 days follow‐up. The 7‐day infusion was well tolerated and no premature discontinuations occurred. Both systolic and diastolic blood pressure decreased maximally by 6 mmHg in the lower and by 11 mmHg in the higher levosimendan dose groups during the infusion period (p < 0.05 for both groups). The mean heart rate values increased maximally by 18 and 26 beats/min in the lower and higher levosimendan dose groups, respectively (p < 0.001 for both groups). The hemodynamic effects peaked at the end of the infusion period and thereafter slowly declined during the follow‐up. After the recommended infusion period of 24 hours, the mean heart rate increase was only 2 and 6 beats/min in the lower and higher levosimendan dose groups, respectively. The elimination half‐life of levosimendan was approximately 1 hour and of the metabolites 70 to 80 hours. It can be concluded that levosimendan, even administered considerably longer than the recommended 24 hours, was well tolerated. The 7‐day infusion induced a prolonged increase in heart rate and a minor decrease in blood pressure. The long‐lasting effects are probably explained by the active metabolite.

Pharmacokinetics of levosimendan in healthy volunteers and patients with congestive heart failure.

Levosimendan is a new inodilatory agent that sensitizes troponin-C in heart muscle cells to calcium, thus improving contractility. The pharmacokinetics of levosimendan were evaluated using a double-isotope technique in eight healthy volunteers and in eight patients with mild congestive heart failure (CHF). A single i.v. dose of 0.50 mg 14C-labeled levosimendan and a single oral dose of 0.50 mg 13C15N-labeled levosimendan were administered concomitantly. The elimination half-lives (mean +/- SD) of levosimendan were 0.96 +/- 0.16 h in healthy volunteers and 1.03 +/- 0.11 h in patients. The respective figures for total drug were 5.73 +/- 1.53 h and 5.23 +/- 0.99 h. Clearances of levosimendan averaged 359 +/- 69 ml/min in healthy volunteers and 296 +/- 61 ml/min in patients and of total drug 104 +/- 15 and 85 +/- 20 ml/min, respectively. Volumes of distribution at steady state were for levosimendan 21.9 +/- 5.9 L in healthy volunteers and 19.5 +/- 4.5 L in patients and for 14C-drug 27.9 +/- 5.3 L and 23.8 +/- 2.8 L, respectively. The bioavailability of oral levosimendan was 85 +/- 6% in healthy volunteers and 84 +/- 4% in patients.

Pharmacokinetics and Pharmacodynamics of Intravenous Inotropic Agents

Positive inotropic drugs have various mechanisms of action. Long-term use of cyclic adenosine monophosphate (cAMP)-dependent drugs has adverse effects on the prognosis of heart failure patients, whereas digoxin has neutral effect on mortality. There are, however, little data on the effects of intravenous inotropic drugs on the outcome of patients.Intravenous inotropic agents are used to treat cardiac emergencies and refractory heart failure. β-Adrenergic agonists are rapid acting and easy to titrate, with short elimination half-life. However, they increase myocardial oxygen consumption and are thus hazardous during myocardial ischaemia. Furthermore they may promote myocyte apoptosis. Phosphodiesterase (PDE) III inhibiting drugs (amrinone, milrinone and enoximone) increase contractility by reducing the degradation of cAMP. In addition, they reduce both preload and afterload via vasodilation. Short-term use of intravenous milrinone is not associated with increased mortality, and some symptomatic benefit may be obtained when it is used in refractory heart failure. Furthermore, PDE III inhibitors facilitate weaning from the cardiopulmonary bypass machine after cardiac surgery.Levosimendan belongs to a new group of positive inotropic drugs, the calcium sensitisers. It has complex pharmacokinetics and long-lasting haemodynamic effects as a result of its active metabolites. In comparative trials, it has been better tolerated than the most widely used β-agonist inotropic drug, dobutamine.The pharmacokinetics of the intravenous inotropic drugs might sometimes greatly modify and prolong the response to the therapy, for example because of long-acting active metabolites. These drugs display considerable differences in their pharmacokinetics and pharmacodynamics, and the selection of the most appropriate inotropic drug for each patient should be based on careful consideration of the clinical status of the patient and on the pharmacology of the drug.

Diseases and drugs causing prolongation of the QT interval

The prolonged QT interval and its association with diseases and drugs was studied on the basis of computerized electrocardiograms recorded in the region of the Kuopio University Central Hospital, East Finland. Altogether, 33,655 persons in whom at least 1 electrocardiogram was recorded from 1975 to 1983 were found. The study population consisted of 183 persons with prolonged QT intervals (at least 470 ms) and 187 with normal QTc intervals (440 ms or less), aged 45 to 64 years. These subjects were selected from 14,990 persons eligible. No difference in the prevalence of diseases affecting the QTc interval was found between those with long QTc intervals and those with normal QTc intervals. No difference between the groups was found in use of quinidine, procainamide or disopyramide. When the comparison was made on the basis of all group 1A antiarrhythmic drugs (quinidine, procainamide and disopyramide combined), persons with prolonged QTc intervals used these drugs more often than did those with normal QTc intervals (p = 0.031). Use of sotalol was significantly more common (p less than 0.001) in subjects with long QTc intervals. The mortality rate was also higher in persons with prolonged QTc interval (p less than 0.001), and most deaths during follow-up were due to coronary artery disease.

Effect of severe renal failure and haemodialysis on the pharmacokinetics of levosimendan and its metabolites

Background and objectivesLevosimendan is a calcium sensitiser developed for the treatment of congestive heart failure. It increases myocardial contractility, reduces the filling pressure and dilates both the peripheral and coronary vessels. The circulating metabolites of levosimendan, OR-1855 and OR-1896, are formed and eliminated slowly after intravenous administration of levosimendan. The aim of this study was to investigate the effect of impaired renal function and haemodialysis on the pharmacokinetics of levosimendan, OR-1855 and OR-1896.Study designThis study was an open-label, nonrandomised, phase I pharmacokinetic study. Levosimendan was administered as a single-dose infusion of 0.1 μg/kg/minute for 24 hours. The follow-up period lasted 3 weeks.Study settingTwenty-five patients were included: 12 patients with severe chronic renal failure (CRF) with creatinine clearance of <30 mL/minute/1.73m2 and 13 patients with end-stage renal disease (ESRD) undergoing haemodialysis. A group of 12 healthy subjects served as controls.ResultsLevosimendan, the parent drug, was eliminated rapidly from the plasma after discontinuation of its infusion, with an elimination half-life (t½) [mean ±standard error of mean] of 1.5 ± 0.09 hours in ESRD patients undergoing haemodialysis, 1.0 ± 0.2 hours in patients with severe CRF and 0.91 ± 0.03 hours in healthy subjects. The t½ of levosimendan was significantly longer (p < 0.001) in ESRD patients undergoing haemodialysis than in healthy subjects. The t½ of OR-1855 and OR-1896 were 94.0 ± 20.4 hours and 96.5 ± 19.5 hours, respectively, in ESRD patients undergoing haemodialysis compared with 60.8 ± 5.2 and 61.6 ± 5.2 hours, respectively, in healthy subjects (p = not significant). The t½ of OR-1855 was significantly longer (85.0 ± 13.6 hours) in patients with severe CRF than in healthy subjects (60.8 ± 5.2 hours, p < 0.05). The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of the metabolites were approximately 2-fold higher in patients with ESRD undergoing haemodialysis and patients with severe CRF compared with healthy subjects. The mean unbound fraction (fu) of levosimendan in plasma was approximately 2% in each study group, whereas the fu of the metabolites was considerably higher (63−70%). In contrast to levosimendan, the metabolites were dialysable, with dialysis clearance of approximately 100 mL/minute. The haemodynamic responses and adverse event profiles were similar in the study groups, with headache, palpitations and dizziness being the most frequently recorded adverse events.ConclusionThe t½ of the levosimendan metabolites was prolonged 1.5-fold and their AUC and Cmax were 2-fold higher in patients with severe CRF and ESRD patients undergoing haemodialysis as compared with healthy subjects. These results suggest that the dose should be reduced when levosimendan is used for the treatment of congestive heart failure in patients with severe renal insufficiency.

Cholesterol Lowering Effect of Metformin in Combined Hyperlipidemia: Placebo Controlled Double Blind Trial

Metformin, an antidiabetic biguanide derivative, prevents experimental atherosclerosis and induces structural changes in lipoproteins in experimental animals. In the present study we investigated the effect of metformin on serum lipoproteins and platelet function in 24 non-diabetic patients with type II B hyperlipidemia. The patients were randomly given metformin in two dosage levels (1.0 g/day and 2.0 g/day) and placebo for periods of nine weeks in a crossover trial. Metformin caused a dose dependent fall in the concentrations of total serum cholesterol and of LDL-cholesterol. The average concentration of total cholesterol was 8.54 +/- 0.22 (SE) mmol/l, 8.12 +/- 0.19 mmol/l and 7.79 +/- 0.15 mmol/l during placebo, metformin 1.0 g/day and 2.0 g/day treatments, respectively. Both metformin values differed significantly (P less than 0.05) from the placebo value. Thus there was an average fall of 8.1% in total cholesterol after the higher metformin dose. LDL-cholesterol was 5.25 +/- 0.23 mmol/l after placebo, falling by 3.1% and 9.6% after metformin doses of 1.0 g/day and 2.0 g/day, respectively. The concentrations of HDL-cholesterol and total serum triglycerides showed no significant changes. Body weight, blood glucose, plasma insulin, blood lactate, platelet function and urinary excretion of prostanoids remained unchanged during the study. The reduction of total- and LDL-cholesterol levels may be a welcome additional consequence of metformin during treatment of diabetic patients with hypercholesterolemia.

Pharmacological Aspects of Corticosteroid Pulse Therapy

Pulse corticosteroid therapy involves intravenous administration of suprapharmacological doses (0.5-2 g) of prednisolone or its equivalents. This dose is usually given on three consecutive days and possibly once a month thereafter. The pharmacological effects of the single pulse dose lasted for about two days. Whether these effects differ quantitatively or qualitatively from the effects of the smaller, conventional doses is unclear at present. The usual side-effects of glucocorticoid therapy may occur with pulse therapy but evidently less frequently than with conventional modes of steroid therapy.

Rhabdomyolysis associated with concomitant use of simvastatin and clarithromycin

TO THE EDITOR: We report a case of rhabdomyolysis due to a probable simvastatin–clarithromycin interaction. Case Report. A 49-year-old man had been followed as an outpatient in a cardiovascular prevention clinic for 2 years due to familial combined hyperlipidemia. His fasting serum cholesterol level fluctuated between 275 and 697 mg/dL (normal <194) and triglycerides between 425 and 4098 mg/dL (35–150). The patient was a binge alcoholic, but reported abstinence between binges. He had been treated throughout with simvastatin, which was increased to 80 mg once daily. Six weeks later, the patient was admitted to the Helsinki University Central Hospital for muscle pain and weakness. Four days earlier, a general practitioner had prescribed clarithromycin 500 mg twice daily for bronchitis. On admission, serum creatine kinase (CK) and myoglobin values were increased and, on hospital day 2, reached their maximum levels of 43 200 U/L (normal <270) and 20 577 μg/L (<70 μg/L), respectively. Therefore, the patient underwent hemodiafiltration 3 times over the following 2 days until the serum myoglobin value had been reduced to 4763 μg/L. Simvastatin and clarithromycin had been discontinued on admission. Concurrently with hemodiafiltration, urinary alkalization with sodium bicarbonate was provided for 4 days, with a target urine pH >7.5. On hospital day 5, the patient was transferred from the intensive care unit, to which he was admitted on hospital day 1, to the general ward and was discharged after 14 days in the hospital. At his 2-week follow-up visit, the patient felt well and the muscle weakness had subsided. The CK value was normal. Discussion. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) decrease cardiovascular morbidity and mortality both in primary and secondary prevention.1 In general, statins are well tolerated, and serious adverse effects are rare. Dose-dependent hepatic enzyme elevations are seen in approximately 1% of statin recipients.2 Even rarer is the elevation of muscle enzymes, which occurs in approximately 0.1–0.5% of statin recipients and is also dose related. CYP3A4 is predominantly responsible for the metabolism of lovastatin, simvastatin, and atorvastatin.3 The myotoxicity of statins may increase up to tenfold when they are given concomitantly with agents that either inhibit or are metabolized by the CYP3A4 pathway, such as clarithromycin. In our case, rhabdomyolysis resulted from the myotoxicity of simvastatin during combined treatment with clarithromycin. An objective causality assessment using the Naranjo algorithm revealed that this effect was probable.4 This accords with the findings by Kantola et al.,5 who studied the pharmacokinetics of simvastatin coadministered with another macrolide antimicrobial, erythromycin. Erythromycin increased the peak serum concentration of simvastatin 3.4-fold and the AUC at 24 hours 6.2-fold (p < 0.001). Although rhabdomyolysis associated with the use of statins is rare, this potentially serious and expensive complication might be avoided by better awareness of drug– drug interactions among physicians, pharmacists, and patients.

Pharmacokinetics of Intravenous Levosimendan and Its Metabolites in Subjects With Hepatic Impairment

Levosimendan is a vasodilator used in the treatment of acute heart failure. In the present study, the effect of hepatic impairment on the pharmacokinetics of levosimendan and its 2 metabolites, OR‐1855 and OR‐1896 (pharmacologically active), was investigated in 12 healthy subjects and 12 subjects with moderate hepatic impairment due to alcoholic cirrhosis of the liver but with no heart failure. In addition, the effect of acetylator status on the pharmacokinetics of levosimendan, OR‐1855, and OR‐1896 was evaluated. Safety and tolerability of levosimendan were also assessed. Levosimendan was given as an intravenous infusion of 0.1 μg/kg/min for 24 hours. Levosimendan showed similar Cmax, AUC, and elimination half‐life (t1/2), with a mean (±SEM) t1/2 of 0.9 ± 0.0 hours in healthy subjects and 0.8 ± 0.1 hours in hepatically impaired subjects, respectively (not significant). The t1/2 of OR‐1855 was 61 ± 5 hours in healthy subjects and 82 ± 3 hours (P < .01) in subjects with hepatic impairment. The t1/2 of OR‐1896 was 62 ± 5 hours and 91 ± 5 hours (P <.01), respectively. However, the AUCs of OR‐1855 and OR‐1896 were similar in healthy volunteers and hepatically impaired subjects. The effect of acetylator status was seen as higher Cmax and AUC of OR‐1855 in slow acetylators. Correspondingly, higher Cmax and AUC of OR‐1896 were observed in rapid acetylators. Levosimendan was well tolerated in both study groups. In conclusion, the pharmacokinetics of the parent drug levosimendan was unaltered in subjects with moderate hepatic impairment, whereas the elimination of the metabolites was prolonged. However, because the maximum duration of levosimendan infusion is 24 hours, dosing adjustments of levosimendan may not be required in subjects with impaired hepatic function.

OCCURRENCE OF ANTIBODIES TO TEICHOIC ACID IN PATIENTS WITH DISEASES OTHER THAN STAPHYLOCOCCAL INFECTION

To determine the usefulness of the teichoic acid antibody (TAA) test in conditions where unspecific viral and bacterial antibodies are often encountered, we measured TAA by the gel-diffusion method in 475 patients without known staphylococcal disease; they included 213 patients with arthritis, 108 with liver diseases, 100 with gastro-intestinal disorders and 54 with acute pharyngitis. Positive controls were 104 patients with Staphylococcus aureus bacteraemia and 203 healthy adults were negative controls. Thirteen (6%) of the healthy adults had positive TAA titres (greater than or equal to 4), and the highest titre was 8 in two people (1%). Positive titres were found in 38% of patients with S. aureus bacteraemia and high titres (greater than or equal to 8) were seen in 24%. Among the patients with arthritis, positive TAA titres were found significantly more often than in healthy controls in patients with Yersinia arthritis (p less than 0.01) and systemic lupus erythematosus (SLE; p less than 0.02). In other patient groups, the percentage of positive TAA titres did not differ significantly from that in healthy adults. Eight (2%) of the 475 patients without known staphylococcal infection had TAA titres greater than or equal to 8 but these high titres were not associated with any particular disease group. Only two of these eight patients had slightly raised antibody to staphylococcal alpha-haemolysin. We conclude that the TAA test cannot be used as a reliable indicator of septic staphylococcal disease in patients with Yersinia arthritis or SLE, but that in general, TAA titres greater than or equal to 8 point strongly to S. aureus infection even in patients with autoimmune or liver diseases.