Clinical pharmacology of levosimendan.

Levosimendan has been developed for the treatment of decompensated heart failure and is used intravenously when patients with heart failure require immediate initiation of drug therapy. It increases cardiac contractility and induces vasodilatation. The pharmacokinetics of levosimendan are linear at the therapeutic dose range of 0.05-0.2 microg/kg/minute. The short half-life (about 1 hour) of the parent drug, levosimendan, enables fast onset of drug action, although the effects are long-lasting due to the active metabolite OR-1896, which has an elimination half-life of 70-80 hours in patients with heart failure (New York Heart Association functional class III-IV). Although levosimendan is administered intravenously, it is excreted into the small intestine and reduced by intestinal bacteria to an amino phenolpyridazinone metabolite (OR-1855). This metabolite is further metabolised by acetylation to N-acetylated conjugate (OR-1896). The circulating metabolites OR-1855 and OR-1896 are formed slowly, and their maximum concentrations are seen on average 2 days after stopping a 24-hour infusion. The haemodynamic effects after levosimendan seem to be similar between fast and slow acetylators despite the fact that the enzyme N-acetyltransferase-2, which is responsible for the metabolism of OR-1855 to OR-1896, is polymorphically distributed in the population. Levosimendan reduces peripheral vascular resistance and has direct contractility-enhancing effects on the failing left ventricle. It also improves indices of diastolic function and seems to improve the function of stunned myocardium. Despite an improvement in ventricular function, levosimendan does not increase myocardial oxygen uptake significantly. An increase in coronary blood flow and a reduction in coronary vascular resistance have been observed. Levosimendan reduces plasma brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) levels substantially, and a decrease in plasma endothelin-1 has been observed. Levosimendan also exerts beneficial effects on proinflammatory cytokines and apoptosis mediators. The effects of a 24-hour levosimendan infusion on filling pressure, ventricular function and BNP, as well as NT-proBNP, last for at least 7 days.

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. beta-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 beta-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.

Government registries containing sensitive health data and the implementation of EU directive on the protection of personal data in Finland.

Legislation on the protection of personal data was first enacted in Finland in 1987 (Act 471/1987) and revised in 1999 (Act 523/1999). The Personal Registries Act of 1987 established a special authority, the "data protection ombudsman" to ensure that a citizen's right to privacy would be maintained despite increased usage of computerised registries containing sensitive data. Health care and medical research, however, have been largely outside the scope of effective scrutiny due to special legislation that gives health care authorities the right to gather and register information on the medical history of an individual citizen. In Finland, the National Research and Development Centre for Welfare and Health (STAKES)--which works in close co-operation with the Ministry of Social Affairs and Health--maintains or supervises several centralised registries containing sensitive data. These registries which are based on an exemption (Act 556/1989) from the general data protection legislation, contain in practice a complete database on all Finnish citizens that have used public health care services. Furthrmore, additional personal information is added into these databases. For example, the central registry on abortions contains not only the identification data of a subject who has had an abortion but also information on the reason for abortion and on the methods of contraception she used. It is noteworthy that these registers are not accessible to the physicians who treat the patient whose data is registered, but are used by the governmental authorities only. At the moment it is unclear whether the recent implementation of an EU directive into the Finnish legislation and the constitutional right to privacy in the revised Finnish constitution (effective from March 1, 2000 onwards) will have any impact on the content or usage of these centralised registers.

The Bioethics Convention of the Council of Europe and organ sharing for transplant recipients in Scandinavia.

Even though organ transplantation is often life saving, the lack of donor organs is limiting the number of transplantation procedures. In small countries, like the Scandinavian countries, the small population level highlights this problem of organ availability which is further complicated by the fact that the utilisation of available organs may be prevented by histoincompatibility between the host and donor. This problem can only be solved by sharing both medical information and organs across countries. In Scandinavia, an organ sharing program (Scandiatransplant) was initiated between Denmark, Finland, Iceland, Norway and Sweden in the late 1960's long before the establishment of European Economic Area and the expansion of the European Union in Northern Europe. Even though trade in human organs is prohibited by international conventions, medical procedures and services that are associated with transplant activities are such services whose "free movement" within the Union is guaranteed by the Convention of Rome. These services can thus be offered across the national borders for remuneration. The potential impact of the conventions of the Council of Europe on transplantation services and organ sharing programs within European Union will be discussed.