CYP2D6 and CYP2C19 genotypes and amitriptyline metabolite ratios in a series of medicolegal autopsies

In a series of 202 postmortem toxicology cases, the CYP2D6 and CYP2C19 genes were genotyped, and the concentrations of amitriptyline (AT) and six metabolites were analyzed. The polymorphic CYP2D6 and CYP2C19 genes encode enzymes participating in the metabolism of several potentially toxic drugs, and mutations in these genes may lead to adverse drug reactions, possibly even intoxications. AT was chosen as the substrate of interest because it is mainly metabolized by these enzymes, is considered relatively toxic, and ranks among the major causes of fatal drug poisoning in Finland. Our objective was to evaluate genetically determined interindividual variation in conjunction with metabolite ratios of drugs found in toxicological analysis in a series of medicolegal autopsies. Positive correlations were found between the proportion of trans-hydroxylated metabolites and the number of functional copies of CYP2D6 and between the proportion of demethylated metabolites and the number of functional copies of CYP2C19. None of the accidental or undetermined AT poisonings coincided with the CYP2D6 or CYP2C19 genotype which predicts a poor metabolizer phenotype. However, an unusually high femoral blood concentration of AT, 60mg/l, was found in one suicide case with no functional CYP2D6 genes. Our study shows a concordance of AT metabolite patterns with CYP2D6 and CYP2C19 genotypes in the presence of confounding factors typical for postmortem material. This result demonstrates the feasibility of postmortem pharmacogenetic analysis and supports the dominant role of genes in drug metabolism.     

Blood levels of 3-methylfentanyl in 3 fatal poisoning cases

Three fatal poisoning cases due to 3-methylfentanyl are described. In each case, the death was accidental and occurred after injection of the opioid combined with amphetamine, heroin, or other drugs. The victims' ages, ranging from 30 to 41 years, were higher than those typically found in heroin poisonings in Finland. The blood concentrations of cis-3-methylfentanyl, measured here for the first time by a specific tandem mass spectrometric method, ranged from 0.3 to 0.9 microg/L (mean 0.5 microg/L). These values are significantly lower than the levels reported for alpha-methylfentanyl and fentanyl in fatal poisonings. Repeated seizures of fentanyl and its analogs have been reported in Europe close to the Russian border.     

An Independent Central Bank and an Independent Monetary Policy: The Role of the Government Budget—The Case of Poland 1924–26

Poland's 1924 stabilization plan created, as measured by contemporary criteria, an independent central bank. The stabilization's success was undermined by a fiscal disequilibrium when a capital levy failed to raise revenue. The Polish government covered the revenue shortfall by exploiting the right of the state to issue subsidiary coins. Although central bank independence was not compromised, Poland did not have an independent monetary policy. When the fiscal disequilibrium was corrected in 1926, the central bank gained complete control over monetary policy. Thus, a balanced budget may be more important to achieving price stability than arrangements to foster central bank independence.